The relationship between telomere length and mortality risk in non-model vertebrate systems: a meta-analysis.
Telomere length (TL) has become a biomarker of increasing interest within ecology and evolutionary biology, and has been found to predict subsequent survival in some recent avian studies but not others. Here, we undertake the first formal meta-analysis to test whether there is an overall association between TL and subsequent mortality risk in vertebrates other than humans and model laboratory rodents. We identified 27 suitable studies and obtained standardized estimates of the hazard ratio associated with TL from each. We performed a meta-analysis on these estimates and found an overall significant negative association implying that short telomeres are associated with increased mortality risk, which was robust to evident publication bias. While we found that heterogeneity in the hazard ratios was not explained by sex, follow-up period, maximum lifespan or the age group of the study animals, the TL-mortality risk association was stronger in studies using qPCR compared to terminal restriction fragment methodologies. Our results provide support for a consistent association between short telomeres and increased mortality risk in birds, but also highlight the need for more research into non-avian vertebrates and the reasons why different telomere measurement methods may yield different results.This article is part of the theme issue 'Understanding diversity in telomere dynamics'.


In-vitro platform to study ultrasound as source for wireless energy transfer and communication for implanted medical devices.
A platform to study ultrasound as a source for wireless energy transfer and communication for implanted medical devices is described. A tank is used as a container for a pair of electroacoustic transducers, where a control unit is fixed to one wall of the tank and a transponder can be manually moved in three axes and rotate using a mechanical system. The tank is filled with water to allow acoustic energy and data transfer, and the system is optimized to avoid parasitic effects due to cables, reflection paths and cross talk problems. A printed circuit board is developed to test energy scavenging such that enough acoustic intensity is generated by the control unit to recharge a battery loaded to the transponder. In the same manner, a second printed circuit board is fabricated to study transmission of information through acoustic waves.


Biological significance of iron-related magnetic resonance imaging changes in the brain.
Iron, an essential element for basic cellular metabolism, regularly accumulates in certain brain areas in normal subjects and in patients with certain diseases. Magnetic resonance imaging can depict iron deposition, offering a singular opportunity to correlate the regional iron content with the functional status of the human brain in vivo. We studied the relationship between age and the iron-related signal loss on T2-weighted images in basal ganglia, and observed a strongly significant signal decrease in the globus pallidus at the age of brain development (first two decades of life), but we found no such decrease in later years. Moreover, in healthy adults, subject-to-subject variability was relevant in changes due to iron deposition in magnetic resonance imaging. We found increased signal loss to be associated with poor performance on motor and specific cognitive tasks, suggesting that these image changes can provide functional information with respect to the brain in normal subjects.


First report on the whitefly, Aleurodicus pseudugesii on the coconut palm, Cocos nucifera in Brazil.
The coconut palm, Cocos nucifera L. (Arecales: Arecaceae), is currently grown extensively throughout the intertropical zones of the world, including Brazil, where it constitutes an important source of income for growers. Although whiteflies are not normally considered coconut pests, these insects can damage crops directly by sucking the sap, which weakens the plant; indirect damage may be caused by sooty mold formation over the excreted honeydew and by the transmission of pathogens. Whiteflies have infested coconut plants in the northeastern, northern, and southeastern regions of Brazil. Infested materials were collected and the causative insect was identified as Aleurodicus pseudugesii Martin (Hemiptera: Aleyrodidae). This is the first report of A. pseudugesii in Brazil as a pest of the coconut palm.


Magnetic Resonance Imaging Distortion and Targeting Errors from Strong Rare Earth Metal Magnetic Dental Implant Requiring Revision.
Recently, the use of magnetic dental implants has been re-popularized with the introduction of strong rare earth metal, for example, neodymium, magnets. Unrecognized magnetic dental implants can cause critical magnetic resonance image distortions. We report a case involving surgical failure caused by a magnetic dental implant. A 62-year-old man underwent deep brain stimulation for medically insufficiently controlled Parkinson"s disease. Stereotactic magnetic resonance imaging performed for the first deep brain stimulation showed that the overdenture was removed. However, a dental implant remained and contained a neodymium magnet, which was unrecognized at the time of imaging; the magnet caused localized non-linear distortions that were the largest around the dental magnets. In the magnetic field, the subthalamic area was distorted by a 4.6 mm right shift and counter clockwise rotation. However, distortions were visually subtle in the operation field and small for distant stereotactic markers, with approximately 1-2 mm distortions. The surgeon considered the distortion to be normal asymmetry or variation. Stereotactic marker distortion was calculated to be in the acceptable range in the surgical planning software. Targeting errors, approximately 5 mm on the right side and 2 mm on the left side, occurred postoperatively. Both leads were revised after the removal of dental magnets. Dental magnets may cause surgical failures and should be checked and removed before stereotactic surgery. Our findings should be considered when reviewing surgical precautions and making distortion-detection algorithm improvements.


A study of knowledge, attitudes and practices (KAP) of a rural community on malaria and the mosquito vector.
A study of malaria on the Kano Plain, Kisumu District, Western Kenya, was carried out between April and August, 1985. The study included a knowledge, attitudes and practices (K.A.P.) survey on malaria illness and the mosquito vector. Overall knowledge about malaria illness was found to be good. However, treatment and prevention practices of malaria were found to be poor. Knowledge of the mosquito and its relationship to malaria was found to be high. Knowledge of methods of prevention of mosquito bites was also found to be high but actual use of the methods was low. Knowledge of traditional methods of prevention of mosquito bites was also found to be high. Actual use was again found to be low.


Removal of polar organic micropollutants by pilot-scale reverse osmosis drinking water treatment.
The robustness of reverse osmosis (RO) against polar organic micropollutants (MPs) was investigated in pilot-scale drinking water treatment. Experiments were carried in hypoxic conditions to treat a raw anaerobic riverbank filtrate spiked with a mixture of thirty model compounds. The chemicals were selected from scientific literature data based on their relevance for the quality of freshwater systems, RO permeate and drinking water. MPs passage and the influence of permeate flux were evaluated with a typical low-pressure RO membrane and quantified by liquid chromatography coupled to high-resolution mass spectrometry. A strong inverse correlation between size and passage of neutral hydrophilic compounds was observed. This correlation was weaker for moderately hydrophobic MPs. Anionic MPs displayed nearly no passage due to electrostatic repulsion with the negatively charged membrane surface, whereas breakthrough of small cationic MPs could be observed. The passage figures observed for the investigated set of MPs ranged from less than 1%-25%. Statistical analysis was performed to evaluate the relationship between physicochemical properties and passage. The effects of permeate flux were more pronounced for small neutral MPs, which displayed a higher passage after a pressure drop.


Niche conservatism constrains Australian honeyeater assemblages in stressful environments.
The hypothesis of phylogenetic niche conservatism proposes that most extant members of a clade remain in ancestral environments because expansion into new ecological space imposes a selectional load on a population. A prediction that follows is that local assemblages contain increasingly phylogenetically clustered subsets of species with increasing difference from the ancestral environment of a clade. We test this in Australian Meliphagidae, a continental radiation of birds that originated in wet, subtropical environments, but subsequently spread to drier environments as Australia became more arid during the late Cenozoic. We find local assemblages are increasingly phylogenetically clustered along a gradient of decreasing precipitation. The pattern is less clear along a temperature gradient. We develop a novel phyloclimatespace to visualise the expansion of some lineages into drier habitats. Although few species extend into arid regions, those that do occupy larger ranges and thus local species richness does not decline predictably with precipitation.


Activation of PPAR gamma receptors reduces levodopa-induced dyskinesias in 6-OHDA-lesioned rats.
Long-term administration of l-3,4-dihydroxyphenylalanine (levodopa), the mainstay treatment for Parkinson's disease (PD), is accompanied by fluctuations in its duration of action and motor complications (dyskinesia) that dramatically affect the quality of life of patients. Levodopa-induced dyskinesias (LID) can be modeled in rats with unilateral 6-OHDA lesions via chronic administration of levodopa, which causes increasingly severe axial, limb, and orofacial abnormal involuntary movements (AIMs) over time. In previous studies, we showed that the direct activation of CB1 cannabinoid receptors alleviated rat AIMs. Interestingly, elevation of the endocannabinoid anandamide by URB597 (URB), an inhibitor of endocannabinoid catabolism, produced an anti-dyskinetic response that was only partially mediated via CB1 receptors and required the concomitant blockade of transient receptor potential vanilloid type-1 (TRPV1) channels by capsazepine (CPZ) (Morgese et al., 2007). In this study, we showed that the stimulation of peroxisome proliferator-activated receptors (PPAR), a family of transcription factors activated by anandamide, contributes to the anti-dyskinetic effects of URB+CPZ, and that the direct activation of the PPARγ subtype by rosiglitazone (RGZ) alleviates levodopa-induced AIMs in 6-OHDA rats. AIM reduction was associated with an attenuation of levodopa-induced increase of dynorphin, zif-268, and of ERK phosphorylation in the denervated striatum. RGZ treatment did not decrease striatal levodopa and dopamine bioavailability, nor did it affect levodopa anti-parkinsonian activity. Collectively, these data indicate that PPARγ may represent a new pharmacological target for the treatment of LID.


Continuity of care in mental health: understanding and measuring a complex phenomenon.
Continuity of care is considered by patients and clinicians an essential feature of good quality care in long-term disorders, yet there is general agreement that it is a complex concept. Most policies emphasize it and encourage systems to promote it. Despite this, there is no accepted definition or measure against which to test policies or interventions designed to improve continuity. We aimed to operationalize a multi-axial model of continuity of care and to use factor analysis to determine its validity for severe mental illness. A multi-axial model of continuity of care comprising eight facets was operationalized for quantitative data collection from mental health service users using 32 variables. Of these variables, 22 were subsequently entered into a factor analysis as independent components, using data from a clinical population considered to require long-term consistent care. Factor analysis produced seven independent continuity factors accounting for 62.5% of the total variance. These factors, Experience and Relationship, Regularity, Meeting Needs, Consolidation, Managed Transitions, Care Coordination and Supported Living, were close but not identical to the original theoretical model. We confirmed that continuity of care is multi-factorial. Our seven factors are intuitively meaningful and appear to work in mental health. These factors should be used as a starting-point in research into the determinants and outcomes of continuity of care in long-term disorders.


Single-Molecule Imaging of PSD-95 mRNA Translation in Dendrites and Its Dysregulation in a Mouse Model of Fragile X Syndrome.
Fragile X syndrome (FXS) is caused by the loss of the fragile X mental retardation protein (FMRP), an RNA binding protein that regulates translation of numerous target mRNAs, some of which are dendritically localized. Our previous biochemical studies using synaptoneurosomes demonstrate a role for FMRP and miR-125a in regulating the translation of PSD-95 mRNA. However, the local translation of PSD-95 mRNA within dendrites and spines, as well as the roles of FMRP or miR-125a, have not been directly studied. Herein, local synthesis of a Venus-PSD-95 fusion protein was directly visualized in dendrites and spines using single-molecule imaging of a diffusion-restricted Venus-PSD-95 reporter under control of the PSD-95 3'UTR. The basal translation rates of Venus-PSD-95 mRNA was increased in cultured hippocampal neurons from Fmr1 KO mice compared with WT neurons, which correlated with a transient elevation of endogenous PSD-95 within dendrites. Following mGluR stimulation with (S)-3,5-dihydroxyphenylglycine, the rate of Venus-PSD-95 mRNA translation increased rapidly in dendrites of WT hippocampal neurons, but not in those of Fmr1 KO neurons or when the binding site of miR125a, previously shown to bind PSD-95 3'UTR, was mutated. This study provides direct support for the hypothesis that local translation within dendrites and spines is dysregulated in FXS. Impairments in the regulated local synthesis of PSD-95, a critical regulator of synaptic structure and function, may affect the spatiotemporal control of PSD-95 levels and affect dendritic spine development and synaptic plasticity in FXS.


Design, synthesis and pharmacological evaluation of pyrimidobenzothiazole-3-carboxylate derivatives as selective L-type calcium channel blockers.
L-type voltage gated calcium channels play essential role in contraction of various skeletal and vascular smooth muscles, thereby plays important role in regulating blood pressure. Dihydropyridine receptors have been targeted for development of newer antihypertensive agents, one of the structurally analogs nucleus dihydropyrimidines have been reported earlier by us as a potential agent toward development of calcium channel modulator. A pre-synthetic QSAR was run and on the basis of structure activity relationship a series of twenty three molecules was synthesized and studied by myosin light chain kinase assay (MLCK), Angiotensin Converting Enzyme (ACE) colorimetric assay, non-invasive blood pressure (NIBP) and invasive blood pressure (IBP) methods. Molecules with significant efficacy were studied for their single crystal X-ray diffraction, molecular docking, molecular dynamics and post-synthetic QSAR. The NIBP and IBP methods screened molecules with better percentage inhibition versus time compared to standard drug Nifedipine. The lead compound ethyl 2-methyl-4-(3-nitrophenyl)-4H-pyrimido [2,1-b] [1,3] benzothiazole-3-carboxylate (26) presented a triclinic structure with polymeric chain packing in lattice. 26 exhibited IC50 on MLCK assay of 2.1±1.7 μM with selectivity of L-type calcium channels and comparative to Nifedipine. It offered satisfactory physicochemical properties with partition coefficient of (ClogP) 4.64. Its pharmacokinetic profile is also good with Cmax at 0.40 μg/ml by oral route with Tmax reaching in 0.5 h which means in 30 min. 26 also exhibits superior t1/2 of 5.4 h and oral bioavailability of (F) 56.75% with an AUC0-∞ of 0.84 μg h/ml. Molecular docking studies indicates toward the interaction of lead compound via hydrogen bonds with Lys144, Glu181 and Asp183, it forms the Van der Walls interactions with Ser18, Asp20, Asn187, Pro185, Glu180, Glu181 and Arg10 with Glide score and Glide energy to be -3.602 and -47.098, respectively. Post-synthetic QSAR of newly synthesized molecules indicates toward improvement with respect to steric descriptor which contributed negatively in former series.


Lay people's evaluations of health: are there variations between different subgroups?
To elicit lay concepts of health and to see whether these are related to various sociodemographic factors, as has been suggested by previous smaller studies. A total of 196 people aged 18 and over were selected, as a representative sample of the general population, from the electoral registers of Walsall and Dudley in the West Midlands. Respondents were interviewed in their own homes in the autumn of 1989. Open ended and structured questions were used to elicit concepts of health. The three main stages consisted of an unprompted section in which respondents were asked to describe the features of good or poor health in themselves or others; a prompted section in which they were asked to rate 37 health statements using a series of categories from "very important" to "not at all important"; and a section in which they were asked to indicate which of six groups of statements, each representing a particular concept of health, best represented their own notions of health. Health was seen as multidimensional. Irrespective of whether respondents addressed health in self or health in others, or good or poor health, the biomedical dimension remained an important one. The manner by which concepts of health are elicited may provide some explanation as to why so many and varied concepts are alleged to be held by different subgroups of the population (notably different social classes). The differences found in this study between models of health employed by different subgroups of the general population have not been as great as has previously been suggested in the published reports. This is encouraging for those using existing health status measurements.


An aligned octahedral core in a nanocage: synthesis, plasmonic, and catalytic properties.
Plasmonic metal nanostructures with complex morphologies provide an important route to tunable optical responses and local electric field enhancement at the nanoscale for a variety of applications including sensing, imaging, and catalysis. Here we report a high-concentration synthesis of gold core-cage nanoparticles with a tethered and structurally aligned octahedral core and examine their plasmonic and catalytic properties. The obtained nanostructures exhibit a double band extinction in the visible-near infrared range and a large area electric field enhancement due to the unique structural features, as demonstrated using finite difference time domain (FDTD) simulations and confirmed experimentally using surface enhanced Raman scattering (SERS) tests. In addition, the obtained structures had a photoelectrochemical response useful for catalyzing the CO2 electroreduction reaction. Our work demonstrates the next generation of complex plasmonic nanostructures attainable via bottom-up synthesis and offers a variety of potential applications ranging from sensing to catalysis.


Harnessing Biomedical Natural Language Processing Tools to Identify Medicinal Plant Knowledge from Historical Texts.
The growing amount of data describing historical medicinal uses of plants from digitization efforts provides the opportunity to develop systematic approaches for identifying potential plant-based therapies. However, the task of cataloguing plant use information from natural language text is a challenging task for ethnobotanists. To date, there have been only limited adoption of informatics approaches used for supporting the identification of ethnobotanical information associated with medicinal uses. This study explored the feasibility of using biomedical terminologies and natural language processing approaches for extracting relevant plant-associated therapeutic use information from historical biodiversity literature collection available from the Biodiversity Heritage Library. The results from this preliminary study suggest that there is potential utility of informatics methods to identify medicinal plant knowledge from digitized resources as well as highlight opportunities for improvement.


Anosognosia for plegia: specificity, extension, partiality and disunity of bodily unawareness.
This study of anosognosia for hemiplegia investigated: whether it is homogeneous; specificity to plegia of unawareness; extension to different kinds of and objects of awareness regarding plegia; partiality of unawareness. Sixty-four hemiplegic stroke patients were assessed with control subjects on (a) motor and somatosensory function, immediately followed by participants' evaluations of performance; (b) conventional structured interview questions addressing awareness of various capacities: (c) Neglect, Mental Flexibility, General Mental State, Verbal Fluency, Short-Term Memory; (d) pre- and post-performance estimates of ability on the last two; (e) estimates of current ability on bilateral and unilateral tasks, addressed by questions in 1st- and 3rd-person forms, explanations of how overestimated tasks would be accomplished, attempts at 3 bimanual tasks and post-attempt estimates of ability on these. Anosognosia for plegia was mostly associated with right-brain damage. No single factor or combination accounted for all patients. Double dissociations indicated that anosognosia can be specific to plegia: and patients do not generally overestimate other abilities. Although unawareness of paralysis and of its consequences appear linked, the latter is more widespread and persistent. Double dissociation showed that concurrent unawareness of movement failures is a separate deficit from these. There was differential awareness of different aspects of plegia. Further, some patients who overestimated current bilateral task ability when asked in 1st-person form did not overestimate when asked how well the examiner, if he was in their current condition, could do each task. This suggests split awareness of a single aspect of plegia. Patients anosognosic on conventional questioning showed two distinctions. (1) Some were unaware of movement failures when they occurred; others were aware but quickly forgot such failures and seem unable to update long-term body knowledge. (2) Some patients' explanations of bimanual task performance reflect unawareness of hemiplegia; others' explanations were bizarre and imply some awareness. The latter group's deficit appears to be nonspecific and linked to right-hemisphere predominance of anosognosia, an account of which is offered. Anosognosia for hemiplegia is not a unitary phenomenon: several factors underlie deficits in bodily awareness.


Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity.
Adiponectin is an adipocyte-specific secretory protein that circulates in serum as a hexamer of relatively low molecular weight (LMW) and a larger multimeric structure of high molecular weight (HMW). Serum levels of the protein correlate with systemic insulin sensitivity. The full-length protein affects hepatic gluconeogenesis through improved insulin sensitivity, and a proteolytic fragment of adiponectin stimulates beta oxidation in muscle. Here, we show that the ratio, and not the absolute amounts, between these two oligomeric forms (HMW to LMW) is critical in determining insulin sensitivity. We define a new index, S(A), that can be calculated as the ratio of HMW/(HMW + LMW). db/db mice, despite similar total adiponectin levels, display decreased S(A) values compared with wild type littermates, as do type II diabetic patients compared with insulin-sensitive individuals. Furthermore, S(A) improves with peroxisome proliferator-activated receptor-gamma agonist treatment (thiazolidinedione; TZD) in mice and humans. We demonstrate that changes in S(A) in a number of type 2 diabetic cohorts serve as a quantitative indicator of improvements in insulin sensitivity obtained during TZD treatment, whereas changes in total serum adiponectin levels do not correlate well at the individual level. Acute alterations in S(A) (DeltaS(A)) are strongly correlated with improvements in hepatic insulin sensitivity and are less relevant as an indicator of improved muscle insulin sensitivity in response to TZD treatment, further underscoring the conclusions from previous clamp studies that suggested that the liver is the primary site of action for the full-length protein. These observations suggest that the HMW adiponectin complex is the active form of this protein, which we directly demonstrate in vivo by its ability to depress serum glucose levels in a dose-dependent manner.


[Pars plana vitrectomy, phacoemulsification and intraocular lens implantation for the management of cataract and proliferative diabetic retinopathy: comparison of a combined versus two-step surgical approach].
To report the intra-and postoperative complications and visual acuity outcomes in pars plana vitrectomy (PPV), phacoemulsification and intraocular lens (IOL) implantation in patients with cataract and proliferative diabetic retinopathy (PDR). A comparison of the combined versus two-step surgical approach is given. Retrospective uncontrolled interventional clinical trial. Forty-eight eyes of 48 consecutive patients with PDR were included. Twenty-eight (58.3%) eyes with combined surgery and 20 (41.7%) eyes with sequential surgery were analyzed. Postoperative follow-up time was between 6 and 63 months (mean: 18 months). 1) Combined surgery: Preoperative best-corrected visual acuity (BCVA) ranged from 20/200 to hand motions, and postoperative BCVA ranged from 20/30 to hand motions. BCVA improved in 17 eyes (60.7%), while in 7 (25%) eyes there was no change (> or =2 ETDRS lines) in VA, and in 4 (14.3%) eyes BCVA decreased. Postoperative complications included vitreous hemorrhage (VH) in 10 (35.7%) eyes, and fibrinous exudation in 9 (32.1%) eyes. 2) Two-step surgery: Preoperative BCVA ranged from 10/200 to light perception, and from 20/40 to light perception in the postoperative period. Best-corrected visual acuity improved in 15 (75%) eyes, remained the same in 4 (20%) eyes, and decreased in 1 (5%) eye. Postoperative complications included fibrinous exudation in 6 (30%) eyes, and VH in 3 (15%) eyes. Combined PPV, phacoemulsification and IOL implantation as well as the two-step procedure are safe and effective for the management of cataract in PDR. Sequential surgery could be advantageous to BCVA outcomes by minimizing postoperative VH, which is significantly more frequent after combined surgery.


Fungal oxidative dissolution of the Mn(II)-bearing mineral rhodochrosite and the role of metabolites in manganese oxide formation.
Microbially mediated oxidation of Mn(II) to Mn(III/IV) oxides influences the cycling of metals and remineralization of carbon. Despite the prevalence of Mn(II)-bearing minerals in nature, little is known regarding the ability of microbes to oxidize mineral-hosted Mn(II). Here, we explored oxidation of the Mn(II)-bearing mineral rhodochrosite (MnCO3 ) and characteristics of ensuing Mn oxides by six Mn(II)-oxidizing Ascomycete fungi. All fungal species substantially enhanced rhodochrosite dissolution and surface modification. Mineral-hosted Mn(II) was oxidized resulting in formation of Mn(III/IV) oxides that were all similar to δ-MnO2 but varied in morphology and distribution in relation to cellular structures and the MnCO3 surface. For four fungi, Mn(II) oxidation occurred along hyphae, likely mediated by cell wall-associated proteins. For two species, Mn(II) oxidation occurred via reaction with fungal-derived superoxide produced at hyphal tips. This pathway ultimately resulted in structurally unique Mn oxide clusters formed at substantial distances from any cellular structure. Taken together, findings for these two fungi strongly point to a role for fungal-derived organic molecules in Mn(III) complexation and Mn oxide templation. Overall, this study illustrates the importance of fungi in rhodochrosite dissolution, extends the relevance of biogenic superoxide-based Mn(II) oxidation and highlights the potential role of mycogenic exudates in directing mineral precipitation.


Encephalomyocarditis virus viroporin 2B activates NLRP3 inflammasome.
Nod-like receptors (NLRs) comprise a large family of intracellular pattern- recognition receptors. Members of the NLR family assemble into large multiprotein complexes, termed the inflammasomes. The NLR family, pyrin domain-containing 3 (NLRP3) is triggered by a diverse set of molecules and signals, and forms the NLRP3 inflammasome. Recent studies have indicated that both DNA and RNA viruses stimulate the NLRP3 inflammasome, leading to the secretion of interleukin 1 beta (IL-1β) and IL-18 following the activation of caspase-1. We previously demonstrated that the proton-selective ion channel M2 protein of influenza virus activates the NLRP3 inflammasome. However, the precise mechanism by which NLRP3 recognizes viral infections remains to be defined. Here, we demonstrate that encephalomyocarditis virus (EMCV), a positive strand RNA virus of the family Picornaviridae, activates the NLRP3 inflammasome in mouse dendritic cells and macrophages. Although transfection with RNA from EMCV virions or EMCV-infected cells induced robust expression of type I interferons in macrophages, it failed to stimulate secretion of IL-1β. Instead, the EMCV viroporin 2B was sufficient to cause inflammasome activation in lipopolysaccharide-primed macrophages. While cells untransfected or transfected with the gene encoding the EMCV non-structural protein 2A or 2C expressed NLRP3 uniformly throughout the cytoplasm, NLRP3 was redistributed to the perinuclear space in cells transfected with the gene encoding the EMCV 2B or influenza virus M2 protein. 2B proteins of other picornaviruses, poliovirus and enterovirus 71, also caused the NLRP3 redistribution. Elevation of the intracellular Ca(2+) level, but not mitochondrial reactive oxygen species and lysosomal cathepsin B, was important in EMCV-induced NLRP3 inflammasome activation. Chelation of extracellular Ca(2+) did not reduce virus-induced IL-1β secretion. These results indicate that EMCV activates the NLRP3 inflammasome by stimulating Ca(2+) flux from intracellular storages to the cytosol, and highlight the importance of viroporins, transmembrane pore-forming viral proteins, in virus-induced NLRP3 inflammasome activation.


Equivalent Discrete-Time Channel Modeling for Molecular Communication With Emphasize on an Absorbing Receiver.
This paper introduces the equivalent discrete-time channel model (EDTCM) to the area of diffusion-based molecular communication (DBMC). Emphasis is on an absorbing receiver, which is based on the so-called first passage time concept. In the wireless communications community the EDTCM is well known. Therefore, it is anticipated that the EDTCM improves the accessibility of DBMC and supports the adaptation of classical wireless communication algorithms to the area of DBMC. Furthermore, the EDTCM has the capability to provide a remarkable reduction of computational complexity compared to random walk based DBMC simulators. Besides the exact EDTCM, three approximations thereof based on binomial, Gaussian, and Poisson approximation are proposed and analyzed in order to further reduce computational complexity. In addition, the Bahl-Cocke-Jelinek-Raviv (BCJR) algorithm is adapted to all four channel models. Numerical results show the performance of the exact EDTCM, illustrate the performance of the adapted BCJR algorithm, and demonstrate the accuracy of the approximations.


Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling.
Endoglin is a transforming growth factor β (TGF-β) coreceptor that serves as a prognostic, diagnostic and therapeutic vascular target in human cancer. A number of endoglin ectodomain-targeting antibodies (Abs) can effectively suppress both normal and tumor-associated angiogenesis, but their molecular actions remain poorly characterized. Here we define a key mechanism for TRACON105 (TRC105), a humanized monoclonal Ab in clinical trials for treatment of advanced or metastatic tumors. TRC105, along with several other endoglin Abs tested, enhance endoglin shedding through direct coupling of endoglin and the membrane-type 1 matrix metalloproteinase (MMP)-14 at the cell surface to release the antiangiogenic factor, soluble endoglin (sEng). In addition to this coupling process, endoglin shedding is further amplified by increased MMP-14 expression that requires TRC105 concentration-dependent c-Jun N-terminal kinase (JNK) activation. There were also notable counterbalancing effects on canonical Smad signaling in which TRC105 abrogated both the steady-state and TGF-β-induced Smad1/5/8 activation while augmenting Smad2/3 activation. Interestingly, TRC105-induced sEng and aberrant Smad signaling resulted in an excessive migratory response through enhanced stress fiber formation and disruption of endothelial cell-cell junctions. Collectively, our study defines endoglin shedding and deregulated TGF-β signaling during migration as major mechanisms by which TRC105 inhibits angiogenesis.


Autophagy signaling in skeletal muscle of infarcted rats.
Heart failure (HF)-induced skeletal muscle atrophy is often associated to exercise intolerance and poor prognosis. Better understanding of the molecular mechanisms underlying HF-induced muscle atrophy may contribute to the development of pharmacological strategies to prevent or treat such condition. It has been shown that autophagy-lysosome system is an important mechanism for maintenance of muscle mass. However, its role in HF-induced myopathy has not been addressed yet. Therefore, the aim of the present study was to evaluate autophagy signaling in myocardial infarction (MI)-induced muscle atrophy in rats. Wistar rats underwent MI or Sham surgeries, and after 12 weeks were submitted to echocardiography, exercise tolerance and histology evaluations. Cathepsin L activity and expression of autophagy-related genes and proteins were assessed in soleus and plantaris muscles by fluorimetric assay, qRT-PCR and immunoblotting, respectively. MI rats displayed exercise intolerance, left ventricular dysfunction and dilation, thereby suggesting the presence of HF. The key findings of the present study were: a) upregulation of autophagy-related genes (GABARAPL1, ATG7, BNIP3, CTSL1 and LAMP2) was observed only in plantaris while muscle atrophy was observed in both soleus and plantaris muscles, and b) Cathepsin L activity, Bnip3 and Fis1 protein levels, and levels of lipid hydroperoxides were increased specifically in plantaris muscle of MI rats. Altogether our results provide evidence for autophagy signaling regulation in HF-induced plantaris atrophy but not soleus atrophy. Therefore, autophagy-lysosome system is differentially regulated in atrophic muscles comprising different fiber-types and metabolic characteristics.


Sequence and evolution of HLA-DR7- and -DRw53-associated beta-chain genes.
cDNA clones representing products of the DR7 and DRw53 beta-chain genes were isolated from the human B-lymphoblastoid cell line MANN (DR7,DRw53,DQw2, DPw2). The DRw53 beta sequence was identical to a DRw53 beta sequence derived from cells with a DR4 haplotype. In contrast, the DR7 beta sequence was as unrelated to DR4 beta sequence as it was to other DR beta-related genes, except at the 3'-untranslated region. These results suggest that the DR7 and DR4 haplotypes may have been derived relatively recently from a common ancestral haplotype and that the DR4 and DR7 beta-chain genes have undergone more rapid diversification in their beta 1 domains, most probably as a result of natural selection, than have the DRw53 beta-chain genes. Short tracts of sequence within the DR7 and DRw53 beta 1 domains were shared with other DR beta sequences, indicating that exchanges of genetic information between beta 1 domains of DR beta-related genes have played a part in their evolution. Serological analysis of mouse L-cell transfectants expressing surface HLA-DR7 molecules, confirmed by antibody binding and allelic sequence comparisons, identified amino acid residues that may be critical to the binding of a monomorphic DR- and DP-specific monoclonal antibody.


Mechanisms of quadriceps muscle weakness in knee joint osteoarthritis: the effects of prolonged vibration on torque and muscle activation in osteoarthritic and healthy control subjects.
A consequence of knee joint osteoarthritis (OA) is an inability to fully activate the quadriceps muscles, a problem termed arthrogenic muscle inhibition (AMI). AMI leads to marked quadriceps weakness that impairs physical function and may hasten disease progression. The purpose of the present study was to determine whether γ-loop dysfunction contributes to AMI in people with knee joint OA. Fifteen subjects with knee joint OA and 15 controls with no history of knee joint pathology participated in this study. Quadriceps and hamstrings peak isometric torque (Nm) and electromyography (EMG) amplitude were collected before and after 20 minutes of 50 Hz vibration applied to the infrapatellar tendon. Between-group differences in pre-vibration torque were analysed using a one-way analysis of covariance, with age, gender and body mass (kg) as the covariates. If the γ-loop is intact, vibration should decrease torque and EMG levels in the target muscle; if dysfunctional, then torque and EMG levels should not change following vibration. One-sample t tests were thus undertaken to analyse whether percentage changes in torque and EMG differed from zero after vibration in each group. In addition, analyses of covariance were utilised to analyse between-group differences in the percentage changes in torque and EMG following vibration. Pre-vibration quadriceps torque was significantly lower in the OA group compared with the control group (P = 0.005). Following tendon vibration, quadriceps torque (P < 0.001) and EMG amplitude (P ≤0.001) decreased significantly in the control group but did not change in the OA group (all P > 0.299). Hamstrings torque and EMG amplitude were unchanged in both groups (all P > 0.204). The vibration-induced changes in quadriceps torque and EMG were significantly different between the OA and control groups (all P < 0.011). No between-group differences were observed for the change in hamstrings torque or EMG (all P > 0.554). γ-loop dysfunction may contribute to AMI in individuals with knee joint OA, partially explaining the marked quadriceps weakness and atrophy that is often observed in this population.


Animal studies in endometriosis: a review.
Endometriosis is a common women's health problem that is characterized by the presence of tissue resembling endometrium outside the uterus. The condition causes painful periods, chronic pelvic pain, and subfertility, which are potentially debilitating; and it affects millions of women worldwide. The diagnosis is made on visual inspection of the pelvis, usually at laparoscopy. The natural history is unknown, and well-controlled experiments are difficult to perform because of the need for repeated surgical procedures to assess endometriotic lesions over time. Thus, despite over 50 years' research, the cause of endometriosis remains unclear, and treatment options are limited. Animal models provide an invaluable tool to study risk factors, prevalence, and the natural history of endometriosis especially in those menstruating nonhuman primates that develop the disease spontaneously. Many of the practical problems associated with studying the disease in humans can therefore be overcome. The pathophysiology of endometriosis can also be investigated and new treatments assessed in both nonprimates and nonhuman primates, with "disease" induced by placing autologous uterine tissue in ectopic sites, or human endometrium in the case of nude mice. However, although nonprimates have obvious advantages as a model, the extent to which the induced lesions are truly representative of the disease itself is debatable. This review explores the value of the experimental models that have been used to date.


The experience of dying with dementia: a retrospective study.
To describe the last year of life of people with dementia, their symptoms, care needs, use of and satisfaction with health services and the bereavement state of the respondent. The study is drawn from the Regional Study of Care for the Dying, a retrospective sample survey of the carers, family members or others who knew about the last year of life of a random sample of people age 15 and over dying in the last quarter of 1990. The samples were drawn in 20 English health districts which, although self-selected, were nationally representative. There was a total of 3696 patients (response rate of 69%) dying from all causes. Within this sample, 170 dementia patients were identified and compared with 1513 cancer patients. The symptoms most commonly reported in the last year were mental confusion (83%), urinary incontinence (72%), pain (64%), low mood (61%), constipation (59%) and loss of appetite (57%). Dementia patients saw their GP less often than cancer patients and their respondents rated GP assistance less highly. Dementia patients needed more help at home compared with cancer patients, and received more social services; 78% of respondents for dementia patients and 64% for cancer said they had come to terms with the patient's death. Patients dying from dementia have symptoms and health care needs comparable with cancer patients. Greater attention should be given to these needs.


Astaxanthin (ATX) enhances the intestinal mucosal functions in immunodeficient mice.
Increasing pressure of life may bring some disease risks and stress injuries, which may destroy the immune system and result in intestinal mucosal immune disorders. In this study, the effects of different doses of ATX (30 mg per kg b.w., 60 mg per kg b.w. and 120 mg per kg b.w.) on intestinal mucosal functions were explored in cyclophosphamide (Cy)-induced immunodeficient mice. The results showed that continuous intraperitoneal injection of 100 mg per kg b.w. Cy for three days led to a persistent decrease of body weight and a range of abnormalities in the intestine of C57BL/6 mice. However, administration of ATX at 60 and 120 mg per kg b.w. could effectively prevent intestinal mucosa from this damage, including reduced levels of oxidative stress (MDA, GSH and GSH-PX), increased intestinal morphological structural integrity, stimulative growth of goblet cells and mucous secretion, decreased development of Paneth cells and expression levels of antimicrobial peptides (AMPs) (Reg-3γ and lysozyme), increased IgA secretion, ameliorative main gut flora (especially total bacteria, Lactobacillus and Enterobacteriaceae spp. ) and its metabolites (acetic acid, propionic acid and butyric acid). These protective effects of ATX were better than those of control-β-carotene in general. Our results may provide a new protective measure to keep intestinal mucosal barriers, which is of great significance for maintaining immune function in the body.


Altered deposition of inhaled nanoparticles in subjects with chronic obstructive pulmonary disease.
Respiratory tract deposition of airborne particles is a key link to understand their health impact. Experimental data are limited for vulnerable groups such as individuals with respiratory diseases. The aim of this study is to investigate the differences in lung deposition of nanoparticles in the distal lung for healthy subjects and subjects with respiratory disease. Lung deposition of nanoparticles (50 and 100 nm) was measured after a 10 s breath-hold for three groups: healthy never-smoking subjects (n = 17), asymptomatic (active and former) smokers (n = 15) and subjects with chronic obstructive pulmonary disease (n = 16). Measurements were made at 1300 mL and 1800 mL volumetric lung depth. Each subject also underwent conventional lung function tests, including post bronchodilator FEV1, VC, and diffusing capacity for carbon monoxide, DL,CO. Patients with previously diagnosed respiratory disease underwent a CT-scan of the lungs. Particle lung deposition fraction, was compared between the groups and with conventional lung function tests. We found that the deposition fraction was significantly lower for subjects with emphysema compared to the other subjects (p = 0.001-0.01), but no significant differences were found between healthy never-smokers and smokers. Furthermore, the particle deposition correlated with pulmonary function tests, FEV1%Pred (p < 0.05), FEV1/VC%Pred (p < 0.01) and DL,CO (p < 0.0005) when all subjects were included. Furthermore, for subjects with emphysema, deposition fraction correlated strongly with DL,CO (Pearson's r = 0.80-0.85, p < 0.002) while this correlation was not found within the other groups. Lower deposition fraction was observed for emphysematous subjects and this can be explained by enlarged distal airspaces in the lungs. As expected, deposition increases for smaller particles and deeper inhalation. The observed results have implications for exposure assessment of air pollution and dosimetry of aerosol-based drug delivery of nanoparticles.


Statistical examination of hair color as a potential biasing factor in hair analysis.
We review eight different data sets in this paper for the purposes of assessing the possibility that reported color of hair can produce a systematic bias in the interpretation of hair assays. We review studies or data sets that include heroin and its metabolites, cocaine and its metabolites, MDMA and its analogs, and amphetamine and methamphetamine. The studies have utilized a variety of different degrees of color categorization, ranging from the simple dichotomy of brown and black, to a high of 12 categories. The mean number of categories reported approaches 6 (mean = 5.875). There are a total of 2791 data points in this analysis. We utilize two major statistical techniques for assessing significance; one-way analysis of variance, and Tukey's Honestly Significant Difference procedure. In circumstances were only dichotomous contrasts are possible, one-way analysis of variance is used. In contrasts involving three or more categorical groups, Tukey's procedure is used. In circumstances where the homogeneity of group variances is not sustained by the Levene statistic, we use the Tamahane procedure, allowing an assessment that assumes unequal variances. The analysis of this data fails to discern a significant color effect. We speculate that it may be that variance is large in many domains affecting analyte recovery from hair. In large groups these variations tend to regress towards a typical or mean value. Thus the data here show that while there are group or aggregate differences in these 'typical' values, they are not great when considered in relation to the within-group variations which exist for those values. It is our view that color may play a role in the accumulation of drugs in hair, however it is likely to account for only a very small part of the complex process of drug accumulation.


Drug Prescription and Delirium in Older Inpatients: Results From the Nationwide Multicenter Italian Delirium Day 2015-2016.
This study aimed to evaluate the association between polypharmacy and delirium, the association of specific drug categories with delirium, and the differences in drug-delirium association between medical and surgical units and according to dementia diagnosis. Data were collected during 2 waves of Delirium Day, a multicenter delirium prevalence study including patients (aged 65 years or older) admitted to acute and long-term care wards in Italy (2015-2016); in this study, only patients enrolled in acute hospital wards were selected (n = 4,133). Delirium was assessed according to score on the 4 "A's" Test. Prescriptions were classified by main drug categories; polypharmacy was defined as a prescription of drugs from 5 or more classes. Of 4,133 participants, 969 (23.4%) had delirium. The general prevalence of polypharmacy was higher in patients with delirium (67.6% vs 63.0%, P = .009) but varied according to clinical settings. After adjustment for confounders, polypharmacy was associated with delirium only in patients admitted to surgical units (OR = 2.9; 95% CI, 1.4-6.1). Insulin, antibiotics, antiepileptics, antipsychotics, and atypical antidepressants were associated with delirium, whereas statins and angiotensin receptor blockers exhibited an inverse association. A stronger association was seen between typical and atypical antipsychotics and delirium in subjects free from dementia compared to individuals with dementia (typical: OR = 4.31; 95% CI, 2.94-6.31 without dementia vs OR = 1.64; 95% CI, 1.19-2.26 with dementia; atypical: OR = 5.32; 95% CI, 3.44-8.22 without dementia vs OR = 1.74; 95% CI, 1.26-2.40 with dementia). The absence of antipsychotics among the prescribed drugs was inversely associated with delirium in the whole sample and in both of the hospital settings, but only in patients without dementia. Polypharmacy is significantly associated with delirium only in surgical units, raising the issue of the relevance of medication review in different clinical settings. Specific drug classes are associated with delirium depending on the clinical setting and dementia diagnosis, suggesting the need to further explore this relationship.


Novel truncated isoform of SK3 potassium channel is a potent dominant-negative regulator of SK currents: implications in schizophrenia.
The small-conductance calcium-activated K(+) channel SK3 (SKCa3/KCNN3) regulates electrical excitability and neurotransmitter release in monoaminergic neurons, and has been implicated in schizophrenia, ataxia and anorexia nervosa. We have identified a novel SK3 transcript, SK3-1B that utilizes an alternative first exon (exon 1B), but is otherwise identical to SK3. SK3-1B, mRNA is widely distributed in human tissues and is present at 20-60% of SK3 in the brain. The SK3-1B protein lacks the N-terminus and first transmembrane segment, and begins eight residues upstream of the second transmembrane segment. When expressed alone, SK3-1B did not produce functional channels, but selectively suppressed endogenous SK3 currents in the pheochromocytoma cell line, PC12, in a dominant-negative fashion. This dominant inhibitory effect extended to other members of the SK subfamily, but not to voltage-gated K(+) channels, and appears to be due to intracellular trapping of endogenous SK channels. The effect of SK3-1B expression is very similar to that produced by expression of the rare SK3 truncation allele, SK3-Delta, found in a patient with schizophrenia. Regulation of SK3 and SK3-1B levels may provide a potent mechanism to titrate neuronal firing rates and neurotransmitter release in monoaminergic neurons, and alterations in the relative abundance of these proteins could contribute to abnormal neuronal excitability, and to the pathogenesis of schizophrenia.


Screening the expression of ABCB6 in erythrocytes reveals an unexpectedly high frequency of Lan mutations in healthy individuals.
Lan is a high-incidence blood group antigen expressed in more than 99.9% of the population. Identification of the human ABC transporter ABCB6 as the molecular basis of Lan has opened the way for studies assessing the relation of ABCB6 function and expression to health and disease. To date, 34 ABCB6 sequence variants have been described in association with reduced ABCB6 expression based on the genotyping of stored blood showing weak or no reactivity with anti-Lan antibodies. In the present study we examined the red blood cell (RBC) surface expression of ABCB6 by quantitative flow cytometry in a cohort of 47 healthy individuals. Sequencing of the entire coding region of the ABCB6 gene in low RBC ABCB6 expressors identified a new allele (IVS9+1G>A, affecting a putative splice site at the boundary of exon 9) and two nonsynonymous SNPs listed in the SNP database (R192Q (rs150221689) and G588 S (rs145526996)). The R192Q mutation showed co-segregation with reduced RBC ABCB6 expression in a family, and we found the G588 S mutation in a compound heterozygous individual with undetectable ABCB6 expression, suggesting that both mutations result in weak or no expression of ABCB6 on RBCs. Analysis of the intracellular expression pattern in HeLa cells by confocal microscopy indicated that these mutations do not compromise overall expression or the endolysosomal localization of ABCB6. Genotyping of two large cohorts, containing 235 and 1039 unrelated volunteers, confirmed the high allele frequency of Lan-mutations. Our results suggest that genetic variants linked to lower or absent cell surface expression of ABCB6/Langereis may be more common than previously thought.


Acetaldehyde involvement in positive and negative alcohol expectancies in han Chinese persons with alcoholism.
The ALDH2*2 allele has been shown to be a protective factor against alcoholism in a normal population owing in part to the elevated blood level of acetaldehyde and its accompanying physiological discomforts after drinking alcohol. Despite the well-established link between the ALDH2*2 allele and the physiological discomforts after drinking, very little is known regarding the psychological expectancies of drinking among persons with alcoholism with different ALDH genotypes. To determine whether there are differences in craving, alcohol consumption, and alcohol outcome expectancies between persons with alcoholism who have the ALDH2*1/*2 genotype and persons with alcoholism who have the ALDH2*1/*1 genotype. Cross-sectional survey. Six outpatient alcohol treatment facilities in Taiwan. Ninety-eight persons with alcoholism who met the DSM-IV criteria for current alcohol dependence. Alcohol Craving Scale, Form 90, and Alcohol Expectancies Scale scores. Overall, the ALDH2*1/*2 group had lower negative alcohol outcome expectancies (F(4,93) = 2.43, P < or = .05, eta(p)2 = 0.10). Specifically, they had fewer expected negative outcomes in the social or interpersonal domain (P < .05) and the emotional and physical domain (P < or = .005) than did the ALDH2*1/*1 group. Moreover, the ALDH2*1/*2 group had higher positive alcohol outcome expectancies (F(7,90) = 2.36, P < .05, eta(p)2 = 0.16), and they had more expected positive outcomes in the relaxation and tension reduction domain (P < .05). The 2 groups did not differ in alcohol craving (P = .61) or consumption (P = .11). Although the ALDH2*2 allele has been associated with negative physiological responses in normal samples in past research, the psychological expectancies of drinking are more positive and less negative for persons with alcoholism who have the ALDH2*1/*2 genotype. A role of acetaldehyde is implied in these effects, which seem to override the usual discomfort effects associated with protection against alcohol drinking. Future studies are needed to assess alcohol outcome expectancies at different phases of alcohol dependence and to evaluate the concurrent relationships of blood levels of acetaldehyde with physiological and psychological outcomes among persons with alcoholism who have different ALDH genotypes.


iFlow: A Graphical User Interface for Flow Cytometry Tools in Bioconductor.
Flow cytometry (FCM) has become an important analysis technology in health care and medical research, but the large volume of data produced by modern high-throughput experiments has presented significant new challenges for computational analysis tools. The development of an FCM software suite in Bioconductor represents one approach to overcome these challenges. In the spirit of the R programming language (Tree Star Inc., "FlowJo," http://www.owjo.com), these tools are predominantly console-driven, allowing for programmatic access and rapid development of novel algorithms. Using this software requires a solid understanding of programming concepts and of the R language. However, some of these tools|in particular the statistical graphics and novel analytical methods|are also useful for nonprogrammers. To this end, we have developed an open source, extensible graphical user interface (GUI) iFlow, which sits on top of the Bioconductor backbone, enabling basic analyses by means of convenient graphical menus and wizards. We envision iFlow to be easily extensible in order to quickly integrate novel methodological developments.


Heritable and inducible gene knockdown in astrocytes or neurons in vivo by a combined lentiviral and RNAi approach.
Gene knockout by homologous recombination is a popular method to study gene functions in the mouse in vivo. However, its lack of temporal control has limited the interpretation of knockout studies because the complete elimination of a gene product often alters developmental processes, and can induce severe malformations or lethality. Conditional gene knockdown has emerged as a compelling alternative to gene knockout, an approach well-established in vitro but that remains challenging in vivo, especially in the adult brain. Here, we report a method for conditional and cell-specific gene knockdown in the mouse brain in vivo that combines Cre-mediated RNA interference (RNAi) with classical and lentivirus-mediated transgenesis. The method is based on the inducible expression of a silencing short hairpin RNA (shRNA) introduced in mice by lentivirus-mediated transgenesis, and on its activation by excision of a floxed stop EGFP reporter with an inducible Cre recombinase expressed in astrocytes or in neurons. This dual system should be of broad utility for comparative studies of gene functions in these two cell types in vivo.


High resolution methylation analysis of the HoxA5 regulatory region in different somatic tissues of laboratory mouse during development.
Homeobox genes encode a group of DNA binding regulatory proteins whose key function occurs in the spatial-temporal organization of genome during embryonic development and differentiation. The role of these Hox genes during ontogenesis makes it an important model for research. HoxA5 is a member of Hox gene family playing a central role during axial body patterning and morphogenesis. DNA modification studies have shown that the function of Hox genes is partly governed by the methylation-mediated gene expression regulation. Therefore the study aimed to investigate the role of epigenetic events in regulation of tissue-specific expression pattern of HoxA5 gene during mammalian development. The methodology adopted were sodium bisulfite genomic DNA sequencing, quantitative real-time PCR and chromatin-immunoprecipitation (ChIP). Methylation profiling of HoxA5 gene promoter shows higher methylation in adult as compared to fetus in various somatic tissues of mouse being highest in adult spleen. However q-PCR results show higher expression during fetal stages being highest in fetal intestine followed by brain, liver and spleen. These results clearly indicate a strict correlation between DNA methylation and tissue-specific gene expression. The findings of chromatin-immunoprecipitation (ChIP) have also reinforced that epigenetic event like DNA methylation plays important role in the regulation of tissue specific expression of HoxA5.


UV-ozone-treated ultra-thin NaF film as anode buffer layer on organic light emitting devices.
An ultra-thin NaF film was thermally deposited between ITO and NPB as the buffer layer and then treated with the ultraviolet (UV) ozone, in the fabrication of organic light emitting diodes (ITO/NaF/NPB/Alq(3)/LiF/Al) to study its effect on hole-injection properties. The treatment drastically transforms the role of NaF film from hole-blocking to hole-injecting. This transformation is elucidated using hole-only devices, energy band measurement, surface energy, surface polarity, and X-ray photoelectron spectra. With the optimal thickness (3 nm) of the UV-ozone-treated NaF layer, the device performance is significantly improved, with a turn-on voltage, maximum luminance, and maximum current efficiency of 2.5 V, 15700 cd/m(2), and 4.9 cd/A, respectively. Results show that NaF film is not only a hole-blocking layer, but also a promising hole-injecting layer after UV-ozone treatment.


Lessons from the Crypt: HMGA1-Amping up Wnt for Stem Cells and Tumor Progression.
High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing self-renewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also "builds" a stem cell niche by upregulating Sox9, a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs. HMGA1 is also highly upregulated in colon cancer compared with nonmalignant epithelium and SOX9 becomes overexpressed during colon carcinogenesis. Intriguingly, HMGA1 is overexpressed in diverse cancers with poor outcomes, where it regulates developmental genes. Similarly, HMGA1 induces genes responsible for pluripotency and self-renewal in embryonic stem cells. These findings demonstrate that HMGA1 maintains Wnt and other developmental transcriptional networks and suggest that HMGA1 overexpression fosters carcinogenesis and tumor progression through dysregulation of these pathways. Studies are now needed to determine more precisely how HMGA1 modulates chromatin structure to amplify developmental genes and how to disrupt this process in cancer therapy. Cancer Res; 78(8); 1890-7. ©2018 AACR.


Laparoscopic Roux-en-Y gastric bypass and the role of the surgical resident.
Open Roux-en-Y gastric bypass (RYGB) is the gold standard for obesity surgery in this country. The introduction of a totally laparoscopic technique in 1994 has increased the demand for obesity surgery and for this particular approach. Several studies show comparable results and complications between the open and laparoscopic procedure. However, the continued study of surgical technique, analysis of results, and, in particular, the education of the surgical resident in this approach must be accomplished. A retrospective analysis was performed of 204 patients undergoing attempted laparoscopic RYGB, with surgical resident involvement, from March of 2000 to April of 2002. Surgical candidates had a body mass index (BMI) greater than 40 with a history of failed diets. All procedures were performed by a single board-certified general surgeon (P.F.R.) at a tertiary-care, teaching, community hospital with surgical residents assisting. Age, sex, ideal body weight, preoperative BMI and weight, surgical time, length of stay, complications, and resident level and role were recorded. Surgical technique was refined during the study period. A total of 204 patients underwent attempted laparoscopic RYGB with 4 (2%) being converted to open procedures and 1 mortality. Surgical time averaged 182 minutes. The average length of stay was 1.8 days. Four patients (2%) developed postoperative anastomotic leaks. Three patients (1.5%) developed internal hernias requiring reoperation. Four patients (2%) developed postoperative hemorrhage. One patient (0.5%) had a pulmonary embolism. Surgical residents were involved in all procedures and gradually expanded their role as skill increased. Laparoscopic RYGB can be performed safely in a community setting with surgical residents as either assistant or surgeon, further preparing them to perform this and other advanced laparoscopic procedures after completion of their training.


IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis.
Whole genome sequencing (WGS) was performed to identify the variants responsible for inherited retinal degeneration (IRD) in a Caucasian family. Segregation analysis of selected rare variants with pathogenic potential identified a set of compound heterozygous changes p.Arg266*:c.796C>T and p.Ala568Thr:c.1702G>A in the intraflagellar transport protein-88 (IFT88) gene segregating with IRD. Expression of IFT88 with the p.Arg266* and p.Ala568Thr mutations in mIMDC3 cells by transient transfection and in HeLa cells by introducing the mutations using CRISPR-cas9 system suggested that both mutations result in the formation of abnormal ciliary structures. The introduction of the IFT88 p.Arg266* variant in the homozygous state in HeLa cells by CRISPR-Cas9 genome-editing revealed that the mutant transcript undergoes nonsense-mediated decay leading to a significant depletion of IFT88 transcript. Additionally, abnormal ciliogenesis was observed in these cells. These observations suggest that the rare and unique combination of IFT88 alleles observed in this study provide insight into the physiological role of IFT88 in humans and the likely mechanism underlying retinal pathology in the pedigree with IRD.


[Enzyme replacement therapy for mucopolysaccharidoses I, II and VI: recommendations from a group of Brazilian F experts].
Mucopolysaccharidoses (MPS) are rare genetic diseases caused by deficiency of specific lysosomal enzymes that affect catabolism of glycosaminoglycans (GAG). Accumulation of GAG in various organs and tissues in MPS patients results in a series of signs and symptoms, producing a multisystemic condition affecting bones and joints, the respiratory and cardiovascular systems and many other organs and tissues, including in some cases, cognitive performance. So far, eleven enzyme defects that cause seven different types of MPS have been identified. Before introduction of therapies to restore deficient enzyme activity, treatment of MPS focused primarily on prevention and care of complications, still a very important aspect in the management of these patients. In the 80's treatment of MPS with bone marrow transplantation/hematopoietic stem cells transplantation (BMT/HSCT) was proposed and in the 90's, enzyme replacement therapy (ERT),began to be developed and was approved for clinical use in MPS I, II and VI in the first decade of the 21st century. The authors of this paper are convinced that a better future for patients affected by mucopolysaccharidoses depends upon identifying, understanding and appropriately managing the multisystemic manifestations of these diseases. This includes the provision of support measures (which should be part of regular multidisciplinary care of these patients) and of specific therapies. Although inhibition of synthesis of GAG and the recovery of enzyme activity with small molecules also may play a role in the management of MPS, the breakthrough is the currently available intravenous ERT. ERT radically changed the setting for treatment of mucopolysaccharidosis I, II and VI in the last decade., Benefits can even be extended soon to MPS IV A (ERT for this condition is already in clinical development), with prediction for treatment of MPS III A and the cognitive deficit in MPS II by administration of the enzyme directly into the central nervous system (CNS). A large number of Brazilian services, from all regions of the country, already have experience with ERT for MPS I, II and VI. This experience was gained not only by treating patients but also with the participation of some groups in clinical trials involving ERT for these conditions. Summing up the three types of MPS, more than 250 patients have already been treated with ERT in Brazil. The experience of professionals coupled to the data available in international literature, allowed us to elaborate this document, produced with the goal of bringing together and harmonize the information available for the treatment of these severe and progressive diseases, which, fortunately, are now treatable, a situation which bring new perspectives for Brazilian patients, affected by these conditions.


Symptoms Experience and Quality of Life in The Patients With Breast Cancer Receiving The Taxane Class of Drugs.
The aim of this study is to evaluate the symptoms experience and quality of life in patients with breast cancer receiving the taxane class of drugs. This study was performed between November 2015 March 2016 in a chemotherapy unit of a university hospital with 48 patients, who agreed to participate in the study. The Memorial Symptom Rating Score (MSAS), Socio-demographic and Clinical Features Form, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Breast (EORTC QLQ- BR23) measures specific to breast cancer were used to obtain data. The average age of the patients was 45.65. The majority of patients were treated with the paclitaxel/paclitaxel+trastuzumab treatment protocol (60.42%), and more than half (54.16%) of these patients were on 5 or 6 treatments. The symptoms patients experienced the most commonly included being sensitive, weakness or energy loss and pain. The symptoms they experienced severely were included fatigue and energy loss and being sensitive. The most distressing symptoms were pain, worry, numbness in hands and feet. The overall well-being score of the patients as per the quality of life findings was 46.18±11.66. While the lowest score for the functional scales was in the social function subscale (66.32±15.18), the highest score for the symptom scales was in the pain subscale (42.01±15.37). The lowest score for the EORTC QLQ-BR23 scales was in the sexual life subscale (20.83±20.19); the highest score was in the body appearance subscale (65.8±23.96). The results of the study are thought to be helpful for the oncology nurses in evaluating the patients in all aspects and in determining priorities for care.


The role of upper lateral cartilage in dorsal reconstruction after hump excision: section 1. Spreader flap modification with asymmetric mattress suture and extension of the spreading effect by cartilage graft.
A spreader flap, or autospreader flap, is a flap used for dorsal reconstruction in primary rhinoplasty after cartilage dorsum excision. Despite its significant advantages, the spreader flap also has distinct shortcomings. The most common problem encountered in using a spreader flap is the technique's inability to provide adequate dorsal width compared with spreader grafts. Additionally, the use of a spreader flap has not been described for special cases such as crooked noses, cases with minimal dorsal humps, and secondary cases. This report presents the authors' modification of the spreader flap technique to expand its indications and extend the spreader effect down to the entire dorsum. This modification positions and fixes the medial borders of the upper lateral cartilages (ULCs) on both sides of the septum by asymmetric mattress sutures. Using the ULCs without folding affords the opportunity to restore a dorsum with sufficient width. Different entry and exit points of the suture help to maintain the cartilage substance horizontally rather than folded as in the conventional spreader flap technique. Another drawback of the spreader flap technique is its inability to address the lower third of the dorsum when ULCs do not extend down to the anterior septal angle (ASA). In these cases, attempts were made to extend the spreader effect by placing two small cartilage grafts on both sides of the ASA. Over a period of 2 years, the authors operated on 169 patients. For 81 of these patients, the modified spreader flap alone was used, and for the remaining 88 patients, both the modified spreader flap technique and ASA grafting (combined modification) were used. During a mean follow-up period of 17 months, no narrowing in the middle nasal dorsum and no inner valve deficiencies were seen in any of the cases.


Homeopathic medical practice for anxiety and depression in primary care: the EPI3 cohort study.
The purpose of the study was to compare utilization of conventional psychotropic drugs among patients seeking care for anxiety and depression disorders (ADDs) from general practitioners (GPs) who strictly prescribe conventional medicines (GP-CM), regularly prescribe homeopathy in a mixed practice (GP-Mx), or are certified homeopathic GPs (GP-Ho). This was one of three epidemiological cohort studies (EPI3) on general practice in France, which included GPs and their patients consulting for ADDs (scoring 9 or more in the Hospital Anxiety and Depression Scale, HADS). Information on all medication utilization was obtained by a standardised telephone interview at inclusion, 1, 3 and 12 months. Of 1562 eligible patients consulting for ADDs, 710 (45.5 %) agreed to participate. Adjusted multivariate analyses showed that GP-Ho and GP-Mx patients were less likely to use psychotropic drugs over 12 months, with Odds ratio (OR) = 0.29; 95 % confidence interval (CI): 0.19 to 0.44, and OR = 0.62; 95 % CI: 0.41 to 0.94 respectively, compared to GP-CM patients. The rate of clinical improvement (HADS <9) was marginally superior for the GP-Ho group as compared to the GP-CM group (OR = 1.70; 95 % CI: 1.00 to 2.87), but not for the GP-Mx group (OR = 1.49; 95 % CI: 0.89 to 2.50). Patients with ADD, who chose to consult GPs prescribing homeopathy reported less use of psychotropic drugs, and were marginally more likely to experience clinical improvement, than patients managed with conventional care. Results may reflect differences in physicians' management and patients' preferences as well as statistical regression to the mean.


Meropenem-clavulanic acid has high in vitro activity against multidrug-resistant Mycobacterium tuberculosis.
We investigated the activity of meropenem-clavulanic acid (MEM-CLA) against 68 Mycobacterium tuberculosis isolates. We included predominantly multi- and extensively drug-resistant tuberculosis (MDR/XDR-TB) isolates, since the activity of MEM-CLA for resistant isolates has previously not been studied extensively. Using Middlebrook 7H10 medium, all but four isolates showed an MIC distribution of 0.125 to 2 mg/liter for MEM-CLA, below the non-species-related breakpoint for MEM of 2 mg/liter defined by EUCAST. MEM-CLA is a potential treatment option for MDR/XDR-TB.


Correntropy measures to detect daytime sleepiness from EEG signals.
Excessive daytime sleepiness (EDS) is one of the main symptoms of several sleep related disorders and has a great impact on patients' lives. While many studies have been carried out in order to assess daytime sleepiness, automatic EDS detection still remains an open problem. In this work, a novel approach to this issue based on correntropy function analysis of EEG signals was proposed in order to detect patients suffering from EDS. Multichannel EEG signals were recorded during five Maintenance of Wakefulness Tests (MWT) and Multiple Sleep Latency Tests (MSLT) alternated throughout the day for patients suffering from sleep disordered breathing (SDB). A group of 20 patients with EDS was compared with a group of 20 patients without daytime sleepiness (WDS), by analyzing 60 s EEG windows in a waking state. Measures obtained from the cross-correntropy function (CCORR) and auto-correntropy function (ACORR) were calculated in the EEG frequency bands: δ, 0.1-4 Hz; θ, 4-8 Hz; α, 8-12 Hz; β, 12-30 Hz; total band TB, 0.1-45 Hz. These functions permitted the quantification of complex signal properties and the non-linear couplings between different areas of the scalp. Statistical differences between EDS and WDS groups were mainly found in the β band during MSLT events (p-value < 0.0001). The WDS group presented more complexity in the occipital zone than the EDS group, while a stronger nonlinear coupling between the occipital and frontal regions was detected in EDS patients than in the WDS group. At best, ACORR and CCORR measures yielded sensitivity and specificity above 80% and the area under ROC curve (AUC) was above 0.85 in classifying EDS and WDS patients. These performances represent an improvement with respect to classical EEG indices applied in the same database (sensitivity and specificity were never above 80% and AUC was under 0.75).


Effect of esomeprazole with/without acetylsalicylic acid, omeprazole and lansoprazole on pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers.
The effect of proton pump inhibitors (PPIs) on the pharmacokinetics and pharmacodynamics of clopidogrel was assessed in two healthy volunteer crossover studies. Study 1: subjects received clopidogrel alone (300-mg loading dose, then 75 mg/day for 28 days) and two of three PPIs (omeprazole 80 mg, esomeprazole 40 mg or lansoprazole 60 mg) plus clopidogrel for 29 days in three treatment periods (randomized treatment sequence assignment). Study 2: subjects received clopidogrel alone (75 mg/day for 9 days) and clopidogrel alone for 4 days followed by clopidogrel plus fixed-combination esomeprazole 20 mg/low-dose acetylsalicylic acid (ASA) 81 mg for 5 days in two treatment periods (randomized treatment sequence assignment). Pharmacokinetic effects were estimated by measuring active metabolite of clopidogrel, and pharmacodynamic effects by inhibition of adenosine diphosphate (ADP)-induced platelet aggregation. There was a relative decrease of up to 50 % in exposure to the active metabolite of clopidogrel with the different PPIs (study 1), and close to 40 % with esomeprazole/low-dose ASA (study 2), compared with clopidogrel alone. There was an absolute decrease of up to 17 % in inhibition of ADP-induced platelet aggregation with co-administration of different PPIs, compared with clopidogrel alone; however, no differences in platelet inhibition were observed during co-administration with the esomeprazole/low-dose ASA fixed-dose combination. Omeprazole, esomeprazole and lansoprazole decreased systemic exposure to the active metabolite of clopidogrel in healthy volunteers, leading to modest decreases in its antiplatelet effect. However, no apparent differences in platelet inhibition were observed when esomeprazole was co-administered with low-dose ASA as a fixed-dose combination.


Relationship between Body Mass Index, Waist-to-Hip Ratio, and Serum Lipid Concentrations and Thyroid-Stimulating Hormone in the Euthyroid Adult Population.
The aim of this cross-sectional study was to investigate the relationship between body mass index (BMI), waist-to-hip ratio, and lipid parameters and serum thyroid-stimulating hormone (TSH) levels in healthy euthyroid individuals. This cross-sectional study was conducted between June 1st and July 20th, 2013, at Bushehr University of Medical Sciences. One hundred forty euthyroid individuals were divided into 2 groups: a high-TSH group (TSH between 2.0 and 5.5 mIU/L, n=67) and a low-TSH group (TSH between 0.3 and 2.0 mIU/L, n=73). After overnight fast, total cholesterol, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), TSH, thyroxine (T4), and triiodothyronine (T3) were measured. Height and weight were measured with a stadiometer, and BMI was calculated as weight in kilograms divided by the square of height in meters. Waist-to-hip ratio was determined as waist circumference divided by hip circumference. The simple independent t-test and a general linear model were used for statistical analysis. All statistical analyses were done using the SPSS, version 15, statistical software package. BMI and LDL-C were significantly higher in the high-TSH group than in the low-TSH group after adjustment for age, sex, calorie intake, total fat and carbohydrate intakes, and physical activity. No significant differences were found between the groups in TG, cholesterol, and HDL-C. The association between TSH levels andT4 was significant. Individuals with TSH levels at the upper limit of normality might be at risk of hypercholesterolemia and obesity.


The hologenomic basis of speciation: gut bacteria cause hybrid lethality in the genus Nasonia.
Although the gut microbiome influences numerous aspects of organismal fitness, its role in animal evolution and the origin of new species is largely unknown. Here we present evidence that beneficial bacterial communities in the guts of closely related species of the genus Nasonia form species-specific phylosymbiotic assemblages that cause lethality in interspecific hybrids. Bacterial constituents and abundance are irregular in hybrids relative to parental controls, and antibiotic curing of the gut bacteria significantly rescues hybrid survival. Moreover, feeding bacteria to germ-free hybrids reinstates lethality and recapitulates the expression of innate immune genes observed in conventionally reared hybrids. We conclude that in this animal complex, the gut microbiome and host genome represent a coadapted "hologenome" that breaks down during hybridization, promoting hybrid lethality and assisting speciation.


Comprehensive assessment of HER2 alteration in a colorectal cancer cohort: from next-generation sequencing to clinical significance.
Human epidermal growth factor receptor 2 (HER2) is an emerging therapeutic target in colorectal cancer (CRC). Currently, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) have been used to determine HER2-positive CRCs; however, the clinical utility of next-generation sequencing (NGS)-based techniques for determining HER2 status in CRC has been limited. Here, we detail our experience regarding the assessment of HER2 alterations in a CRC cohort. We prospectively enrolled 73 CRC patients who underwent surgery and received adjuvant oxaliplatin treatment. We then examined HER2 alterations using the Oncomine Comprehensive Assay version 1, as well as clinical outcomes, in this cohort. Using the NGS-based assay, HER2 copy number gains in 12 of 73 CRCs were determined to range from 2.74 to 92.62. Of these 12 tumors, 6 had HER2 high-level copy number gain (92.6, 57.9, 57.0, 52.0, 35.2, and 8.42) and were all defined as HER2-positive CRC using HERACLES Diagnostic Criteria. Nevertheless, other 6 patients with low-level copy number gain (ranging from 2.74 to 3.04) and the remaining 61 patients without increase in HER2 copy number were all HER2-negative. Among the 6 HER2-positive CRCs, KRAS and PIK3CA mutations were detected in 1 (17%; G13D) and 2 (33.3%; 1 Q546R and 1 H1047R) patients, respectively. Moreover, 2 of the 6 (33.3%) HER2-positive patients had recurrent disease, while one patient had a partial response after anti-HER2 therapy. NGS-based tools could assist in the simultaneous detection of HER2 and other genomic alterations in patients with CRC. Only CRCs with HER2 high-level copy number gain were HER2-postive by current diagnostic criteria.


Preventing diabetes with digital health and coaching for translation and scalability (PREDICTS): A type 1 hybrid effectiveness-implementation trial protocol.
Diabetes prevention remains a top public health priority; digital approaches are potential solutions to existing scalability and accessibility challenges. There remains a gap in our understanding of the relationship between effectiveness, costs, and potential for sustained implementation of digital diabetes prevention strategies within typical healthcare settings. To describe the methods and design of a type 1 hybrid effectiveness-implementation trial of a digital diabetes prevention program (DPP) using the iPARIHS and RE-AIM frameworks. The trial will contrast the effects of two DPP interventions: (1) small group, in-person class, and (2) a digital DPP consisting of small group support, personalized health coaching, digital tracking tools, and weekly behavior change curriculum. Each intervention includes personal action planning with a focus on key elements of the lifestyle intervention from the CDC National DPP. Adults at risk for diabetes (BMI ≥25 and 5.7% ≤ HbA1c ≤ 6.4) will be randomly assigned to either the intervention group (n = 241) or the small group (n = 241). Assessment of primary (HbA1c) and secondary (weight loss, costs, cardiovascular risk factors) outcomes will occur at baseline, 4, and 12 months. Additionally, the trial will explore the potential for future adoption, implementation, and sustainability of the digitally-based intervention within a regional healthcare system based on key informant interviews and assessments of organizational administrators and primary care physicians. This trial of a digital DPP will allow the research team to determine the relationships between reach, effectiveness, implementation, and costs.


Characterization of Viral Capsid Protein Self-Assembly around Short Single-Stranded RNA.
For many viruses, the packaging of a single-stranded RNA (ss-RNA) genome is spontaneous, driven by capsid protein-capsid protein (CP) and CP-RNA interactions. Furthermore, for some multipartite ss-RNA viruses, copackaging of two or more RNA molecules is a common strategy. Here we focus on RNA copackaging in vitro by using cowpea chlorotic mottle virus (CCMV) CP and an RNA molecule that is short (500 nucleotides (nts)) compared to the lengths (≈3000 nts) packaged in wild-type virions. We show that the degree of cooperativity of virus assembly depends not only on the relative strength of the CP-CP and CP-RNA interactions but also on the RNA being short: a 500-nt RNA molecule cannot form a capsid by itself, so its packaging requires the aggregation of multiple CP-RNA complexes. By using fluorescence correlation spectroscopy (FCS), we show that at neutral pH and sufficiently low concentrations RNA and CP form complexes that are smaller than the wild-type capsid and that four 500-nt RNAs are packaged into virus-like particles (VLPs) only upon lowering the pH. Further, a variety of bulk-solution techniques confirm that fully ordered VLPs are formed only upon acidification. On the basis of these results, we argue that the observed high degree of cooperativity involves equilibrium between multiple CP/RNA complexes.


An investigation into ciguatoxin bioaccumulation in sharks.
Ciguatoxins (CTXs) produced by benthic Gambierdiscus dinoflagellates, readily biotransform and bioaccumulate in food chains ultimately bioconcentrating in high-order, carnivorous marine species. Certain shark species, often feeding at, or near the top of the food-chain have the ability to bioaccumulate a suite of toxins, from both anthropogenic and algal sources. As such, these apex predators are likely sinks for CTXs. This assumption, in conjunction with anecdotal knowledge of poisoning incidents, several non-specific feeding trials whereby various terrestrial animals were fed suspect fish flesh, and a single incident in Madagascar in 1994, have resulted in the widespread acceptance that sharks may accumulate CTXs. This prompted a study to investigate original claims within the literature, as well as investigate CTX bioaccumulation in the muscle and liver of 22 individual sharks from nine species, across four locations along the east coast of Australia. Utilizing an updated ciguatoxin extraction method with HPLC-MS/MS, we were unable to detect P-CTX-1, P-CTX-2 or P-CTX-3, the three primary CTX congeners, in muscle or liver samples. We propose four theories to address this finding: (1) to date, methods have been optimized for teleost species and may not be appropriate for elasmobranchs, or the CTXs may be below the limit of detection; (2) CTX may be biotransformed into elasmobranch-specific congeners as a result of unique metabolic properties; (3) 22 individuals may be an inadequate sample size given the rare occurrence of high-order ciguatoxic organisms and potential for CTX depuration; and (4) the ephemeral nature and inconsistent toxin profiles of Gambierdiscus blooms may have undermined our classifications of certain areas as CTX hotspots. These results, in combination with the lack of clarity within the literature, suggest that ciguatoxin bioaccumulation in sharks remains elusive, and warrants further investigation to determine the dynamics of toxin production, accumulation and transformation throughout the entire food-web.


Acute peripheral immune activation alters cytokine expression and glial activation in the early postnatal rat brain.
Neuroinflammation can modulate brain development; however, the influence of an acute peripheral immune challenge on neuroinflammatory responses in the early postnatal brain is not well characterized. To address this gap in knowledge, we evaluated the peripheral and central nervous system (CNS) immune responses to a mixed immune challenge in early postnatal rats of varying strains and sex. On postnatal day 10 (P10), male and female Lewis and Brown Norway rats were injected intramuscularly with either a mix of bacterial and viral components in adjuvant, adjuvant-only, or saline. Immune responses were evaluated at 2 and 5 days post-challenge. Cytokine and chemokine levels were evaluated in serum and in multiple brain regions using a Luminex multiplex assay. Multi-factor ANOVAs were used to compare analyte levels across treatment groups within strain, sex, and day of sample collection. Numbers and activation status of astrocytes and microglia were also analyzed in the cortex and hippocampus by quantifying immunoreactivity for GFAP, IBA-1, and CD68 in fixed brain slices. Immunohistochemical data were analyzed using a mixed-model regression analysis. Acute peripheral immune challenge differentially altered cytokine and chemokine levels in the serum versus the brain. Within the brain, the cytokine and chemokine response varied between strains, sexes, and days post-challenge. Main findings included differences in T helper (Th) type cytokine responses in various brain regions, particularly the cortex, with respect to IL-4, IL-10, and IL-17 levels. Additionally, peripheral immune challenge altered GFAP and IBA-1 immunoreactivity in the brain in a strain- and sex-dependent manner. These findings indicate that genetic background and sex influence the CNS response to an acute peripheral immune challenge during early postnatal development. Additionally, these data reinforce that the developmental time point during which the challenge occurs has a distinct effect on the activation of CNS-resident cells.


Reporting data on homeopathic treatments (RedHot): a supplement to CONSORT*.
When homeopathy is tested in clinical trials, understanding and appraisal are likely to be improved if published reports contain details of prescribing strategies and treatments. An international Delphi panel was convened to develop consensus guidelines for reporting homeopathic methods and treatments. The panel agreed 28 treatment- and provider-specific items that supplement the CONSORT (Consolidated Standards of Reporting Trials) Statement items 2, 3, 4 and 19. The authors recommend these for adoption by authors and journals when reporting trials of homeopathy.


Does education reduce the probability of being overweight?
The prevalence of overweight and obesity is growing rapidly in many countries. Education policies might be important for reducing this increase. This paper analyses the causal effect of education on the probability of being overweight by using longitudinal data of Australian identical twins. The data include self-reported and clinical measures of body size. Our cross-sectional estimates confirm the well-known negative association between education and the probability of being overweight. For men we find that education also reduces the probability of being overweight within pairs of identical twins. The estimated effect of education on overweight status increases with age. Remarkably, for women we find no negative effect of education on body size when fixed family effects are taken into account. Identical twin sisters who differ in educational attainment do not systematically differ in body size. Peer effects within pairs of identical twin sisters might play a role.


Breathing and swallowing dynamics across the adult lifespan.
Aberrations in the physiologic components of normal oropharyngeal swallowing have been linked to aspiration events and to predisposition to aspiration pneumonia, a common, deadly disease in elderly persons. Studies have demonstrated a temporal, physiologic link between breathing and the principal physiologic swallowing components involved in airway protection during swallowing. We developed a normative model of integrated breathing and swallowing patterns using concomitant videofluoroscopic images and nasal respiratory airflow recordings. To establish normative temporal and respiratory-phase pattern relationships between breathing and swallowing in adult human beings across the aging continuum; to relate any alterations in these patterns to swallowing abnormality, an aspiration event during swallowing, and predisposition to aspiration pneumonia; and to develop clinically practical evaluation methods for identifying breathing and swallowing discoordination. Fluoroscopy suite in an acute care hospital. Eighty-two healthy adult volunteers gave informed consent. All eligible healthy volunteers were welcome and were screened for age, race, and sex for equal distribution of each. Respiratory-phase patterns and the onset and duration of 11 predetermined swallowing events and associated respiratory activities were studied. All participants' single-liquid barium swallow examinations were studied with simultaneous videofluoroscopy and respiratory recordings. Onset of each of the 11 predetermined breathing and swallowing events was digitally recorded and analyzed. The phases of breathing before and after swallowing were identified. The presence, depth, and response to airway penetration were recorded and related to respiratory pattern. Four respiratory-phase patterns were identified that changed with advanced age. The correlation analyses of the temporal breathing and swallowing events revealed a normal pattern of 4 clearly distinguishable functional units. Differences in apnea duration and apnea offset occurred with advanced age. This research provides evidence for clearly distinguishable patterns and functional groupings of breathing and swallowing events, a necessary first step toward determining whether abnormal breathing and swallowing patterns in patients with dysphagia are associated with health outcome.


Advances in β cell replacement and regeneration strategies for treating diabetes.
In the past decade, new approaches have been explored that are aimed at restoring functional β cell mass as a treatment strategy for diabetes. The two most intensely pursued strategies are β cell replacement through conversion of other cell types and β cell regeneration by enhancement of β cell replication. The approach closest to clinical implementation is the replacement of β cells with human pluripotent stem cell-derived (hPSC-derived) cells, which are currently under investigation in a clinical trial to assess their safety in humans. In addition, there has been success in reprogramming developmentally related cell types into β cells. Reprogramming approaches could find therapeutic applications by inducing β cell conversion in vivo or by reprogramming cells ex vivo followed by implantation. Finally, recent studies have revealed novel pharmacologic targets for stimulating β cell replication. Manipulating these targets or the pathways they regulate could be a strategy for promoting the expansion of residual β cells in diabetic patients. Here, we provide an overview of progress made toward β cell replacement and regeneration and discuss promises and challenges for clinical implementation of these strategies.


Melatonin--a pleiotropic, orchestrating regulator molecule.
Melatonin, the neurohormone of the pineal gland, is also produced by various other tissues and cells. It acts via G protein-coupled receptors expressed in various areas of the central nervous system and in peripheral tissues. Parallel signaling mechanisms lead to cell-specific control and recruitment of downstream factors, including various kinases, transcription factors and ion channels. Additional actions via nuclear receptors and other binding sites are likely. By virtue of high receptor density in the circadian pacemaker, melatonin is involved in the phasing of circadian rhythms and sleep promotion. Additionally, it exerts effects on peripheral oscillators, including phase coupling of parallel cellular clocks based on alternate use of core oscillator proteins. Direct central and peripheral actions concern the up- or downregulation of various proteins, among which inducible and neuronal NO synthases seem to be of particular importance for antagonizing inflammation and excitotoxicity. The methoxyindole is also synthesized in several peripheral tissues, so that the total content of tissue melatonin exceeds by far the amounts in the circulation. Emerging fields in melatonin research concern receptor polymorphism in relation to various diseases, the control of sleep, the metabolic syndrome, weight control, diabetes type 2 and insulin resistance, and mitochondrial effects. Control of electron flux, prevention of bottlenecks in the respiratory chain and electron leakage contribute to the avoidance of damage by free radicals and seem to be important in neuroprotection, inflammatory diseases and, presumably, aging. Newly discovered influences on sirtuins and downstream factors indicate that melatonin has a role in mitochondrial biogenesis.