Gut dysbiosis is prevailing in Sjögren's syndrome and is related to dry eye severity.
To investigate gut dysbiosis in patients with Sjögren's syndrome (SS) or dry eye syndrome (DES) compared to normal subjects and to evaluate the association of dysbiosis with dry eye severity. 10 subjects with SS, 14 subjects with DES and 12 controls were enrolled. Corneal staining, tear break up time (TBUT) and tear secretion were evaluated. Bacterial genomic 16s rRNA from stool samples were analyzed. Main outcomes were microbiome compositional differences among groups and their correlation to dry eye signs. Gut microbiome analysis revealed significant compositional differences in SS compared to controls and DES. In phylum, Bacteriodetes increased, while Firmicutes/Bacteroidetes ratio and Actinobacteria decreased (p<0.05). In genus, Bifidobacterium was reduced (vs controls; p = 0.025, vs DES; p = 0.026). Beta diversity of SS also showed significant distances from controls and DES (p = 0.007 and 0.019, respectively). SS showed decreased genus of Blautia (p = 0.041), Dorea (p = 0.025) and Agathobacter (p = 0.035) compared to controls and increased genus of Prevotella (p = 0.026), Odoribacter (p = 0.028) and Alistipes (p = 0.46) compared to DES. On the other hand, DES only had increased genus Veillonella (p = 0.045) and reduced Subdoligranulum (p = 0.035) compared to controls. Bacteroidetes, Actinobacteria and Bifidobacterium were significantly related with dry eye signs (p<0.05). After adjustment of age, gender and group classification, multivariate linear regression analysis revealed tear secretion was strongly affected by Prevotella (p = 0.025). With additional adjustment of hydroxychloroquine use, TBUT was markedly affected by Prevotella (p = 0.037) and Actinobacteria (p = 0.001). Sjögren's syndrome showed significant gut dysbiosis compared to controls and environmental dry eye syndrome, while dry eye patients showed compositional changes of gut microbiome somewhere in between Sjögren's syndrome and controls. Dysbiosis of the gut microbiota was partly correlated to dry eye severity.


Dynamics and computation of continuous attractors.
Continuous attractor is a promising model for describing the encoding of continuous stimuli in neural systems. In a continuous attractor, the stationary states of the neural system form a continuous parameter space, on which the system is neutrally stable. This property enables the neutral system to track time-varying stimuli smoothly, but it also degrades the accuracy of information retrieval, since these stationary states are easily disturbed by external noise. In this work, based on a simple model, we systematically investigate the dynamics and the computational properties of continuous attractors. In order to analyze the dynamics of a large-size network, which is otherwise extremely complicated, we develop a strategy to reduce its dimensionality by utilizing the fact that a continuous attractor can eliminate the noise components perpendicular to the attractor space very quickly. We therefore project the network dynamics onto the tangent of the attractor space and simplify it successfully as a one-dimensional Ornstein-Uhlenbeck process. Based on this simplified model, we investigate (1) the decoding error of a continuous attractor under the driving of external noisy inputs, (2) the tracking speed of a continuous attractor when external stimulus experiences abrupt changes, (3) the neural correlation structure associated with the specific dynamics of a continuous attractor, and (4) the consequence of asymmetric neural correlation on statistical population decoding. The potential implications of these results on our understanding of neural information processing are also discussed.


Molecular basis of the therapeutic properties of hemorphins.
Hemorphins are endogenous peptides, 4-10 amino acids long, belonging to the family of atypical opioid peptides released during the sequential cleavage of hemoglobin protein. Hemorphins have been shown to exhibit diverse therapeutic effects in both human and animal models. However, the precise cellular and molecular mechanisms involved in such effects remain elusive. In this review, we summarize and propose potential mechanisms based on studies that investigated the biological activity of hemorphins of different lengths on multiple therapeutic targets. Special emphasis is given to molecular events related to renin-angiotensin system (RAS), opioid receptors and insulin-regulated aminopeptidase receptor (IRAP). This review provides a comprehensive coverage of the molecular mechanisms that underpin the therapeutic potential of hemorphins. Furthermore, it highlights the role of various hemorphin residues in pathological conditions, which could be explored further for therapeutic purposes.


Salmonella typhimurium infection increases p53 acetylation in intestinal epithelial cells.
The ability of Salmonella typhimurium to enter intestinal epithelial cells constitutes a crucial step in pathogenesis. Salmonella invasion of the intestinal epithelium requires bacterial type three secretion system. Type three secretion system is a transport device that injects virulence proteins, called effectors, to paralyze or reprogram the eukaryotic cells. Avirulence factor for Salmonella (AvrA) is a Salmonella effector that inhibits the host's inflammatory responses. The mechanism by which AvrA modulates host cell signaling is not entirely clear. p53 is situated at the crossroads of a network of signaling pathways that are essential for genotoxic and nongenotoxic stress responses. We hypothesized that Salmonella infection activates the p53 pathway. We demonstrated that Salmonella infection increased p53 acetylation. Cells infected with AvrA-sufficient Salmonella have increased p53 acetylation, whereas cells infected with AvrA-deficient Salmonella have less p53 acetylation. In a cell-free system, AvrA possessed acetyltransferase activity and used p53 as a substrate. AvrA expression increased p53 transcriptional activity and induced cell cycle arrest. HCT116 p53-/- cells had less inflammatory responses. In a mouse model of Salmonella infection, intestinal epithelial p53 acetylation was increased by AvrA expression. Our studies provide novel mechanistic evidence that Salmonella modulates the p53 pathway during intestinal inflammation and infection.


Implicit methods for probabilistic modeling of Gene Regulatory Networks.
In silico modeling of Gene Regulatory Networks (GRN) has recently aroused a lot of interest in the biological community for modeling and understanding complex pathways. Boolean Networks (BN) are a common modeling tool for in silico dynamic analysis of such pathways. Although they are known to have effectively modeled many real and complex regulatory networks, they are deterministic in nature and have shortcomings in modeling non-determinism that is inherent in biological systems. Probabilistic Boolean Networks (PBN) have been proposed to counter these shortcomings. The capabilities of PBNs have been so far under-utilised because of the lack of an efficient PBN toolbox. This work addresses some issues associated with traditional methods of PBN representation and proposes efficient algorithms to model gene regulatory networks using PBNs.


The influence of organic and conventional crop management, variety and year on the yield and flavonoid level in common buckwheat groats.
Common buckwheat (Fagopyrum esculentum Moench) is a pseudocereal that is cultivated for its achenes that possess a high level of flavonoids. Some scientific studies have found that the growing conditions can significantly affect the flavonoid content in conventional and organic food products. Hence, the present study compared conventionally and organically produced common buckwheat with respect to the content of selected flavonoids, thousand achenes weight and achene yield. Three buckwheat varieties were grown with organic and conventional crop management under the same environmental conditions. The thousand achenes weight and achene yield were not significantly influenced by way of crop management. The level of rutin, epicatechin, catechin, and epicatechin gallate in buckwheat groats (hulled achenes) were quantified with high pressure liquid chromatography. Only rutin and epicatechin gallate reached significantly higher level in organic groats. However, the differences were influenced by environmental conditions in the given year and variety.


Early outbreaks of 'epidemic neuromyasthenia'.
The literature of the outbreaks of 'epidemic neuromyasthenia' (ENM) from 1934 to 1955 has been selected to show that the disease affects other people besides young adult females in hospitals and nursing homes. There have been district epidemics, in which the male: female ratio was almost even and several male outbreaks affecting soldiers in barracks. Some outbreaks appear to have been triggered off by an epidemic of poliomyelitis, and the epidemiology of outbreaks in Iceland in 1948 and 1955 suggests that the normal cytopathological effects of poliomyelitis infection have been suppressed by the new disease. In the Durban epidemic (1955) a toxic metabolite was discovered in the urine of many patients and a markedly increased urinary excretion of creatine was noted in two New York State outbreaks. The results of the transmission of an agent from patients with ENM to monkeys suggest that the neurological disorder might be in the form of mild disseminated lesions scattered throughout the nervous system from the brain to peripheral nerves and associated with perivascular round cell infiltration without significant cellular damage. ENM infection was widespread in the North of England in 1955 and associated with lymphocyte abnormalities, which have persisted in some cases for several years. This suggests a continuous organic process.


Deletion of the amino acid transporter Slc6a14 suppresses tumour growth in spontaneous mouse models of breast cancer.
SLC6A14 mediates Na(+)/Cl(-)-coupled concentrative uptake of a broad-spectrum of amino acids. It is expressed at low levels in many tissues but up-regulated in certain cancers. Pharmacological blockade of SLC6A14 causes amino acid starvation in estrogen receptor positive (ER+) breast cancer cells and suppresses their proliferation in vitro and in vivo. In the present study, we interrogated the role of this transporter in breast cancer by deleting Slc6a14 in mice and monitoring the consequences of this deletion in models of spontaneous breast cancer (Polyoma middle T oncogene-transgenic mouse and mouse mammary tumour virus promoter-Neu-transgenic mouse). Slc6a14-knockout mice are viable, fertile and phenotypically normal. The plasma amino acids were similar in wild-type and knockout mice and there were no major compensatory changes in the expression of other amino acid transporter mRNAs. There was also no change in mammary gland development in the knockout mouse. However, when crossed with PyMT-Tg mice or MMTV/Neu (mouse mammary tumour virus promoter-Neu)-Tg mice, the development and progression of breast cancer were markedly decreased on Slc6a14(-/-) background. Analysis of transcriptomes in tumour tissues from wild-type mice and Slc6a14-null mice indicated no compensatory changes in the expression of any other amino acid transporter mRNA. However, the tumours from the null mice showed evidence of amino acid starvation, decreased mTOR signalling and decreased cell proliferation. These studies demonstrate that SLC6A14 is critical for the maintenance of amino acid nutrition and optimal mammalian target of rapamycin (mTOR) signalling in ER+ breast cancer and that the transporter is a potential target for development of a novel class of anti-cancer drugs targeting amino acid nutrition in tumour cells.


Interaction of Autographa californica multiple nucleopolyhedrovirus cathepsin protease progenitor (proV-CATH) with insect baculovirus chitinase as a mechanism for proV-CATH cellular retention.
The insect baculovirus chitinase (CHIA) and cathepsin protease (V-CATH) enzymes cause terminal host insect liquefaction, enhancing the dissemination of progeny virions away from the host cadavers. Regulated and delayed cellular release of these host tissue-degrading enzymes ensures that liquefaction starts only after optimal viral replication has occurred. Baculoviral CHIA remains intracellular due to its C-terminal KDEL endoplasmic reticulum (ER) retention motif. However, the mechanism for cellular retention of the inactive V-CATH progenitor (proV-CATH) has not yet been determined. Signal peptide cleavage occurs upon cotranslational ER import of the v-cath-expressed protein, and ER-resident CHIA is needed for the folding of proV-CATH. Although this implies that CHIA and proV-CATH bind each other in the ER, the putative CHIA-proV-CATH interaction has not been experimentally verified. We demonstrate that the amino-terminal 22 amino acids (aa) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) preproV-CATH are responsible for the entry of proV-CATH into the ER. Furthermore, the CHIA-green fluorescent protein (GFP) and proV-CATH-red fluorescent protein (RFP) fusion proteins colocalize in the ER. Using monomeric RFP (mRFP)-based bimolecular fluorescence complementation (BiFC), we determined that CHIA and proV-CATH interact directly with each other in the ER during virus replication. Moreover, reciprocal Ni/His pulldowns of His-tagged proteins confirmed the CHIA-proV-CATH interaction biochemically. The reciprocal copurification of CHIA and proV-CATH suggests a specific CHIA-proV-CATH interaction and corroborates our BiFC data. Deletion of the CHIA KDEL motif allowed for premature CHIA secretion from cells, and proV-CATH was similarly prematurely secreted from cells along with ΔKDEL-CHIA. These data suggest that CHIA and proV-CATH interact directly with each other and that this interaction aids the cellular retention of proV-CATH.


A routing path construction method for key dissemination messages in sensor networks.
Authentication is an important security mechanism for detecting forged messages in a sensor network. Each cluster head (CH) in dynamic key distribution schemes forwards a key dissemination message that contains encrypted authentication keys within its cluster to next-hop nodes for the purpose of authentication. The forwarding path of the key dissemination message strongly affects the number of nodes to which the authentication keys in the message are actually distributed. We propose a routing method for the key dissemination messages to increase the number of nodes that obtain the authentication keys. In the proposed method, each node selects next-hop nodes to which the key dissemination message will be forwarded based on secret key indexes, the distance to the sink node, and the energy consumption of its neighbor nodes. The experimental results show that the proposed method can increase by 50-70% the number of nodes to which authentication keys in each cluster are distributed compared to geographic and energy-aware routing (GEAR). In addition, the proposed method can detect false reports earlier by using the distributed authentication keys, and it consumes less energy than GEAR when the false traffic ratio (FTR) is ≥ 10%.


Optical resolution and the duality of light.
For 15 years, lensless microscopes have been constructed based on the use of holography, a digital CCD detector, and a computer for image reconstruction by use of, e.g., Fourier transformation. Thus, no lens is involved and therefore the conventional resolution limit of half the wavelength no longer applies. Instead of being limited by the wavelength, the resolution is in this case limited by how exact one can measure the phases of the light. It is remarkable that the interference-limited resolution is approximately 0.01 lambda, whereas the diffraction-limited resolution is only of the order of 0.5 lambda. It is my hope that by combining these two techniques it will be possible to increase the magnification in optical systems by at least an order of magnitude. The calculations also indicate that information does not necessarily decrease with distance.


Cerebellar motor learning deficits in medicated and medication-free men with recent-onset schizophrenia.
The notion that cerebellar deficits may underlie clinical symptoms in people with schizophrenia is tested by evaluating 2 forms of cerebellar learning in patients with recent-onset schizophrenia. A potential medication effect is evaluated by including patients with or without antipsychotics. We assessed saccadic eye movement adaptation and eyeblink conditioning in men with recent-onset schizophrenia who were taking antipsychotic medication or who were antipsychotic-free and in age-matched controls. We included 39 men with schizophrenia (10 who were taking clozapine, 16 who were taking haloperidol and 13 who were antipsychotic-free) and 29 controls in our study. All participants showed significant saccadic adaptation. Adaptation strength did not differ between healthy controls and men with schizophrenia. The speed of saccade adaptation, however, was significantly lower in men with schizophrenia. They showed a significantly lower increase in the number of conditioned eyeblink responses. Over all experiments, no consistent effects of medication were observed. These outcomes did not correlate with age, years of education, psychopathology or dose of antipsychotics. As patients were not randomized for treatment, an influence of confounding variables associated with medication status cannot be excluded. Individual patients also varied along the schizophrenia spectrum despite the relative homogeneity with respect to onset of illness and short usage of medication. Finally, the relatively small number of participants may have concealed effects as a result of insufficient statistical power. We found several cerebellar learning deficits in men with schizophrenia that we cannot attribute to the use of antipsychotics. Although this finding, combined with the fact that deficits are already present in patients with recent-onset schizophrenia, could suggest that cerebellar impairments are a trait deficit in people with schizophrenia. This should be confirmed in longitudinal studies.


Emissions from thaw ponds largely offset the carbon sink of northern permafrost wetlands.
Northern regions have received considerable attention not only because the effects of climate change are amplified at high latitudes but also because this region holds vast amounts of carbon (C) stored in permafrost. These carbon stocks are vulnerable to warming temperatures and increased permafrost thaw and the breakdown and release of soil C in the form of carbon dioxide (CO2) and methane (CH4). The majority of research has focused on quantifying and upscaling the effects of thaw on CO2 and CH4 emissions from terrestrial systems. However, small ponds formed in permafrost wetlands following thawing have been recognized as hotspots for C emissions. Here, we examined the importance of small ponds for C fluxes in two permafrost wetland ecosystems in northern Sweden. Detailed flux estimates of thaw ponds during the growing season show that ponds emit, on average (±SD), 279 ± 415 and 7 ± 11 mmol C m-2 d-1 of CO2 and CH4, respectively. Importantly, addition of pond emissions to the total C budget of the wetland decreases the C sink by ~39%. Our results emphasize the need for integrated research linking C cycling on land and in water in order to make correct assessments of contemporary C balances.


Initial experience and outcome of a new hemodialysis access device for catheter-dependent patients.
The effects of a new long-term subcutaneous vascular access device were studied in access-challenged patients who were poor candidates for fistulas or grafts due to venous obstruction. Bacteremia rates, patency, and function of the Hemodialysis Reliable Outflow (HeRO) Vascular Access Device (Hemosphere Inc, Minneapolis, Minn) were evaluated. The HeRO device consists of a 6-mm expanded polytetrafluoroethylene graft attached to a 5-mm nitinol-reinforced silicone outflow component designed to bypass venous stenoses and enter the internal jugular vein directly, providing continuous arterial blood flow into the right atrium. The HeRO device was studied in a multicenter clinical trial to test the hypothesis that access-challenged patients would experience a statistically significant reduction in bacteremia rates compared with a tunneled dialysis catheter (TDC) literature control of 2.3/1000 days. HeRO-related bacteremia rates, adequacy of dialysis, patency, and adverse events were analyzed. The HeRO device was implanted in 36 access-challenged patients who were followed for a mean 8.6 months (9931 HeRO days). The HeRO-related bacteremia rate was 0.70/1000 days. All HeRO-related bacteremias occurred during the bridging period when a TDC was still implanted before HeRO graft incorporation. HeRO adequacy of dialysis (mean Kt/V) was 1.7. HeRO primary patency was 38.9%, and secondary patency was 72.2%. In access-challenged patients, a statistically significant reduction in HeRO-related bacteremia was noted compared with TDC literature. The device had similar function and patency compared with conventional arteriovenous graft literature.


Unhealthy landscapes: Policy recommendations on land use change and infectious disease emergence.
Anthropogenic land use changes drive a range of infectious disease outbreaks and emergence events and modify the transmission of endemic infections. These drivers include agricultural encroachment, deforestation, road construction, dam building, irrigation, wetland modification, mining, the concentration or expansion of urban environments, coastal zone degradation, and other activities. These changes in turn cause a cascade of factors that exacerbate infectious disease emergence, such as forest fragmentation, disease introduction, pollution, poverty, and human migration. The Working Group on Land Use Change and Disease Emergence grew out of a special colloquium that convened international experts in infectious diseases, ecology, and environmental health to assess the current state of knowledge and to develop recommendations for addressing these environmental health challenges. The group established a systems model approach and priority lists of infectious diseases affected by ecologic degradation. Policy-relevant levels of the model include specific health risk factors, landscape or habitat change, and institutional (economic and behavioral) levels. The group recommended creating Centers of Excellence in Ecology and Health Research and Training, based at regional universities and/or research institutes with close links to the surrounding communities. The centers' objectives would be 3-fold: a) to provide information to local communities about the links between environmental change and public health; b) to facilitate fully interdisciplinary research from a variety of natural, social, and health sciences and train professionals who can conduct interdisciplinary research; and c) to engage in science-based communication and assessment for policy making toward sustainable health and ecosystems.


Wavelike statistics from pilot-wave dynamics in a circular corral.
Bouncing droplets can self-propel laterally along the surface of a vibrated fluid bath by virtue of a resonant interaction with their own wave field. The resulting walking droplets exhibit features reminiscent of microscopic quantum particles. Here we present the results of an experimental investigation of droplets walking in a circular corral. We demonstrate that a coherent wavelike statistical behavior emerges from the complex underlying dynamics and that the probability distribution is prescribed by the Faraday wave mode of the corral. The statistical behavior of the walking droplets is demonstrated to be analogous to that of electrons in quantum corrals.


The majority of yeast UPF1 co-localizes with polyribosomes in the cytoplasm.
In Saccharomyces cerevisiae the UPF1 protein is required for nonsense-mediated mRNA decay, the accelerated turnover of mRNAs containing a nonsense mutation. Several lines of evidence suggest that translation plays an important role in the mechanism of nonsense mRNA decay, including a previous report that nonsense mRNAs assemble in polyribosomes. In this study we show that UPF1 and ribosomal protein L1 co-localize in the cytoplasm and that UPF1 co-sediments with polyribosomes. To detect UPF1, three copies of the influenza hemagglutinin epitope were placed at the C-terminus. The tagged protein, UPF1-3EP, retains 86% (+/- 5%) of function. Using immunological detection, we found that UPF1-3EP is primarily cytoplasmic and was not detected either in the nucleus or in the mitochondrion. UPF1-3EP and L1 co-distributed with polyribosomes fractionated in a 7-47% sucrose gradient. The sucrose sedimentation profiles for UPF1-3EP and L1 exhibited similar changes using three different sets of conditions that altered the polyribosome profile. When polyribosomes were disaggregated, UPF1-3EP and L1 accumulated in fractions coincident with 80S ribosomal particles. These results suggest that UPF1-3EP associates with polyribosomes. L3 and S3 mRNAs, which code for ribosomal proteins of the 60S and 40S ribosomal subunits, respectively, were on average about 100-fold more abundant than UPF1 mRNA. Assuming that translation rates for L3, S3, and UPF1 mRNA are similar, this result suggests that there are far fewer UPF1 molecules than ribosomes per cell. Constraints imposed by the low UPF1 abundance on the functional relationships between UPF1, polyribosomes, and nonsense mRNA turnover are discussed.


Different genetic factors underlie fear conditioning and episodic memory.
Fear conditioning seems to account for the acquisition of post-traumatic stress disorder, whereas conscious recall of events in aftermath of trauma reflects episodic memory. Studies show that both fear conditioning and episodic memory are heritable, but no study has evaluated whether they reflect common or separate genetic factors. To this end, we studied episodic memory and fear conditioning in 173 healthy twin pairs using visual stimuli predicting unconditioned electric shocks. Fear conditioning acquisition and extinction was determined using conditioned visual stimuli predicting unconditioned mild electric shocks, whereas electrodermal activity served as the fear learning index. Episodic memory was evaluated using cued recall of pictorial stimuli unrelated to conditioning. We used multivariate structural equation modeling to jointly analyze memory performance and acquisition as well as extinction of fear conditioning. Best-fit twin models estimated moderate genetic loadings for conditioning and memory measures, with no genetic covariation between them. Individual differences in fear conditioning and episodic memory reflect distinct genetically influenced processes, suggesting that the genetic risk for learning-induced anxiety disorders includes at least two memory-related genetic factors. These findings are consistent with the facts that the two separate learning forms are distant in their evolutionary development, involve different brain mechanisms, and support that genetically independent memory systems are pivotal in the development and maintenance of syndromes related to fear learning.


Concepts of scientific integrative medicine applied to the physiology and pathophysiology of catecholamine systems.
This review presents concepts of scientific integrative medicine and relates them to the physiology of catecholamine systems and to the pathophysiology of catecholamine-related disorders. The applications to catecholamine systems exemplify how scientific integrative medicine links systems biology with integrative physiology. Concepts of scientific integrative medicine include (i) negative feedback regulation, maintaining stability of the body's monitored variables; (ii) homeostats, which compare information about monitored variables with algorithms for responding; (iii) multiple effectors, enabling compensatory activation of alternative effectors and primitive specificity of stress response patterns; (iv) effector sharing, accounting for interactions among homeostats and phenomena such as hyperglycemia attending gastrointestinal bleeding and hyponatremia attending congestive heart failure; (v) stress, applying a definition as a state rather than as an environmental stimulus or stereotyped response; (vi) distress, using a noncircular definition that does not presume pathology; (vii) allostasis, corresponding to adaptive plasticity of feedback-regulated systems; and (viii) allostatic load, explaining chronic degenerative diseases in terms of effects of cumulative wear and tear. From computer models one can predict mathematically the effects of stress and allostatic load on the transition from wellness to symptomatic disease. The review describes acute and chronic clinical disorders involving catecholamine systems-especially Parkinson disease-and how these concepts relate to pathophysiology, early detection, and treatment and prevention strategies in the post-genome era.


Femtosecond versus picosecond laser machining of nano-gratings and micro-channels in silica glass.
The ability of 8 picosecond pulse lasers for three dimensional direct-writing in the bulk of transparent dielectrics is assessed through a comparative study with a femtosecond laser delivering 600 fs pulses. The comparison addresses two main applications: the fabrication of birefringent optical elements and two-step machining by laser exposure and post-processing by chemical etching. Formation of self-organized nano-gratings in glass by ps-pulses is demonstrated. Differential etching between ps-laser exposed regions and unexposed silica is observed. Despite attaining values of retardance (>100 nm) and etching rate (2 μm/min) similar to fs pulses, ps pulses are found unsuitable for bulk machining in silica glass primarily due to the build-up of a stress field causing scattering, cracks and non-homogeneous etching. Additionally, we show that the so-called "quill-effect", that is the dependence of the laser damage from the direction of writing, occurs also for ps-pulse laser machining. Finally, an opposite dependence of the retardance from the intra-pulse distance is observed for fs- and ps-laser direct writing.


Single Nucleotide Polymorphism (SNP) in the Adiponectin Gene and Cardiovascular Disease.
Dear Editor, The recent article by Mohammadzadeh et al.[1] on the latest issue of this Journal showed that the T allele +276G/T SNP of ADIPOQ gene is more associated with the increasing risk of coronary artery disease (CAD) in subjects with type 2 diabetes. Adipocytes were described in myocardial tissue of CAD patients and their role recently discussed[2,3]. Susceptibility to CAD by polymorphism in the Q gene of adiponectin has been reported for 3'-UTR, which harbours some genetic loci associated with metabolic risks and atherosclerosis[4]. Actually, previous studies have shown that the haplotype SNP +276G>T was associated with a decreased risk of CAD, after adjustment for potential confounding factors, therefore some controversial opinion still exists[5]. This evidence should be associated with the role exerted by adipocytes and adiponectin in heart physiology. In particular, in hypertensive disorder complicating pregnancy (HDCP), by investigating the population frequency of alleles, genotypes, and haplotypes of two single nucleotide polymorphisms (SNPs), namely +45T>G (rs2241766) and +276G>T (rs1501299), some authors found that the SNP +276 TT genotype was significantly associated with protection against HDCP, when compared to the pooled G genotypes[6]. Moreover, the same +276G/T SNP haplotype was strongly associated with biliary atresia, an intractable neonatal inflammatory and obliterative cholangiopathy, leading to progressive fibrosis and cirrhosis[7]. CAD is closely related to adiponectin biology. The same isoforms of adiponectin seem to be not associated to CAD severity but to glucose metabolism and its impairment[8]. In the paper by Mohammadzadeh et al.[1], T allele in +276G/T SNP haplotype is highly associated with CAD in subjects with type 2 diabetes, but this linkage should be reappraised if related much more to diabetes rather than CAD. Association of T allele in the indicated SNP with CAD may be an indirect consequence of type 2 diabetes, as reported by others[9] or a direct marker for CAD affected patients[10]. The paper by Mohammadzadeh et al.[1] assesses data coming elsewhere from literature but raises important concerns about the suitability of ADIPOQ SNPs in diagnosing susceptibility to CAD and the relationship with plasma adiponectin level. In normal, non diabetic, normoglycemic subject, this relationship does not seem to work. Therefore the question is how much predictive this SNP haplotype may be to foresee metabolic syndrome and CAD onset risk in young health subjects? Maybe, the role of adiponectin in cardiovascular physiology depends on its ability to target adiponectin receptors and to negatively regulate obesity. Some authors reported in healthy volunteers an absence of correlation between circulating adiponectin levels and biochemical markers, particularly lipoproteins and suggested that SNP +276G>T was related to an independent effect on adiponectin levels and on lipoprotein metabolism[11]. On the contrary, adiponectin genetic variants and SNP +276G>T was associated with increasing susceptibility of type 2 diabetes and plasma glucose impairment[12]. The interesting study by Mohammadzadeh et al.[1] suggests that SNP of ADIPOQ +276G>T should be related to susceptibility to glucose metabolism, while indirectly to lipid metabolism and fat-related cardiovascular damage.


Sub-diffractional waveguiding by mid-infrared plasmonic resonators in semiconductor nanowires.
Chains of nanoscale plasmonic resonators are capable of sub-diffractional waveguiding and have applications in nanophotonics and thermal radiation transport. Practical uses have largely been limited, however, due to high optical losses or low group velocities. Here, we predict the waveguide performance of a material structure capable of overcoming these limitations: plasmonic resonators embedded in high-dielectric nanowires. Due to the enhanced near-field coupling between resonators, we find that the group velocities and propagation lengths for doped Si plasmonic resonators in intrinsic Si nanowires can be increased by up to an order of magnitude compared to the case of isotropic vacuum surroundings. We investigate the impact of resonator aspect ratio, doping, and spacing on waveguide performance, and we find that propagation lengths are maximized for large aspect ratios and high dopant concentrations at small spacings. To study these complex anisotropic systems, we develop a new analytical "absorption spectra" method to extract waveguide information from simple far-field absorption experiments (or simulations) of only two coupled resonators.


The protective effect of erdosteine against ototoxicity induced by cisplatin in rats.
The elimination of cisplatin ototoxicity is an ongoing concern. This experimental study was undertaken to investigate the effect of oral erdosteine in ameliorating cisplatin-induced ototoxicity. Twenty-eight adult female Wistar albino rats were randomly divided into four equal groups. Group A received an oral carrier vehicle of the drug erdosteine with 0.2 ml of 0.9% saline. Group B was administered only erdosteine (per oral 10 mg/kg twice a day) for 6 days. Group C was injected with cisplatin intraperitoneally (i.p.) on day 0 (16 mg/kg body weight), once only. Group D was given erdosteine (per oral 10 mg/kg/day) 1 day before and for 5 days consecutively after cisplatin injection (16 mg/kg, i.p.). Distortion product otoacoustic emissions (DPOAEs) were elicited in different frequency regions, ranging from 1,001 to 6,299 Hz as DPgram and input/output (I/O) functions from the control and experimental animals. All experimental animals were killed under general anesthesia on day 5, following the last otoacoustic emission measurements. Prior to death, blood samples were drawn for measurement of superoxide dismutase, xanthine oxidase (XO), malondialdehyde and nitric oxide. Initial DPgram and I/O function baseline measurements were similar in all groups prior to any drug administration ( P>0.05). On day 5, intra-subject measurement parameters of DPgrams and I/O functions in the cisplatin group showed significant deterioration ( P <0.05). The other groups revealed no differences between their pre- and post-test drug administration DPgrams and I/O functions at any test frequency ( P>0.05). Comparison of the amplitudes of DPgrams and I/O functions between the cisplatin and control groups showed significant changes ( P <0.05). Biochemical studies noted an increased XO activity following cisplatin administration ( P <0.007). The other biochemical results did not show significant differences between the study and control groups. This study demonstrates that, in rats, erdosteine is protective for cochlear function against the disruptive effects of cisplatin as measured by DPOAEs.


Crystal structure of a heparin- and integrin-binding segment of human fibronectin.
The crystal structure of human fibronectin (FN) type III repeats 12-14 reveals the primary heparin-binding site, a clump of positively charged residues in FN13, and a putative minor site approximately 60 A away in FN14. The IDAPS motif implicated in integrin alpha4beta1 binding is at the FN13-14 junction, rendering the critical Asp184 inaccessible to integrin. Asp184 clamps the BC loop of FN14, whose sequence (PRARI) is reminiscent of the synergy sequence (PHSRN) of FN9. Mutagenesis studies prompted by this observation reveal that both arginines of the PRARI sequence are important for alpha4beta1 binding to FN12-14. The PRARI motif may represent a new class of integrin-binding sites. The spatial organization of the binding sites suggests that heparin and integrin may bind in concert.


A Priori and a Posteriori Dietary Patterns during Pregnancy and Gestational Weight Gain: The Generation R Study.
Abnormal gestational weight gain (GWG) is associated with adverse pregnancy outcomes. We examined whether dietary patterns are associated with GWG. Participants included 3374 pregnant women from a population-based cohort in the Netherlands. Dietary intake during pregnancy was assessed with food-frequency questionnaires. Three a posteriori-derived dietary patterns were identified using principal component analysis: a "Vegetable, oil and fish", a "Nuts, high-fiber cereals and soy", and a "Margarine, sugar and snacks" pattern. The a priori-defined dietary pattern was based on national dietary recommendations. Weight was repeatedly measured around 13, 20 and 30 weeks of pregnancy; pre-pregnancy and maximum weight were self-reported. Normal weight women with high adherence to the "Vegetable, oil and fish" pattern had higher early-pregnancy GWG than those with low adherence (43 g/week (95% CI 16; 69) for highest vs. lowest quartile (Q)). Adherence to the "Margarine, sugar and snacks" pattern was associated with a higher prevalence of excessive GWG (OR 1.45 (95% CI 1.06; 1.99) Q4 vs. Q1). Normal weight women with higher scores on the "Nuts, high-fiber cereals and soy" pattern had more moderate GWG than women with lower scores (-0.01 (95% CI -0.02; -0.00) per SD). The a priori-defined pattern was not associated with GWG. To conclude, specific dietary patterns may play a role in early pregnancy but are not consistently associated with GWG.


Developing recommendations to improve the quality of diabetes care in Ireland: a policy analysis.
In 2006, the Health Service Executive (HSE) in Ireland established an Expert Advisory Group (EAG) for Diabetes, to act as its main source of operational policy and strategic advice for this chronic condition. The process was heralded as the starting point for the development of formal chronic disease management programmes. Although recommendations were published in 2008, implementation did not proceed as expected. Our aim was to examine the development of recommendations by the EAG as an instrumental case study of the policy formulation process, in the context of a health system undergoing organisational and financial upheaval. This study uses Kingdon's Multiple Streams Theory to examine the evolution of the EAG recommendations. Semi-structured interviews were conducted with a purposive sample of 15 stakeholders from the advisory group. Interview data were supplemented with documentary analysis of published and unpublished documents. Thematic analysis was guided by the propositions of the Kingdon model. In the problem stream, the prioritisation of diabetes within the policy arena was a gradual process resulting from an accumulation of evidence, international comparison, and experience. The policy stream was bolstered by group consensus rather than complete agreement on the best way to manage the condition. The EAG assumed the politics stream was also on course to converge with the other streams, as the group was established by the HSE, which had the remit for policy implementation. However, the politics stream did not converge due to waning support from health service management and changes to the organisational structure and financial capacity of the health system. These changes trumped the EAG process and the policy window remained closed, stalling implementation. Our results reflect the dynamic nature of the policy process and the importance of timing. The results highlight the limits of rational policy making in the face of organisational and fiscal upheaval. Diabetes care is coming on to the agenda again in Ireland under the National Clinical Care Programme. This may represent the opening of a new policy window for diabetes services, the challenge will be maintaining momentum and interest in the absence of dedicated resources.


Oncology drug health technology assessment recommendations: Canadian versus UK experiences.
CANADA HAS TWO HEALTH TECHNOLOGY ASSESSMENT (HTA) AGENCIES RESPONSIBLE FOR ONCOLOGY DRUG FUNDING RECOMMENDATIONS: the Institut National d'Excellence en Santé et Services Sociaux (INESSS) for the province of Québec and the pan-Canadian Oncology Drug Review for the rest of Canada. The objective of the research was to review and compare the recommendations of these two agencies alongside an international comparator - the National Institute for Health and Care Excellence (NICE) in the United Kingdom - with respect to their recommendations records and the influence of clinical and cost-effectiveness evidence on the recommendations. Recommendations were identified from the three agencies from January 1, 2002 to June 1, 2013. Recommendations were limited to five cancer sites (lung, breast, colon, kidney, blood) and to metastatic/advanced settings. Descriptive analyses examined the frequency of positive recommendations and factors related to a positive recommendation. For each recommendation, only publicly available information posted on the agency website was used to abstract data. There was a wide variation in the rate of positive recommendations, ranging from 48% for NICE to 95% for Canada's national process (among the 74% of its recommendations that were publicly posted). Interagency agreement was low, with full agreement for only six of the 14 drugs commonly reviewed by all three agencies. Evidence of a survival gain was not necessary for a positive recommendation; progression-free survival was acceptable. Different approaches were taken when addressing unacceptable cost-effectiveness. NICE was most likely to yield a negative recommendation on these grounds, whereas Canada's national process was most likely to yield a positive recommendation with a required pricing arrangement. In this analysis, the primary reason for the observed divergence between agency recommendations appeared to be the availability of mechanisms in each jurisdiction to address cost-effectiveness subsequent to the HTA assessment process. Furthermore, caution is needed when interpreting cross-agency comparisons between HTA agencies, as recommendations may not correspond directly to subsequent funding decisions and actual patient access. This may be a concern, given the high international profile of assessments conducted by the reviewed HTA agencies.


Global health and transfusion medicine: education and training in developing countries.
Education and training in transfusion medicine have improved over the past decade in developing countries but are still generally deficient for the purpose of maintaining the safety of the global blood supply. In 2009, the World Health Organization global database on blood safety indicated that only 72% of countries in the world were able to meet their training needs necessary for maintaining the safety of their local blood supply. Educational approaches in transfusion medicine vary widely between continents and world regions. In this article, we summarize a session on global health education and training in developing countries that took place at the 2012 AABB conference. The panel consisted of transfusion representatives from South America (Brazil), Asia (China), Africa (South Africa), and the Caribbean (Curaçao), as well as a description of capacitation issues in postearthquake Haiti and the pivotal role of the US President's Emergency Plan for AIDS Relief (PEPFAR) in transfusion training and education in Africa. We present here summaries of each of these panel presentations.


Control of oskar mRNA translation by Bruno in a novel cell-free system from Drosophila ovaries.
The coupled regulation of oskar mRNA localization and translation in time and space is critical for correct anteroposterior patterning of the Drosophila embryo. Localization-dependent translation of oskar mRNA, a mechanism whereby oskar RNA localized at the posterior of the oocyte is selectively translated and the unlocalized RNA remains in a translationally repressed state, ensures that Oskar activity is present exclusively at the posterior pole. Genetic experiments indicate that translational repression involves the binding of Bruno protein to multiple sites, the Bruno Response Elements (BRE), in the 3' untranslated region (UTR) of oskar mRNA. We have established a cell-free translation system derived from Drosophila ovaries, which faithfully reproduces critical features of mRNA translation in vivo, namely cap structure and poly(A) tail dependence. We show that this ovary extract, containing endogenous Bruno, is able to recapitulate oskar mRNA regulation in a BRE-dependent way. Thus, the assembly of a ribonucleoprotein (RNP) complex leading to the translationally repressed state occurs in vitro. Moreover, we show that a Drosophila embryo extract lacking Bruno efficiently translates oskar mRNA. Addition of recombinant Bruno to this extract establishes the repressed state in a BRE-dependent manner, providing a direct biochemical demonstration of the critical role of Bruno in oskar mRNA translation. The approach that we describe opens new avenues to investigate translational regulation in Drosophila oogenesis at a biochemical level.


Thoracic duct lymph flow during head-out water immersion in conscious dogs.
Water immersion (WI) increases plasma volume in awake dogs. The contribution of lymph flow to this fluid shift was studied in six splenectomized conscious dogs with a side fistula of the thoracic duct. Lymph flow, hematocrit (Hct), and plasma (CP) and lymph (CL) protein concentration were measured during 60 min in air and 120 min of WI (37 degrees C). Lymph flow in air averaged 0.96 +/- 1.0 (SE) ml/min. Lymph flow tended to decrease immediately in WI and was maintained at a level averaging 0.66 ml/min. CP/CL did not change significantly, whereas Hct fell significantly by 1.51 +/- 0.2% (Hct units) at 40 min of WI. Urine flow increased significantly to a maximum value of 1.5 +/- 0.5 ml/min at 40-60 min of WI compared with a mean value in air of 0.3 +/- 0.1 ml/min. The Hct and urine flow responses indicate that fluid shifted into the intravascular space during WI. Since lymph flow tended to decrease, the fluid shift in WI occurs across the capillary wall and not via lymphatic channels.


First-in-man implantation of leadless ultrasound-based cardiac stimulation pacing system: novel endocardial left ventricular resynchronization therapy in heart failure patients.
The importance of specific-site pacing is increasingly recognized in cardiac resynchronization therapy (CRT). Using current pacing technology, site selection is still largely limited by coronary vein anatomy, whereas left ventricular (LV) endocardial pacing using current lead technology is risky and challenging. To overcome limitations and complications with current LV pacing, the feasibility of a new technology enabling LV endocardial stimulation without the use of a lead is being evaluated in patients. Patients presented in this report are part of the Wireless Stimulation Endocardially for CRT Trial (WiSE-CRT) study investigating the safety and performance of the WiCS(®)-LV system, an implantable cardiac pacing system capable of leadless pacing based on converting ultrasound energy to electrical energy. Three patients are presented: (i) a patient with an existing implantable defibrillator, (ii) a patient with a CRT system whose LV lead does not capture, and (iii) a CRT patient classified as a non-responder. All three patients were successfully treated. Acute electrical pacing thresholds ranged from 0.7 to 1.0 V at 0.5 ms; all patients retained captured at 6 months. Functional New York Heart Association class significantly changed (Pre: III in two patients, and IV in one patient; Post: I in one patient, II in one patient, and II-III in one patient), and LV ejection fraction increased from 23.7 ± 3.4% to 39 ± 6.2% (P < 0.017). This report on three first-in-man cases shows that leadless endocardial pacing may be safely applied and effective, conferring short- to-mid-term symptomatic benefits. These promising findings are yet to be substantiated by larger ongoing studies. http://clinicaltrials.gov/ct2/show/NCT01294527.


Speckle reduction in line-scan laser projectors using binary phase codes.
A Barker binary phase code of maximum length 13 has previously been used for speckle reduction in line-scan laser projectors, and a speckle contrast factor decrease down to 13% has been achieved. In this Letter, Barker-like binary phase codes of lengths longer than 13 are used at an intermediate image plane. It is shown by theoretical calculation that a much better speckle reduction with a speckle contrast factor up to 6% can be achieved by using longer binary phase codes other than the Barker code.


Therapeutic potential of adult progenitor cells in cardiovascular disease.
Cardiovascular diseases are responsible for high morbidity/mortality rates worldwide. Advances in patient care have significantly reduced deaths from acute myocardial infarction. However, the cardiac remodeling processes induced after ischaemia are responsible for a worsening in the heart condition, which in many cases ends up in failure. In the last decade, a novel therapy based on stem cell transplantation is being intensively studied in animal models and some stem cell types (i.e., skeletal myoblasts and bone marrow-derived cells) are already being tested in clinical trials. A novel stem cell population isolated from the bone marrow, termed multipotent adult progenitor cells was characterised a few years ago by its ability to differentiate, at the single cell level, towards cells derived from the three embryonic germ layers. Later on, other pluripotent cell populations have been also derived from the bone marrow. In this overview, the authors outline different stem cell sources that have been tested for their cardiovascular potential and put the regenerative potential of multipotent adult progenitor cells in animal models of acute and chronic myocardial infarction into perspective.


Systems approaches evaluating the perturbation of xenobiotic metabolism in response to cigarette smoke exposure in nasal and bronchial tissues.
Capturing the effects of exposure in a specific target organ is a major challenge in risk assessment. Exposure to cigarette smoke (CS) implicates the field of tissue injury in the lung as well as nasal and airway epithelia. Xenobiotic metabolism in particular becomes an attractive tool for chemical risk assessment because of its responsiveness against toxic compounds, including those present in CS. This study describes an efficient integration from transcriptomic data to quantitative measures, which reflect the responses against xenobiotics that are captured in a biological network model. We show here that our novel systems approach can quantify the perturbation in the network model of xenobiotic metabolism. We further show that this approach efficiently compares the perturbation upon CS exposure in bronchial and nasal epithelial cells in vivo samples obtained from smokers. Our observation suggests the xenobiotic responses in the bronchial and nasal epithelial cells of smokers were similar to those observed in their respective organotypic models exposed to CS. Furthermore, the results suggest that nasal tissue is a reliable surrogate to measure xenobiotic responses in bronchial tissue.


Stem Cells and Regenerative Medicine: Myth or Reality of the 21th Century.
Since the 1960s and the therapeutic use of hematopoietic stem cells of bone marrow origin, there has been an increasing interest in the study of undifferentiated progenitors that have the ability to proliferate and differentiate into various tissues. Stem cells (SC) with different potency can be isolated and characterised. Despite the promise of embryonic stem cells, in many cases, adult or even fetal stem cells provide a more interesting approach for clinical applications. It is undeniable that mesenchymal stem cells (MSC) from bone marrow, adipose tissue, or Wharton's Jelly are of potential interest for clinical applications in regenerative medicine because they are easily available without ethical problems for their uses. During the last 10 years, these multipotent cells have generated considerable interest and have particularly been shown to escape to allogeneic immune response and be capable of immunomodulatory activity. These properties may be of a great interest for regenerative medicine. Different clinical applications are under study (cardiac insufficiency, atherosclerosis, stroke, bone and cartilage deterioration, diabetes, urology, liver, ophthalmology, and organ's reconstruction). This review focuses mainly on tissue and organ regeneration using SC and in particular MSC.


Improving survival rates after civilian gunshot wounds to the brain.
Gunshot wounds to the brain are the most lethal of all firearm injuries, with reported survival rates of 10% to 15%. The aim of this study was to determine outcomes in patients with gunshot wounds to the brain, presenting to our institution over time. We hypothesized that aggressive management can increase survival and the rate of organ donation in patients with gunshot wounds to the brain. We analyzed all patients with gunshot wounds to the brain presenting to our level 1 trauma center over a 5-year period. Aggressive management was defined as resuscitation with blood products, hyperosmolar therapy, and/or prothrombin complex concentrate (PCC). The primary outcome was survival and the secondary outcome was organ donation. There were 132 patients with gunshot wounds to the brain, and the survival rates increased incrementally every year, from 10% in 2008 to 46% in 2011, with the adoption of aggressive management. Among survivors, 40% (16 of 40) of the patients had bi-hemispheric injuries. Aggressive management with blood products (p = 0.02) and hyperosmolar therapy (p = 0.01) was independently associated with survival. Of the survivors, 20% had a Glasgow Coma Scale score ≥ 13 at hospital discharge. In patients who died (n = 92), 56% patients were eligible for organ donation, and they donated 60 organs. Aggressive management is associated with significant improvement in survival and organ procurement in patients with gunshot wounds to the brain. The bias of resource use can no longer be used to preclude trauma surgeons from abandoning aggressive attempts to save patients with gunshot wound to the brain.


Electrically-evoked Neural Activities of rd1 Mice Retinal Ganglion Cells by Repetitive Pulse Stimulation.
For successful visual perception by visual prosthesis using electrical stimulation, it is essential to develop an effective stimulation strategy based on understanding of retinal ganglion cell (RGC) responses to electrical stimulation. We studied RGC responses to repetitive electrical stimulation pulses to develop a stimulation strategy using stimulation pulse frequency modulation. Retinal patches of photoreceptor-degenerated retinas from rd1 mice were attached to a planar multi-electrode array (MEA) and RGC spike trains responding to electrical stimulation pulse trains with various pulse frequencies were observed. RGC responses were strongly dependent on inter-pulse interval when it was varied from 500 to 10 ms. Although the evoked spikes were suppressed with increasing pulse rate, the number of evoked spikes were >60% of the maximal responses when the inter-pulse intervals exceeded 100 ms. Based on this, we investigated the modulation of evoked RGC firing rates while increasing the pulse frequency from 1 to 10 pulses per second (or Hz) to deduce the optimal pulse frequency range for modulation of RGC response strength. RGC response strength monotonically and linearly increased within the stimulation frequency of 1~9 Hz. The results suggest that the evoked neural activities of RGCs in degenerated retina can be reliably controlled by pulse frequency modulation, and may be used as a stimulation strategy for visual neural prosthesis.


Glial origin of mesenchymal stem cells in a tooth model system.
Mesenchymal stem cells occupy niches in stromal tissues where they provide sources of cells for specialized mesenchymal derivatives during growth and repair. The origins of mesenchymal stem cells have been the subject of considerable discussion, and current consensus holds that perivascular cells form mesenchymal stem cells in most tissues. The continuously growing mouse incisor tooth offers an excellent model to address the origin of mesenchymal stem cells. These stem cells dwell in a niche at the tooth apex where they produce a variety of differentiated derivatives. Cells constituting the tooth are mostly derived from two embryonic sources: neural crest ectomesenchyme and ectodermal epithelium. It has been thought for decades that the dental mesenchymal stem cells giving rise to pulp cells and odontoblasts derive from neural crest cells after their migration in the early head and formation of ectomesenchymal tissue. Here we show that a significant population of mesenchymal stem cells during development, self-renewal and repair of a tooth are derived from peripheral nerve-associated glia. Glial cells generate multipotent mesenchymal stem cells that produce pulp cells and odontoblasts. By combining a clonal colour-coding technique with tracing of peripheral glia, we provide new insights into the dynamics of tooth organogenesis and growth.


Changes In US spending on Mental Health And Substance Abuse Treatment, 1986-2005, and implications for policy.
The United States invests a sizable amount of money on treatments for mental health and substance abuse: $135 billion in 2005, or 1.07 percent of the gross domestic product. We provide treatment spending estimates from the period 1986-2005 to build understanding of past trends and consider future possibilities. We find that the growth rate in spending on mental health medications-a major driver of mental health expenditures in prior years-declined dramatically. As a result, mental health and substance abuse spending grew at a slightly slower rate than gross domestic product in 2004 and 2005, and it continued to shrink as a share of all health spending. Of note, we also find that Medicaid's share of total spending on mental health grew from 17 percent in 1986 to 27 percent in 2002 to 28 percent in 2005. The recent recession, the full implementation of federal parity law, and such health reform-related actions as the planned expansion of Medicaid all have the potential to improve access to mental health and substance abuse treatment and to alter spending patterns further. Our spending estimates provide an important context for evaluating the effect of those policies.


Medical concept representation: the years beyond 2000.
This work aims at understanding the state of the art in the broad contextual research area of "medical concept representation". Our data support the general understanding that the focus of research has moved toward medical ontologies, which we interpret as a paradigm shift. Both the opinion of socially active groups of researchers and changes in bibliometric data since 1988 support this opinion. Socially active researchers mention the OBO foundry, SNOMED CT, and the UMLS as anchor activities.


IgG autoantibody to brain beta tubulin III associated with cytokine cluster-II discriminate cerebral malaria in central India.
The main processes in the pathogenesis of cerebral malaria caused by Plasmodium falciparum involved sequestration of parasitized red blood cells and immunopathological responses. Among immune factors, IgG autoantibodies to brain antigens are increased in P. falciparum infected patients and correlate with disease severity in African children. Nevertheless, their role in the pathophysiology of cerebral malaria (CM) is not fully defined. We extended our analysis to an Indian population with genetic backgrounds and endemic and environmental status different from Africa to determine if these autoantibodies could be either a biomarker or a risk factor of developing CM. We investigated the significance of these self-reactive antibodies in clinically well-defined groups of P. falciparum infected patients manifesting mild malaria (MM), severe non-cerebral malaria (SM), or cerebral malaria (CM) and in control subjects from Gondia, a malaria epidemic site in central India using quantitative immunoprinting and multivariate statistical analyses. A two-fold complete-linkage hierarchical clustering allows classifying the different patient groups and to distinguish the CM from the others on the basis of their profile of IgG reactivity to brain proteins defined by PANAMA Blot. We identified beta tubulin III (TBB3) as a novel discriminant brain antigen in the prevalence of CM. In addition, circulating IgG from CM patients highly react with recombinant TBB3. Overall, correspondence analyses based on singular value decomposition show a strong correlation between IgG anti-TBB3 and elevated concentration of cluster-II cytokine (IFNgamma, IL1beta, TNFalpha, TGFbeta) previously demonstrated to be a predictor of CM in the same population. Collectively, these findings validate the relationship between antibody response to brain induced by P. falciparum infection and plasma cytokine patterns with clinical outcome of malaria. They also provide significant insight into the immune mechanisms associated to CM by the identification of TBB3 as a new disease-specific marker and potential therapeutic target.


Family Carers of People with Young-Onset Dementia: Their Experiences with the Supporter Service.
Family carers and people with young-onset dementia (YOD) require tailored assistance as dementia progresses. A variety of health care services is needed, including supporter services. To our knowledge, research focusing on experiences with the supporter service is scarce. To evaluate the supporter service by examining how primary family carers experience the assistance provided. Qualitative interviews with 16 primary family carers of people with YOD were performed from 2014 to 2015. Content analysis was used to analyze the data. Three main themes emerged from the interviews. First, a good match focused on the carers' experiences of the relationship between the supporter and the person with YOD and included three subthemes: a nice, empathetic personality, a friendship-like relationship, and the content of the meetings. The second theme, relief, addressed the carers' experiences with the service. The third, coordination, concerned the carers' relationship with the health care service. Developing tailored services and assistance initiatives is important. A well-organized supporter service is a valuable supplement to formal programs and should be developed as part of an overall support package.


Vital sign documentation in electronic records: The development of workarounds.
Workarounds are commonplace in healthcare settings. An increase in the use of electronic health records has led to an escalation of workarounds as healthcare professionals cope with systems which are inadequate for their needs. Closely related to this, the documentation of vital signs in electronic health records has been problematic. The accuracy and completeness of vital sign documentation has a direct impact on the recognition of deterioration in a patient's condition. We examined workflow processes to identify workarounds related to vital signs in a 372-bed hospital in Sweden. In three clinical areas, a qualitative study was performed with data collected during observations and interviews and analysed through thematic content analysis. We identified paper workarounds in the form of handwritten notes and a total of eight pre-printed paper observation charts. Our results suggested that nurses created workarounds to allow a smooth workflow and ensure patients safety.


A Pilot Study of a Chronic Pain Self-Management Program Delivered by Community Health Workers to Underserved African American Older Adults.
African American older adults living in disadvantaged communities are disproportionately burdened by disabling pain. To address their needs, we tested the feasibility and potential effects of a cognitive-behavioral chronic pain self-management program delivered by community health workers. A single-group, pre-post evaluation of the STEPS-2 (Seniors using Technology to Engage in Pain Self-management) intervention, in which participants learned pain-management skills through web-based videos. They were also given wearable activity trackers to facilitate incremental increases in walking. In weekly telephone calls, community health workers helped participants apply skills and set goals. Thirty-one adults in Detroit, Michigan (97% African American, 97% female, mean 68.7 years), with chronic musculoskeletal pain. Participants completed telephone surveys at baseline and eight weeks. We measured changes in PROMIS pain interference and pain intensity, as well as Patient Global Impression of Change in pain and functioning. Feasibility indicators included participant engagement and satisfaction, and fidelity to session protocols by community health workers. Participants on average completed 6.6/7 sessions, and 100% agreed or strongly agreed that they improved their understanding of pain management. Average community health worker fidelity score was 1.79 (0 to 2 scale). Pain interference decreased from baseline to post-program (T-score 61.6 to 57.3, P=.000), as did pain intensity (0 to 10 scale, 6.3 to 5.1, P=.004). Approximately 90% of participants reported that pain and function were at least "a little better" since baseline. An intervention combining mobile health tools with support from community health workers holds promise for improving pain outcomes among underserved older adults.


Speed, dissipation, and error in kinetic proofreading.
Proofreading mechanisms increase specificity in biochemical reactions by allowing for the dissociation of intermediate complexes. These mechanisms disrupt and reset the reaction to undo errors at the cost of increased time of reaction and free energy expenditure. Here, we draw an analogy between proofreading and microtubule growth which share some of the features described above. Our analogy relates the statistics of growth and shrinkage of microtubules in physical space to the cycling of intermediate complexes in the space of chemical states in proofreading mechanisms. Using this analogy, we find a new kinetic regime of proofreading in which an exponential speed-up of the process can be achieved at the cost of a somewhat larger error rate. This regime is analogous to the transition region between two known growth regimes of microtubules (bounded and unbounded) and is sharply defined in the limit of large proofreading networks. We find that this advantageous regime of speed-error tradeoff might be present in proofreading schemes studied earlier in the charging of tRNA by tRNA synthetases, in RecA filament assembly on ssDNA, and in protein synthesis by ribosomes.


Reproductive phenotype predicts adult bite-force performance in sex-reversed dragons (Pogona vitticeps).
Sex-related differences in morphology and behavior are well documented, but the relative contributions of genes and environment to these traits are less well understood. Species that undergo sex reversal, such as the central bearded dragon (Pogona vitticeps), offer an opportunity to better understand sexually dimorphic traits because sexual phenotypes can exist on different chromosomal backgrounds. Reproductively female dragons with a discordant sex chromosome complement (sex reversed), at least as juveniles, exhibit traits in common with males (e.g., longer tails and greater boldness). However, the impact of sex reversal on sexually dimorphic traits in adult dragons is unknown. Here, we investigate the effect of sex reversal on bite-force performance, which may be important in resource acquisition (e.g., mates and/or food). We measured body size, head size, and bite force of the three sexual phenotypes in a colony of captive animals. Among adults, we found that males (ZZm) bite more forcefully than either chromosomally concordant females (ZWf) or sex-reversed females (ZZf), and this difference is associated with having relatively larger head dimensions. Therefore, adult sex-reversed females, despite apparently exhibiting male traits as juveniles, do not develop the larger head and enhanced bite force of adult male bearded dragons. This pattern is further illustrated in the full sample by a lack of positive allometry of bite force in sex-reversed females that is observed in males. The results reveal a close association between reproductive phenotype and bite force performance, regardless of sex chromosome complement.


Substance-abusing schizophrenics: do they self-medicate?
In spite of having been formulated nearly two decades back, there is as yet no consensus on the validity of the clinically popular self-medication hypothesis (SMH) of substance use disorders in patients with dual diagnosis. SMH broadly proposes that patients use substances in a non-random fashion so that the psychopharmacologic characteristics of particular substances are used to alleviate a variety of psychiatric symptoms and emotional distress. In order to test the SMH empirically, it was broken down to five sub-hypotheses, which were tested in a group of dual-diagnosis schizophrenia (DDS) patients vis-à-vis a group of only-schizophrenia (S) patients (n = 22 each). The DDS group scored lower than the S group regarding general and some specific psychopathology. The DDS patients ascribed reasons for substance use more often for hedonistic pursuit but also for reduction in symptoms and distress. There was a trend for alcohol to be used more for self-medication purposes compared to opioids and cannabis. The perceived effects of these three substances were significantly different on several symptom/distress dimensions. Finally, there was some degree of "match" between symptom-oriented reasons for use of substances and the effect that was perceived. All of this evidence provides a consistent but modest support for the SMH for "some patients, some substances, and some symptoms." The implications are discussed.


Haemostatic alterations in a group of canine cancer patients are associated with cancer type and disease progression.
Haemostatic alterations are commonly detected in human and canine cancer patients. Previous studies have described haemostatic dysfunction in canine patients with haemangiosarcomas and carcinomas, and haemostasis has been assessed in dogs with various malignant and benign neoplasias. Few studies have addressed the effect of cancer type and progression of disease on the presence of haemostatic alterations in canine patients. The objective of the present study was to evaluate haemostatic variables of coagulation and fibrinolysis in a group of canine cancer patients, and to compare haemostatic changes to the cancer type and progression of disease. The study population consisted of 71 dogs with malignant neoplasia presented to the University Hospital for Companion Animals, Faculty of Life Sciences, University of Copenhagen, Denmark. The study was designed as a prospective observational study evaluating the haemostatic function in canine cancer patients stratified according to type of cancer disease and disease progression. The coagulation response was evaluated by thromboelastrography (TEG), platelet count, activated partial thromboplastin time (aPTT), prothombin time (PT), fibrinogen and antithrombin (AT); and fibrinolysis by d-dimer and plasminogen. Hypercoagulability was the most common haemostatic dysfunction found. Non mammary carcinomas had increased clot strength (TEG G), aPTT and fibrinogen compared to the other groups. When stratifying the patients according to disease progression dogs with distant metastatic disease exhibited significantly increased fibrinogen, and d-dimer compared to dogs with local invasive and local non-invasive cancers. Hypercoagulability was confirmed as the most common haemostatic abnormality in canine cancer patients and haemostatic dysfunction in canine cancer patients was found related to the cancer type and progression of disease. Increase in TEG G, aPTT and fibrinogen were observed in non-mammary carcinomas and were speculated to overall represent a proinflammatory response associated with the disease. Dogs with distant metastatic disease exhibited increased fibrinogen and d-dimer. Future studies are needed to elucidate the clinical importance of these results.


Mortality and morbidity of VLBW infants with trisomy 13 or trisomy 18.
Little is known about how very low birth weight (VLBW) affects survival and morbidities among infants with trisomy 13 (T13) or trisomy 18 (T18). We examined the care plans for VLBW infants with T13 or T18 and compared their risks of mortality and neonatal morbidities with VLBW infants with trisomy 21 and VLBW infants without birth defects. Infants with birth weight 401 to 1500 g born or cared for at a participating center of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network during the period 1994-2009 were studied. Poisson regression models were used to examine risk of death and neonatal morbidities among infants with T13 or T18. Of 52,262 VLBW infants, 38 (0.07%) had T13 and 128 (0.24%) had T18. Intensity of care in the delivery room varied depending on whether the trisomy was diagnosed before or after birth. The plan for subsequent care for the majority of the infants was to withdraw care or to provide comfort care. Eleven percent of infants with T13 and 9% of infants with T18 survived to hospital discharge. Survivors with T13 or T18 had significantly increased risk of patent ductus arteriosus and respiratory distress syndrome compared with infants without birth defects. No infant with T13 or T18 developed necrotizing enterocolitis. In this cohort of liveborn VLBW infants with T13 or T18, the timing of trisomy diagnosis affected the plan for care, survival was poor, and death usually occurred early.


Visceral leishmaniasis relapse in Southern Sudan (1999-2007): a retrospective study of risk factors and trends.
Risk factors associated with L. donovani visceral leishmaniasis (VL; kala azar) relapse are poorly characterized. We investigated patient characteristics and drug regimens associated with VL relapse using data from Médecins Sans Frontières - Holland (MSF) treatment centres in Southern Sudan. We used MSF operational data to investigate trends in VL relapse and associated risk factors. We obtained data for 8,800 primary VL and 621 relapse VL patients treated between 1999 and 2007. Records of previous treatment for 166 VL relapse patients (26.7%) were compared with 7,924 primary VL patients who had no record of subsequent relapse. Primary VL patients who relapsed had larger spleens on admission (Hackett grade >or=3 vs 0, odds ratio (OR) for relapse = 3.62 (95% CI 1.08, 12.12)) and on discharge (Hackett grade >or=3 vs 0, OR = 5.50 (1.84, 16.49)). Age, sex, malnutrition, mobility, and complications of treatment were not associated with risk of relapse, nor was there any trend over time. Treatment with 17-day sodium stibogluconate/paromomycin (SSG/PM) combination therapy vs 30-day SSG monotherapy was associated with increased risk of relapse (OR = 2.08 (1.21, 3.58)) but reduced risk of death (OR = 0.27 (0.20, 0.37)), although these estimates are likely to be residually confounded. MSF operational data showed a crude upward trend in the proportion of VL relapse patients (annual percentage change (APC) = 11.4% (-3.4%, 28.5%)) and a downward trend in deaths (APC = -18.1% (-22.5%, -13.4%)). Splenomegaly and 17-day SSG/PM vs 30-day SSG were associated with increased risk of VL relapse. The crude upward trend in VL relapses in Southern Sudan may be attributable to improved access to treatment and reduced mortality due to SSG/PM combination therapy.


What do cranial bones of LB1 tell us about Homo floresiensis?
Cranial vault thickness (CVT) of Liang Bua 1, the specimen that is proposed to be the holotype of Homo floresiensis, has not yet been described in detail and compared with samples of fossil hominins, anatomically modern humans or microcephalic skulls. In addition, a complete description from a forensic and pathological point of view has not yet been carried out. It is important to evaluate scientifically if features related to CVT bring new information concerning the possible pathological status of LB1, and if it helps to recognize affinities with any hominin species and particularly if the specimen could belong to the species Homo sapiens. Medical examination of the skull based on a micro-CT examination clearly brings to light the presence of a sincipital T (a non-metrical variant of normal anatomy), a scar from an old frontal trauma without any evident functional consequence, and a severe bilateral hyperostosis frontalis interna that may have modified the anterior morphology of the endocranium of LB1. We also show that LB1 displays characteristics, related to the distribution of bone thickness and arrangements of cranial structures, that are plesiomorphic traits for hominins, at least for Homo erectus s.l. relative to Homo neanderthalensis and H. sapiens. All the microcephalic skulls analyzed here share the derived condition of anatomically modern H. sapiens. Cranial vault thickness does not help to clarify the definition of the species H. floresiensis but it also does not support an attribution of LB1 to H. sapiens. We conclude that there is no support for the attribution of LB1 to H. sapiens as there is no evidence of systemic pathology and because it does not have any of the apomorphic traits of our species.


Exploring the role of consumer participation in drug treatment.
Despite recognition of the benefits of involving consumers in their own treatment, there is little research on consumer participation in drug treatment. This paper focuses on clients who use illicit substances and the role of consumer participation in their self-reported satisfaction with their drug treatment and sense of goal achievement in that treatment. As part of a secondary analysis, the data from 492 participants who had previously or who were currently engaged in drug treatment were analysed to assess the importance of consumer participation in drug treatment. Participants who had a history of opiate or psychostimulant use were recruited at various treatment services and health care facilities for drug users located in five urban and rural/regional sites in Australia. They were asked to complete an interviewer-assisted questionnaire assessing a range of variables including five questions about consumer participation. Findings from this study illustrate that clients' opportunity to participate in drug treatment is independently associated with greater satisfaction with drug treatment and a greater sense of achievement of treatment goals. This research provides evidence to support the importance of consumer activity in drug treatment and should encourage drug treatment programs to afford clients appropriate levels of consumer participation.


Prevalence of mitral valve prolapse in ethnic groups.
Mitral valve prolapse (MVP) was reported to be a common disorder occurring in 5% to 15% of the general population and to be frequently associated with serious complications. The reported high prevalence and complication rates of MVP have been challenged recently by the findings of the Framingham Heart Study, which was conducted in a Caucasian population; the findings in other ethnic groups remain uncertain. The prevalence of MVP was studied in a true population sample comprising 972 Canadians of South Asian (n=336), European (n=322) and Chinese (n=314) descent. MVP was diagnosed by two-dimensional echocardiography. The prevalence of MVP for the entire study cohort was 2.7% and did not differ significantly between the three ethnic groups evaluated (2.7% in South Asian, 3.1% in European and 2.2% in Chinese [P=0.79]). Age, sex, history of cardiac risk factors, blood pressure, abnormalities on electrocardiography, left atrial size, left ventricular end-diastolic and end-systolic diameters and volumes, and left ventricular ejection fraction were similar in subjects with and without MVP. There was a trend toward lower body mass index in subjects with MVP compared to those without MVP (24.5+/-5.5 kg/m(2) versus 26.0+/-4.3 kg/m(2), respectively, P=0.10). The prevalence of cardiovascular diseases, including history of angina, previous myocardial infarction, previous cardiac surgery and previous stroke, was similar in subjects with MVP (7.7%) and in those without MVP (6.7%) (P=0.84). The authors concluded that MVP has a much lower prevalence than previously estimated and the prevalence of MVP is similar among different ethnic groups. From a population perspective, the prevalence of serious cardiovascular complications associated with MVP is low.


Establishment and controlled differentiation of neural crest stem cell lines using conditional transgenesis.
Murine neural crest stem cells (NCSCs) are a multipotent transient population of stem cells. After being formed during early embryogenesis as a consequence of neurulation at the apical neural fold, the cells rapidly disperse throughout the embryo, migrating along specific pathways and differentiating into a wide variety of cell types. In vitro the multipotency is lost rapidly, making it difficult to study differentiation potential as well as cell fate decisions. Using a transgenic mouse line, allowing for spatio-temporal control of the transforming c-myc oncogene, we derived a cell line (JoMa1), which expressed NCSC markers in a transgene-activity dependent manner. JoMa1 cells express early NCSC markers and can be instructed to differentiate into neurons, glia, smooth muscle cells, melanocytes, and also chondrocytes. A cell-line, clonally derived from JoMa1 culture, termed JoMa1.3 showed identical behavior and was studied in more detail. This system therefore represents a powerful tool to study NCSC biology and signaling pathways. We observed that when proliferative and differentiation stimuli were given, enhanced cell death could be detected, suggesting that the two signals are incompatible in the cellular context. However, the cells regain their differentiation potential after inactivation of c-MycER(T). In summary, we have established a system, which allows for the biochemical analysis of the molecular pathways governing NCSC biology. In addition, we should be able to obtain NCSC lines from crossing the c-MycER(T) mice with mice harboring mutations affecting neural crest development enabling further insight into genetic pathways controlling neural crest differentiation.


Fluorescence visualization of the distribution of microfilaments in gonads and early embryos of the nematode Caenorhabditis elegans.
Several intracellular motility events in the Caenorhabditis elegans zygote (pseudocleavage, the asymmetric meeting of the pronuclei, the segregation of germ line-specific granules, and the generation of an asymmetric spindle) appear to depend on microfilaments (MFs). To investigate how MFs participate in these manifestations of zygotic asymmetry, the distribution of MFs in oocytes and early embryos was examined, using both antibodies to actin and the F-actin-specific probe rhodamine-phalloidin. In early-stage zygotes, MFs are found in a uniform cortical meshwork of fine fibers and dots or foci. In later zygotes, concomitant with the intracellular movements that are thought to be MF mediated, MFs also become asymmetrically rearranged; as the zygote undergoes pseudocleavage and as the germ line granules become localized in the posterior half of the cell, the foci of actin become progressively more concentrated in the anterior hemisphere. The foci remain anterior as the spindle becomes asymmetric and the zygote undergoes its first mitosis, at which time fibers align circumferentially around the zygote where the cleavage furrow will form. A model for how the anterior foci of actin may participate in zygotic motility events is discussed. Phalloidin and anti-actin antibodies have also been used to visualize MFs in the somatic tissues of the adult gonad. The myoepithelial cells that surround maturing oocytes are visibly contractile and contain an unusual array of MF bundles; the MFs run roughly longitudinally from the loop of the gonad to the spermatheca. Myosin thick filaments are distributed along the MFs in a periodic manner suggestive of a sarcomere-like configuration. It is proposed that these actin and myosin filaments interact to cause sheath cell contraction and the movement of oocytes through the gonad.


Hdac1 and Hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells.
Epidermal and hair follicle development from surface ectodermal progenitor cells requires coordinated changes in gene expression. Histone deacetylases alter gene expression programs through modification of chromatin and transcription factors. We find that deletion of ectodermal Hdac1 and Hdac2 results in dramatic failure of hair follicle specification and epidermal proliferation and stratification, phenocopying loss of the key ectodermal transcription factor p63. Although expression of p63 and its positively regulated basal cell targets is maintained in Hdac1/2-deficient ectoderm, targets of p63-mediated repression, including p21, 14-3-3σ, and p16/INK4a, are ectopically expressed, and HDACs bind and are active at their promoter regions in normal undifferentiated keratinocytes. Mutant embryos display increased levels of acetylated p53, which opposes p63 functions, and p53 is required for HDAC inhibitor-mediated p21 expression in keratinocytes. Our data identify critical requirements for HDAC1/2 in epidermal development and indicate that HDAC1/2 directly mediate repressive functions of p63 and suppress p53 activity.


Glaukos iStent Trabecular Micro-Bypass.
The iStent trabecular micro-bypass system (Glaukos Corp. Laguna Hills, CA) was developed to address the limitations of current medical and surgical therapies for glaucoma treatment. The iStent((R)) is inserted ab interno through a small temporal clear corneal incision, bypassing the trabecular meshwork and placed in Schlemm's canal at the lower nasal quadrant. Implantation of this stent into Schlemm's canal allows aqueous humor to drain directly from the anterior chamber into Schlemm's canal bypassing the obstructed trabecular meshwork. For this review, a Medline search was performed using the terms "trabecular micro-bypass stent" and "trabecular bypass stent." The online abstract database for the American Academy of Ophthalmology was also reviewed. Abstracts which duplicated published articles were excluded. All relevant papers (n is equal to three) and abstracts (n is equal to one) were included in this review. Multiple, prospective multi-country, clinical trials have demonstrated the safety and efficacy of iStent in reducing IOP, when compared to traditional treatment modalities, while reducing/ eliminating the need for ocular antihypertensive drugs when implanted in OAG patients during combined cataract surgery or in patients with glaucoma refractory to traditional treatment modalities.


Comparing the validity of the Modified Modified Ashworth Scale (MMAS) and the Modified Tardieu Scale (MTS) in the assessment of wrist flexor spasticity in patients with stroke: protocol for a neurophysiological study.
Reliable and valid tools must be used to assess spasticity in clinical practise and research settings. There is a paucity of literature regarding the validity of the Modified Modified Ashworth Scale (MMAS) and the Modified Tardieu Scale (MTS). No study, to date, has been performed to compare the validity of the MMAS and the MTS. This neurophysiological study protocol will compare the validity of the MMAS and the MTS in the assessment of poststroke wrist flexor spasticity. Thirty-two patients with stroke from the University Rehabilitation clinics will be recruited to participate in this cross-sectional, non-interventional study. All measurements will be taken in the Physical Medicine and Rehabilitation Department of Shafa University Hospital in Tehran, Iran. First, wrist flexor spasticity will be assessed clinically using the MMAS and MTS. The tests will be applied randomly. For the MTS, the components of R1, R2, R2-R1 and quality of muscle reaction will be measured. Second, neurophysiological measures of H-reflex latency, H(max)/M(max) ratio, H(slp) and H(slp)/M(slp) ratio will be collected from the affected side. The results will be analysed using Spearman's ρ test or Pearson's correlation test to determine the validity of the MMAS and the MTS as well as to compare the validity between the MMAS and the MTS. The Research Council, School of Rehabilitation and the Ethics Committee of Tehran University of Medical Sciences (TUMS) approved the study protocol. The study results will be disseminated in peer-reviewed publications and presented at international congresses.


Perspectives of RAS and RHEB GTPase Signaling Pathways in Regenerating Brain Neurons.
Cellular activation of RAS GTPases into the GTP-binding "ON" state is a key switch for regulating brain functions. Molecular protein structural elements of rat sarcoma (RAS) and RAS homolog protein enriched in brain (RHEB) GTPases involved in this switch are discussed including their subcellular membrane localization for triggering specific signaling pathways resulting in regulation of synaptic connectivity, axonal growth, differentiation, migration, cytoskeletal dynamics, neural protection, and apoptosis. A beneficial role of neuronal H-RAS activity is suggested from cellular and animal models of neurodegenerative diseases. Recent experiments on optogenetic regulation offer insights into the spatiotemporal aspects controlling RAS/mitogen activated protein kinase (MAPK) or phosphoinositide-3 kinase (PI3K) pathways. As optogenetic manipulation of cellular signaling in deep brain regions critically requires penetration of light through large distances of absorbing tissue, we discuss magnetic guidance of re-growing axons as a complementary approach. In Parkinson's disease, dopaminergic neuronal cell bodies degenerate in the substantia nigra. Current human trials of stem cell-derived dopaminergic neurons must take into account the inability of neuronal axons navigating over a large distance from the grafted site into striatal target regions. Grafting dopaminergic precursor neurons directly into the degenerating substantia nigra is discussed as a novel concept aiming to guide axonal growth by activating GTPase signaling through protein-functionalized intracellular magnetic nanoparticles responding to external magnets.


mTORC1/rpS6 and p-FAK-Y407 signaling regulate spermatogenesis: Insights from studies of the adjudin pharmaceutical/toxicant model.
In rodents and humans, the major cellular events at spermatogenesis include self-renewal of spermatogonial stem cells and undifferentiated spermatogonia via mitosis, commitment of spermatogonia to differentiation and transformation to spermatocytes, meiosis, spermiogenesis, and the release of spermatozoa at spermiation. While details of the morphological changes during these cellular events have been delineated, knowledge gap exists between the morphological changes in the seminiferous epithelium and the underlying molecular mechanism(s) that regulate these cellular events. Even though many of the regulatory proteins and biomolecules that modulate spermatogenesis are known based on studies using genetic models, the underlying regulatory mechanism(s), in particular signaling pathways/proteins, remain unexplored since much of the information regarding the signaling regulation is unknown. Studies in the past decade, however, have unequivocally demonstrated that the testis is using several signaling proteins and/or pathways to regulate multiple cellular events to modulate spermatogenesis. These include mTORC1/rpS6/Akt1/2 and p-FAK-Y407. While selective inhibitors and/or agonists and antagonists are available to examine some of these signaling proteins, their use have limitations due to their specificities and also potential systemic cytotoxicity. On the other hand, the use of genetic models has had profound implications for our understanding of the molecular regulation of spermatogenesis, and these knockout (null) models have also revealed the factors that are critical for spermatogenesis. Nonetheless, additional studies using in vitro and in vivo models are necessary to unravel the signaling pathways involved in regulating seminiferous epithelial cycle. Emerging data from studies, such as the use of the adjudin pharmaceutical/toxicant model, have illustrated that this non-hormonal male contraceptive drug is utilizing specific signaling pathways/proteins to induce specific defects in spermatogenesis, yielding mechanistic insights on the regulation of spermatogenesis. We sought to review these recent data in this article, highlighting an interesting approach that can be considered for future studies.


Human eIF4E promotes mRNA restructuring by stimulating eIF4A helicase activity.
Elevated eukaryotic initiation factor 4E (eIF4E) levels frequently occur in a variety of human cancers. Overexpression of eIF4E promotes cellular transformation by selectively increasing the translation of proliferative and prosurvival mRNAs. These mRNAs possess highly structured 5'-UTRs that impede ribosome recruitment and scanning, yet the mechanism for how eIF4E abundance elevates their translation is not easily explained by its cap-binding activity. Here, we show that eIF4E possesses an unexpected second function in translation initiation by strongly stimulating eukaryotic initiation factor 4A (eIF4A) helicase activity. Importantly, we demonstrate that this activity promotes mRNA restructuring in a manner that is independent of its cap-binding function. To explain these findings, we show that the eIF4E-binding site in eukaryotic initiation factor 4G (eIF4G) functions as an autoinhibitory domain to modulate its ability to stimulate eIF4A helicase activity. Binding of eIF4E counteracts this autoinhibition, enabling eIF4G to stimulate eIF4A helicase activity. Finally, we have successfully separated the two functions of eIF4E to show that its helicase promoting activity increases the rate of translation by a mechanism that is distinct from its cap-binding function. Based on our results, we propose that maintaining a connection between eIF4E and eIF4G throughout scanning provides a plausible mechanism to explain how eIF4E abundance selectively stimulates the translation of highly structured proliferation and tumor-promoting mRNAs.


Expanded genetic insight and clinical experience of DNMT1-complex disorder.
To report novel causal mutations, expanded clinical phenotypes, and clinical management of DNA methyltransferase 1 (DNMT1)-complex disorder. Neurophysiologic testing, imaging, and genetic findings were summarized in clinical context for 5 cases with DNMT1-complex disorder. We identified 2 novel DNMT1 mutations (p.E510K and p.P1546A) by whole-exome sequencing (WES). Case 1 (p.E510K) presented with childhood ataxia, treatment-refractory seizures, and rapid cognitive decline in his 50s. Case 2 also had childhood onset and presented with seizures, language regression, hearing loss, narcolepsy with cataplexy symptoms, optic atrophy, sensory neuropathy, and hypogammaglobulinemia requiring IV immunoglobulin. Case 2 (p.P1546A) was identified with a de novo and the first mutation residing outside the targeting sequence domain. Case 3 (p.A570V) had paralytic asymmetric onset attacks triggered by emotionality and lasting sometimes for weeks. Neuropsychological testing showed executive dysfunction localizing to frontosubcortical and frontoparietal structures. He gradually developed left predominant brain atrophy. MRI showed T2 hyperintense lesions that enhanced on T1 postgadolinium images, and brain PET showed hypometabolism in atrophied regions. Case 4 (p.T497P) underwent left cochlear implant, resulting in significant hearing improvements at all tested frequencies (250-6,000 Hz). Case 5 (p.Y511H) had profound gait ataxia with posterior column atrophy of the spinal cord and abnormal evoked potentials primarily affecting the fasciculus gracilis. Broader application of WES further expands genotype-phenotype correlations of DNMT1-complex disorder. Two mutations are identified with early childhood onsets. The expanded new phenotypes include asymmetric brain hemiatrophy with parenchymal gadolinium enhancement, spinal cord atrophy, prolonged cataplectic spells, and hypogammaglobulinemia. Hearing loss treatment by cochlear implantation is helpful and should be considered.