Symptomatic cluster headache: a review of 63 cases.
Cluster headache is a primary headache by definition not caused by any known underlying structural pathology. Symptomatic cases have been described, for example tumours, dissections and infections, but a causal relationship between the underlying lesion and the headache is difficult to determine in many cases. The proper diagnostic evaluation of cluster headache is an issue unresolved. The literature has been reviewed for symptomatic cluster headache or cluster headache-like cases in which causality was likely. The review also attempted to identify clinical predictors of underlying lesions in order to formulate guidelines for neuroimaging. Sixty-three cluster headache or "cluster headache-like"/"cluster-like headache" cases in the literature were identified which were associated with an underlying lesion. A majority of the cases had a non-typical presentation that is atypical symptomatology and abnormal examination (including Horner's syndrome). A striking finding in this appraisal was that a significant proportion of CH cases were secondary to diseases of the pituitary gland or pituitary region. Another notable finding was that a proportion of cluster headache cases were associated with arterial dissection. Even typical cluster headaches can be caused by structural lesions and the response to typical cluster headache treatments does not exclude a secondary form. It is difficult to draw definitive conclusions from this retrospective review of case reports especially considering the size of the material. However, based on this review, I suggest that neuroimaging, preferably contrast-enhanced magnetic resonance imaging/magnetic resonance angiography should be undertaken in patients with atypical symptomatology, late onset, abnormal examination (including Horner's syndrome), or those resistant to the appropriate medical treatment. The decision to perform magnetic resonance imaging in cases of typical cluster headache remains a matter of medical art.


Phenotypic Modulation of Skeletal Muscle Fibers in LPIN1-Deficient Lipodystrophic ( fld) Mice.
Lipin-1 ( Lpin1)-deficient lipodystrophic mice have scant and immature adipocytes and develop transient fatty liver early in life. Unlike normal mice, these mice cannot rely on stored triglycerides to generate adenosine triphosphate (ATP) from the β-oxidation of fatty acids during periods of fasting. To compensate, these mice store much higher amounts of glycogen in skeletal muscle and liver than wild-type mice in order to support energy needs during periods of fasting. Our studies demonstrated that there are phenotypic changes in skeletal muscle fibers that reflect an adaptation to this unique metabolic situation. The phenotype of skeletal muscle (soleus, gastrocnemius, plantaris, and extensor digitorum longus [EDL]) from Lpin1-/- was evaluated using various methods including immunohistochemistry for myosin heavy chains (Myh) 1, 2, 2a, 2b, and 2x; enzyme histochemistry for myosin ATPase, cytochrome-c oxidase (COX), and succinyl dehydrogenase (SDH); periodic acid-Schiff; and transmission electron microscopy. Fiber-type changes in the soleus muscle of Lpin1-/- mice were prominent and included decreased Myh1 expression with concomitant increases in Myh2 expression and myosin-ATPase activity; this change was associated with an increase in the presence of Myh1/2a or Myh1/2x hybrid fibers. Alterations in mitochondrial enzyme activity (COX and SDH) were apparent in the myofibers in the soleus, gastrocnemius, plantaris, and EDL muscles. Electron microscopy revealed increases in the subsarcolemmal mitochondrial mass in the muscles of Lpin1-/- mice. These data demonstrate that lipin-1 deficiency results in phenotypic fiber-specific modulation of skeletal muscle necessary for compensatory fuel utilization adaptations in lipodystrophy.


Estimating the prevalence of diagnosed diabetes in a health district of Wales: the importance of using primary and secondary care sources of ascertainment with adjustment for death and migration.
To determine diagnosed diabetic prevalence within our district (population 434398) in 1996 using data from two sources. A general practice audit comprising data on patients with diabetes from 61 (82%) of 74 general practices was linked to a record linkage-derived patient index in which data from secondary care and other sources underwent a process of probability matching to identify records relating to the same patient and to flag those with diabetes. By linking this dataset to a mortality dataset, patients known to have died before 1996 could be excluded. Age and sex-stratified emigration rates were applied to those identified by the hospital dataset for each year from 1991 onwards. A total of 386988 residents (89.1%) were listed with a general practitioner participating in the audit, of whom 6050 patients were identified as having diabetes in 1996; a prevalence rate of 1.56%. From the hospital-based source, 7639 patients were identified who were alive in 1996, a period prevalence of 1.76%. By combining the two sources, and extrapolating the general practice audit to the population as a whole, a total of 10 530 patients were identified of whom 8735 were confirmed as still resident within South Glamorgan during 1996. This represented a period prevalence of between 2.01% to 2.42%. By applying age and sex-stratified migration rates to the diabetic population identified by hospital sources, a diagnosed diabetic population of 10,004 was identified, a prevalence of 2.3%. This study demonstrates that to calculate the true prevalence of diagnosed diabetes from health sources, it is necessary to use both primary and secondary care sources.


Radioprotection using iodine-131 for thyroid cancer and hyperthyroidism: a review.
Radioiodine (iodine-131, or I-131) therapy has been used successfully for thyroid therapy for more than 50 years. Protocols for treatment with I-131 differ from country to country and even from hospital to hospital in the same country. Daily area surveys of hallways, stairwells, and rooms adjacent to isolation rooms must be conducted and documented to ensure that doses to any individuals in unrestricted areas do not exceed 20 mcSv (2 mrem) in one hour. Nursing and housekeeping staffs must realize that once therapy has begun, no items are to be removed from the room unless first cleared by nuclear medicine or radiation safety personnel. With proper education and instructions for patients and their family members, radiation exposure to healthcare professionals and the general public can be minimized. The objectives of this article are to review (a) practical radiation safety concerns associated with hospitalized patients receiving I-131 therapy, (b) preventive measures to minimize potential exposure and contamination problems, and (c) radiation safety precautions and preventive measures to minimize radiation exposure to family members and helpers living with patients receiving outpatient I-131 therapy.


Dimethyl fumarate regulates histone deacetylase expression in astrocytes.
We previously showed that dimethyl fumarate (DMF) reduces inflammatory activation in astrocytes, involving activation of transcription factor Nrf2. However, the pathways causing Nrf2 activation were not examined. We now show that DMF modifies expression of histone deacetylases (HDACs) in primary rat astrocytes. After 4h incubation, levels of HDAC1, 2, and 4 mRNAs were increased by DMF; however, after 24h, levels returned to or were below control values. At that time, HDAC protein levels and overall activity were also reduced by DMF. Stimulation of astrocytes with pro-inflammatory cytokines significantly increased HDAC mRNA levels after 24h, although protein levels were not increased at that time point. In the presence of cytokines, DMF reduced HDAC mRNAs, proteins, and activity. Proteomic analysis of DMF-treated astrocytes identified 8 proteins in which lysine acetylation was increased by DMF, including histones H2a.1 and H3.3. A role for HDACs in mediating DMF actions is suggested by findings that the selective HDAC inhibitor SAHA increased nuclear Nrf2:DNA binding activity, reduced inflammatory activation of astrocytes which was reversed by a selective inhibitor of the Nrf2 target gene heme-oxygenase 1. These data show that DMF regulates astrocyte HDAC expression, which could contribute to Nrf2 activation, suppression of inflammatory responses and cause long-lasting changes in gene expression.


Ecologic covariates of hookworm infection and reinfection in rural Kwazulu-natal/south Africa: a geographic information system-based study.
Information on hookworm infection and re-infection in a cohort of primary school children and interview data on their socioeconomic background and behavior were combined with environmental data using a geographic information system (GIS). Multivariate models served to explore the covariation of environmental and infection patterns adjusted for possible confounders. Our aim was to identify environmental factors that might serve to predict infection and thus guide control efforts when epidemiologic information is insufficient. Furthermore, we wanted to establish whether soil type has a genuine influence on hookworm infection. Prevalence maps and spatial statistics showed considerable spatial clustering of infection in the small ( approximately 28 x 16 km) study area. The multivariate logistic regression models showed strong positive associations of infection at baseline (baseline prevalence = 83.2%) with settlement density (odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.10-1.38) and vegetation density (OR = 1.66, 95% CI = 1.25-2.22) and a strong negative association with the clay content of the soil (OR = 0.67, 95% CI = 0.62-0.73). Similar but weaker correlations were found after re-infection. Socioeconomic status and behavior did not seem to confound these associations. Spatial analysis of the model residuals suggested that because the models accounted for most of the spatial pattern, the model standard errors were not affected by spatial clustering. Our study shows that the pattern of hookworm infection is strongly influenced by several environmental factors. The GIS-aided prediction of areas in need of treatment is therefore a promising tool to guide control efforts when epidemiologic information is insufficient.


Assembly of the phagocyte NADPH oxidase: binding of Src homology 3 domains to proline-rich targets.
The NADPH oxidase responsible for generation of superoxide anion and related microbicidal oxidants by phagocytes is assembled from at least five distinct proteins. Two are cytosolic components (p47-phox and p67-phox) that contain Src homology 3 (SH3) domains and associate with a transmembrane cytochrome b558 upon activation. We show here that the SH3 domains of p47-phox bind to proline-rich sequences in p47-phox itself and the p22-phox subunit of cytochrome b558. Binding of the p47-phox SH3 domains to p22-phox was abolished by a mutation in one proline-rich sequence (Pro156-->Gln) noted in a distinct form of chronic granulomatous disease and was inhibited by a short proline-rich synthetic peptide corresponding to residues 149-162 of p22-phox. Expression of mutated p22-phox did not restore oxidase activity to p22-phox-deficient B cells and did not enable p22-phox-dependent translocation of p47-phox to membranes in phorbol ester-stimulated cells. We also show that the cytosolic oxidase components associate with one another through the C-terminal SH3 domain of p67-phox and a proline-rich C-terminal sequence in p47-phox. These SH3 target sites conform to consensus features deduced from SH3 binding sites in other systems. We propose a model in which the oxidase complex assembles through a mechanism involving SH3 domains of both cytosolic proteins and cognate proline-rich targets in other oxidase components.


Relaxin-induced reduction of infarct size in male rats receiving MCAO is dependent on nitric oxide synthesis and not estrogenic mechanisms.
Relaxins are members of the insulin peptide superfamily. Previous evidence has shown that relaxin pretreatment reduces cortical infarct size in anesthetized, male rats receiving permanent middle cerebral artery occlusion (MCAO). Therefore, the current study was designed to determine if estrogenic mechanisms or nitric oxide production are involved in mediating this relaxin-induced neuroprotection. In separate groups of rats (n=4-6), the following drugs were injected directly into the cortex 30 min prior to MCAO: (a) relaxin, (b) relaxin and estrogen, and (c) relaxin and an estrogen receptor antagonist (ICI 182,780). To investigate the involvement of nitric oxide, relaxin or relaxin and an inhibitor of endothelial nitric oxide synthase (L-NIO) were injected i.v. 30 min prior to MCAO. Saline-treated rats (both intracortical (i.c.) and intravenously (i.v.)) served as controls. Brains were harvested 4h post stroke, coronally sectioned using a brain matrix and stained using 2,3,5-triphenoltetrazolium chloride (TTC). Digital photographs were taken of brain sections and the ratio comparing the area of the infarct to the area of the ipsilateral hemisphere was calculated. Mean ratios were compared using ANOVA and Tukey's test. Intracortical and intravenous relaxin pretreatment significantly reduced the infarct area in the cortex by 33.7 and 58.6%, respectively compared to saline-treated controls. This effect was not dependent on an interaction with estrogenic receptors as co-injection of relaxin and ICI 182,780 did not reverse this effect. However, inhibition of nitric oxide synthase significantly reduced the relaxin-mediated neuroprotection suggesting that relaxin may induce the endothelin-NOS cascade in cerebral vasculature causing vasodilation and improved perfusion of neural tissue.


Effects of load carriage on physiological determinants in adventure racers.
Adventure racing athletes need run carrying loads during the race. A better understanding of how different loads influence physiological determinants in adventure racers could provide useful insights to gauge training interventions to improve running performance. We compare the maximum oxygen uptake (VO2max), the cost of transport (C) and ventilatory thresholds of twelve adventure running athletes at three load conditions: unloaded, 7 and 15% of body mass. Twelve healthy men experienced athletes of Adventure Racing (age 31.3 ± 7.7 years, height 1.81 ± 0.05 m, body mass 75.5 ± 9.1 kg) carried out three maximal progressive (VO2max protocol) and three submaximal constant-load (running cost protocol) tests, defined in the following quasi-randomized conditions: unloaded, 7% and, 15% of body mass. The VO2max (unload: 59.7 ± 5.9; 7%: 61.7 ± 6.6 and 15%: 64.6 ± 5.4 ml kg-1 min-1) did not change among the conditions. While the 7% condition does neither modify the C nor the ventilatory thresholds, the 15% condition resulted in a higher C (5.2 ± 0.9 J kg-1 m-1; P = 0.001; d = 1.48) than the unloaded condition (4.0 ± 0.7 J kg-1 m-1). First ventilatory threshold was greater at 15% than control condition (+15.5%; P = 0.003; d = 1.44). Interestingly, the velocities on the severe-intensity domain (between second ventilatory threshold and VO2max) were reduced 1% equivalently to 1% increasing load (relative to body mass). The loading until 15% of body mass seems to affect partially the crucial metabolic and ventilatory parameters, specifically the C but not the VO2max. These findings are compatible with the concept that interventions that enhance running economy with loads may improve the running performance of adventure racing's athletes.


Demographic and health surveillance of mobile pastoralists in Chad: integration of biometric fingerprint identification into a geographical information system.
There is a pressing need for baseline demographic and health-related data to plan, implement and evaluate health interventions in developing countries, and to monitor progress towards international development goals. However, mobile pastoralists, i.e. people who depend on a livestock production system and follow their herds as they move, remain marginalized from rural development plans and interventions. The fact that mobile people are hard to reach and stay in contact with is a plausible reason why they are underrepresented in national censuses and/or alternative sequential sample survey systems. We present a proof-of-concept of monitoring highly mobile, pastoral people by recording demographic and health-related data from 933 women and 2020 children and establishing a biometric identification system (BIS) based on the registration and identification of digital fingerprints. Although only 22 women, representing 2.4% of the total registered women, were encountered twice in the four survey rounds, the approach implemented is shown to be feasible. The BIS described here is linked to a geographical information system to facilitate the creation of the first health and demographic surveillance system in a mobile, pastoralist setting. Our ultimate goal is to implement and monitor interventions with the "one health" concept, thus integrating and improving human, animal and ecosystem health.


Typical noise exposure in daily life.
Identify the distribution of typical noise levels present in daily life and identify factors associated with average sound levels. This was an observational study. Participants (N = 286) were 20 to 68 year old men and women, drawn from the general population of Kalamazoo County, Michigan. A total of 73 000 person-hours of noise monitoring were conducted. Median overall daily average levels were 79 and 77 dBLeq(A,8,equiv), with average levels exceeding EPA recommended levels for 70% of participants. Median levels were similar between the hours of 9 a.m. and 9 p.m., and varied little across days of the week. Gender, occupational classification, and history of occupational noise exposure were related to average noise levels, but age, educational attainment, and non-occupational noise exposures were not. A large portion of the general population is exposed to noise levels that could result in long-term adverse effects on hearing. Gender and occupation were most strongly related to exposure, though most participants in this study had occupations that are not conventionally considered noisy.


Modelling of adsorption and intercalation of hydrogen on/into tungsten disulphide multilayers and multiwall nanotubes.
Understanding the interaction of hydrogen with layered materials is crucial in the fields of sensors, catalysis, fuel cells and hydrogen storage, among others. Density functional theory, improved by the introduction of van der Waals dispersion forces, provides an efficient and practical workbench to investigate the interaction of molecular and atomic hydrogen with WS2 multilayers and nanotubes. We find that H2 physisorbs on the surface of those materials on top of W atoms, while atomic H chemisorbs on top of S atoms. In the case of nanotubes, the chemisorption strength is sensitive to the nanotube diameter. Diffusion of H2 on the surface of WS2 encounters quite small activation barriers whose magnitude helps to explain previous and new experimental results for the observed dependence of the hydrogen concentration with temperature. Intercalation of H2 between adjacent planar WS2 layers reveals an endothermic character. Intercalating H atoms is energetically favorable, but the intercalation energy does not compensate for the cost of dissociating the molecules. When H2 molecules are intercalated between the walls of a double wall nanotube, the rigid confinement induces the dissociation of the confined molecules. A remarkable result is that the presence of a full H2 monolayer adsorbed on top of the first WS2 layer of a WS2 multilayer system strongly facilitates the intercalation of H2 between WS2 layers underneath. This opens up an additional gate to intercalation processes.


Seed Germination after 30 Years Storage in Permafrost.
More than 30 years ago, the Nordic Gene Bank established a long-term experiment on seeds stored under permafrost conditions in an abandoned mine corridor in Svalbard, as a tool to monitor storage life under these conditions. The study included seeds from 16 Nordic agricultural and horticultural crops, each represented by two or three cultivars (altogether 38 accessions). All seeds were ultra-dried to 3%-5% moisture before being sealed in glass tubes. Germination tests were performed in accordance with the International Seed Testing Association (ISTA) protocols. At the initiation of the experiment, the samples showed good germination with the median value at 92%. The overall picture remained stable over the first twenty to twenty-five years. However, the variation became larger over time and at 30 years, the median value had dropped to 80%. At the lower end, with a high drop in germination, we found rye, wheat, and English ryegrass. At the upper end, we found Kentucky bluegrass and cucumber. The lowest germination was found in samples with the highest initial seed moisture levels. Pre-storage conditions are likely to be of major importance for longevity.


Modified ADM1 for high-rate anaerobic co-digestion of thermally pre-treated brewery surplus yeast wastewater.
Co-digestion of surplus yeast with brewery wastewater is a potentially economical method for recovering energy, in the form of biogas, from this difficult to dispose of by-product. In this work a modified version of the ADM1 (Anaerobic Digestion Model No. 1) was calibrated for an anaerobic digester fed with thermally pre-treated brewery yeast surplus wastewater. The model could predict changes to reactor methane production and reduction of biodegradable matter when fed with both pre-treated and untreated yeast surplus wastewater at varying loading rates. Model calibration focused on low temperature thermal pre-treatment as experiments into a combined thermal-alkaline pre-treatment did not show any significant improvements. A low temperature pre-treatment of 60 °C for 30 minutes was sufficient for yeast inactivation and allowed for stable and more efficient operation of the high-rate anaerobic digester over a period of 232 days. The low temperature and time for pre-treatment also reduced the evaporation of easily biodegradable residual ethanol present in the influent, while still maintaining a low level of suspended matter. Inline measurements of gas composition, production and effluent chemical oxygen demand were sufficient for reliable model calibration of these same outputs. More detailed characterization of influent and effluent is required if organic acid concentrations for pH control are needed.


Characterization of genetic elements required for site-specific integration of Lactobacillus delbrueckii subsp. bulgaricus bacteriophage mv4 and construction of an integration-proficient vector for Lactobacillus plantarum.
Temperate phage mv4 integrates its DNA into the chromosome of Lactobacillus delbrueckii subsp. bulgaricus strains via site-specific recombination. Nucleotide sequencing of a 2.2-kb attP-containing phage fragment revealed the presence of four open reading frames. The larger open reading frame, close to the attP site, encoded a 427-amino-acid polypeptide with similarity in its C-terminal domain to site-specific recombinases of the integrase family. Comparison of the sequences of attP, bacterial attachment site attB, and host-phage junctions attL and attR identified a 17-bp common core sequence, where strand exchange occurs during recombination. Analysis of the attB sequence indicated that the core region overlaps the 3' end of a tRNA(Ser) gene. Phage mv4 DNA integration into the tRNA(Ser) gene preserved an intact tRNA(Ser) gene at the attL site. An integration vector based on the mv4 attP site and int gene was constructed. This vector transforms a heterologous host, L. plantarum, through site-specific integration into the tRNA(Ser) gene of the genome and will be useful for development of an efficient integration system for a number of additional bacterial species in which an identical tRNA gene is present.


Heterozygous deletion of both sclerostin (Sost) and connexin43 (Gja1) genes in mice is not sufficient to impair cortical bone modeling.
Connexin43 (Cx43) is the main gap junction protein expressed in bone forming cells, where it modulates peak bone mass acquisition and cortical modeling. Genetic ablation of the Cx43 gene (Gja1) results in cortical expansion with accentuated periosteal bone formation associated with decreased expression of the Wnt inhibitor sclerostin. To determine whether sclerostin (Sost) down-regulation might contribute to periosteal expansion in Gja1 deficient bones, we took a gene interaction approach and crossed mice harboring germline null alleles for Gja1 or Sost to generate single Gja1+/-and Sost+/-and double Gja1+/-;Sost+/-heterozygous mice. In vivo μCT analysis of cortical bone at age 1 and 3 months confirmed increased thickness in Sost-/-mice, but revealed no cortical abnormalities in single Gja1+/-or Sost+/-mice. Double heterozygous Gja1+/-Sost+/-also showed no differences in mineral density, cortical thickness, width or geometry relative to wild type control mice. Likewise, 3-point bending measurement of bone strength revealed no significant differences between double Gja1+/-;Sost+/-or single heterozygous and wild type mice. Although these data do not exclude a contribution of reduced sclerostin in the cortical expansion seen in Gja1 deficient bones, they are not consistent with a strong genetic interaction between Sost and Gja1 dictating cortical modeling.


Changes in chronic disease management among community health centers (CHCs) in China: Has health reform improved CHC ability?
Since the 1980s, China has been criticized for its mode of chronic disease management (CDM) that passively provides treatment in secondary and tertiary hospitals but lacks active prevention in community health centers (CHCs). Since there are few systematic evaluations of the CHCs' methods for CDM, this study aimed to analyze their abilities. On the macroperspective, we searched the literature in China's largest and most authoritative databases and the official websites of health departments. Literature was used to analyze the government's efforts in improving CHCs' abilities to perform CDM. At the microlevel, we examined the CHCs' longitudinal data after the New Health Reform in 2009, including financial investment, facilities, professional capacities, and the conducted CDM activities. A policy analysis showed that there was an increasing tendency towards government efforts in developing CDM, and the peak appeared in 2009. By evaluating the reform at CHCs, we found that there was an obvious increase in fiscal and public health subsidies, large-scale equipment, general practitioners, and public health physicians. The benefited vulnerable population in this area also rose significantly. However, rural centers were inferior in their CDM abilities compared with urban ones, and the referral system is still not effective in China. This study showed that CHCs are increasingly valued in managing chronic diseases, especially after the New Health Reform in 2009. However, we still need to improve collaborative management for chronic diseases in the community and strengthen the abilities of CHCs, especially in rural areas.


Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.
Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.


Contact dermatitis: evaluation and treatment.
Contact dermatitis is a common condition that can be categorized as irritant dermatitis and allergic contact dermatitis. Although each of these conditions may have a similar presentation, allergic contact dermatitis is immunologically mediated, whereas irritant contact dermatitis is not. Contact dermatitis can be acute, subacute, or chronic, and each of these phases may progress into the next. Almost any substance may induce a cutaneous reaction, depending on its concentration, the duration of contact, and the condition of the contacted skin. It is estimated that there are more than 6 million chemicals in the environment; approximately 3000 are potential sensitizers. A careful history may identify the responsible agent. If the contactant is identified and eliminated, the contact dermatitis can be a self-limited, mild condition. If the exposure is not discontinued, a cycle of itching, scratching, and skin disruption occurs, which leads to chronic changes in the skin. The history of presentation, including occupational exposures, and distribution of the rash are important in identifying the offending agent. More severe cases may require more extensive evaluation, possibly including patch testing, to determine the offending agent. This article reviews treatment, including antihistamines, topical and oral steroids, physical measures such as cold water compresses, and the treatment of secondary infection.


Frequency of alternative immunization schedule use in a metropolitan area.
Recent studies have described an increase in parental hesitancy regarding vaccines as well as increases in parental adoption of vaccine schedules that delay or limit receipt of recommended vaccines. This study quantifies potential prevalence and trends in alternative schedule compliance by measuring consistent shot-limiting in a metropolitan area of Oregon. Retrospective cohort analysis using the Oregon ALERT Immunization Information System to track children born between 2003 and 2009 in the Portland metropolitan area. Joinpoint regression was used to analyze prevalence trends in consistent shot-limiting during that time period. The 2007-2009 Haemophilus influenzae type b vaccine shortage and increased availability of combination vaccines were also examined for their effects on shot-limiting rates. A total of 4502 of 97,711 (4.6%) children met the definition of consistent shot-limiters. The proportion of consistent shot-limiters in the population increased from 2.5% to 9.5% between 2006 and 2009. Compared with those with no or episodic limiting, consistent shot-limiters by 9 months of age had fewer injections (6.4 vs 10.4) but more visits when immunizations were administered (4.2 vs 3.3). However, only a small minority of shot-limiters closely adhered to published alternative schedules. The percentage of children consistently receiving 2 or fewer vaccine injections per visit between birth and age 9 months increased threefold within a 2-year period, suggesting an increase in acceptance of non-Advisory Committee on Immunization Practices vaccine schedules in this geographic area.


NGF-TrkA Signaling by Sensory Nerves Coordinates the Vascularization and Ossification of Developing Endochondral Bone.
Developing tissues dictate the amount and type of innervation they require by secreting neurotrophins, which promote neuronal survival by activating distinct tyrosine kinase receptors. Here, we show that nerve growth factor (NGF) signaling through neurotrophic tyrosine kinase receptor type 1 (TrkA) directs innervation of the developing mouse femur to promote vascularization and osteoprogenitor lineage progression. At the start of primary ossification, TrkA-positive axons were observed at perichondrial bone surfaces, coincident with NGF expression in cells adjacent to centers of incipient ossification. Inactivation of TrkA signaling during embryogenesis in TrkA(F592A) mice impaired innervation, delayed vascular invasion of the primary and secondary ossification centers, decreased numbers of Osx-expressing osteoprogenitors, and decreased femoral length and volume. These same phenotypic abnormalities were observed in mice following tamoxifen-induced disruption of NGF in Col2-expressing perichondrial osteochondral progenitors. We conclude that NGF serves as a skeletal neurotrophin to promote sensory innervation of developing long bones, a process critical for normal primary and secondary ossification.


Robots with display screens: a robot with a more humanlike face display is perceived to have more mind and a better personality.
It is important for robot designers to know how to make robots that interact effectively with humans. One key dimension is robot appearance and in particular how humanlike the robot should be. Uncanny Valley theory suggests that robots look uncanny when their appearance approaches, but is not absolutely, human. An underlying mechanism may be that appearance affects users' perceptions of the robot's personality and mind. This study aimed to investigate how robot facial appearance affected perceptions of the robot's mind, personality and eeriness. A repeated measures experiment was conducted. 30 participants (14 females and 16 males, mean age 22.5 years) interacted with a Peoplebot healthcare robot under three conditions in a randomized order: the robot had either a humanlike face, silver face, or no-face on its display screen. Each time, the robot assisted the participant to take his/her blood pressure. Participants rated the robot's mind, personality, and eeriness in each condition. The robot with the humanlike face display was most preferred, rated as having most mind, being most humanlike, alive, sociable and amiable. The robot with the silver face display was least preferred, rated most eerie, moderate in mind, humanlikeness and amiability. The robot with the no-face display was rated least sociable and amiable. There was no difference in blood pressure readings between the robots with different face displays. Higher ratings of eeriness were related to impressions of the robot with the humanlike face display being less amiable, less sociable and less trustworthy. These results suggest that the more humanlike a healthcare robot's face display is, the more people attribute mind and positive personality characteristics to it. Eeriness was related to negative impressions of the robot's personality. Designers should be aware that the face on a robot's display screen can affect both the perceived mind and personality of the robot.


Beta-catenin signaling in hepatic development and progenitors: which way does the WNT blow?
The Wnt/β-catenin pathway is an evolutionarily conserved signaling cascade that plays key roles in development and adult tissue homeostasis and is aberrantly activated in many tumors. Over a decade of work in mouse, chick, xenopus, and zebrafish models has uncovered multiple functions of this pathway in hepatic pathophysiology. Specifically, beta-catenin, the central component of the canonical Wnt pathway, is implicated in the regulation of liver regeneration, development, and carcinogenesis. Wnt-independent activation of beta-catenin by receptor tyrosine kinases has also been observed in the liver. In liver development across various species, through regulation of cell proliferation, differentiation, and maturation, beta-catenin directs foregut endoderm specification, hepatic specification of the foregut, and hepatic morphogenesis. Its role has also been defined in adult hepatic progenitors or oval cells especially in their expansion and differentiation. Thus, beta-catenin undergoes tight temporal regulation to exhibit pleiotropic effects during hepatic development and in hepatic progenitor biology.


Long-term changes in renal function after treatment initiation and the importance of early diagnosis in maintaining renal function among IgG4-related tubulointerstitial nephritis patients in Japan.
The present study aimed to investigate associations between long-term renal function, whether IgG4-related tubulointerstitial nephritis (TIN) was diagnosed by renal biopsy at initial examination, chronic kidney disease (CKD) stage, and histological stage in patients with IgG4-related TIN. This study used a retrospective cohort design including almost all patients who underwent renal biopsy at Fujita Health University Hospital and Nagoya University or its affiliated hospitals in Aichi between April 2003 and March 2015 (n = 6977 renal biopsies). The primary outcome was longitudinal changes in eGFR. Main exposures were whether IgG4-related TIN was diagnosed by renal biopsy at the initial examination, CKD stage, and its histological stage. Linear mixed models were performed to examine associations. Of the 6977 samples, there were 24 patients (with 201 records due to repeated measures) with IgG4-related TIN (20 men, mean age, 68.7 ± 9.7 years). They were followed up 6.6 ± 2.8 years after the renal biopsy and underwent glucocorticoid treatment. We found significant increase in eGFR from the baseline to 2 and 6 months after treatment initiation, which was maintained until 60 months. Patients initially diagnosed with IgG4-related TIN had higher eGFR from the baseline (at the start of treatment) to 60 months than those who were not. Compared with patients with CKD stage 3, patients with CKD stages 4 and 5 had lower eGFR at the baseline and other time points. Patients with histological stage B had comparatively lower eGFR at each point than stage A patients. Those mean differences of eGFR were stable from the baseline to 60 months. After the treatment initiation, renal function rapidly improved and maintained for a long period, even with advanced CKD stage. We showed importance of early diagnosis of IgG4-related TIN in maintaining eGFR.


Dynamic programming re-ranking for PPI interactor and pair extraction in full-text articles.
Experimentally verified protein-protein interactions (PPIs) cannot be easily retrieved by researchers unless they are stored in PPI databases. The curation of such databases can be facilitated by employing text-mining systems to identify genes which play the interactor role in PPIs and to map these genes to unique database identifiers (interactor normalization task or INT) and then to return a list of interaction pairs for each article (interaction pair task or IPT). These two tasks are evaluated in terms of the area under curve of the interpolated precision/recall (AUC iP/R) score because the order of identifiers in the output list is important for ease of curation. Our INT system developed for the BioCreAtIvE II.5 INT challenge achieved a promising AUC iP/R of 43.5% by using a support vector machine (SVM)-based ranking procedure. Using our new re-ranking algorithm, we have been able to improve system performance (AUC iP/R) by 1.84%. Our experimental results also show that with the re-ranked INT results, our unsupervised IPT system can achieve a competitive AUC iP/R of 23.86%, which outperforms the best BC II.5 INT system by 1.64%. Compared to using only SVM ranked INT results, using re-ranked INT results boosts AUC iP/R by 7.84%. Statistical significance t-test results show that our INT/IPT system with re-ranking outperforms that without re-ranking by a statistically significant difference. In this paper, we present a new re-ranking algorithm that considers co-occurrence among identifiers in an article to improve INT and IPT ranking results. Combining the re-ranked INT results with an unsupervised approach to find associations among interactors, the proposed method can boost the IPT performance. We also implement score computation using dynamic programming, which is faster and more efficient than traditional approaches.


Biochanin A regulates the growth and migration of NSCLC through suppressing the VEGF/VEGFR2 signaling pathway.
Non-small cell lung cancer (NSCLC) is the most common lung cancer with 15.9% of predicted 5-year survival rate which represents extremely poor prognosis. In this study, we aimed to investigate the effects of Biochanin A (BIO-A) on NSCLC both in vitro and in vivo and to explore its underlying mechanism. We found that BIO-A could effectively inhibit the proliferation of NSCLC cell line A549 in a dose-dependent manner through down-regulating Ki-67 and VEGF, induce apoptosis by activation of cleaved-Caspase-3 and cleaved-Caspase-9, and suppress cell migration by downregulating of MMP-2 and VEGF. Mechanistically, the results of western blot indicated that BIO-A exerted its anti-growth ability through blocking VEGF/VEGFR2 signaling pathway. Moreover, BIOA significantly inhibited the growth of tumor in NSCLC xenograft model. Taken together, our investigation has suggested that BIO-A exhibits potent antitumor activities against NSCLC both in vitro and in vivo and provided a molecular basis for BIO-A potential applications in the treatment of NSCLC and other VEGF-induced diseases.


Generalized drivers in the mammalian endangerment process.
An important challenge for conservation today is to understand the endangerment process and identify any generalized patterns in how threats occur and aggregate across taxa. Here we use a global database describing main current external threats in mammals to evaluate the prevalence of distinct threatening processes, primarily of anthropogenic origin, and to identify generalized drivers of extinction and their association with vulnerability status and intrinsic species' traits. We detect several primary threat combinations that are generally associated with distinct species. In particular, large and widely distributed mammals are affected by combinations of direct exploitation and threats associated with increasing landscape modification that go from logging to intense human land-use. Meanwhile, small, narrowly distributed species are affected by intensifying levels of landscape modification but are not directly exploited. In general more vulnerable species are affected by a greater number of threats, suggesting increased extinction risk is associated with the accumulation of external threats. Overall, our findings show that endangerment in mammals is strongly associated with increasing habitat loss and degradation caused by human land-use intensification. For large and widely distributed mammals there is the additional risk of being hunted.


Prescribing of hormone therapy for menopause, tibolone, and bisphosphonates in women in the UK between 1991 and 2005.
The purpose of this study was to examine recent trends in the prescribing of hormone therapy for menopause, tibolone, and bisphosphonate preparations for the prevention or treatment of osteoporosis, in the UK in relation to publication of research evidence on the health effects of hormone therapy and subsequent changes in prescribing advice. Individual patient-level data were obtained on the prescribing of hormone therapy, tibolone, and bisphosphonates by general practitioners in the UK between 1991 and 2005 to women aged 40 years and older in the UK General Practice Research Database. Overall and age-specific prescribing prevalence were calculated for each therapy type. Prescribing prevalence was also calculated for subcategories of hormone therapy and bisphosphonates. Prescribing of hormone therapy to women aged 40 years and older increased between 1991 and 1996 and remained fairly stable between 1997 and 2001. Hormone therapy prescribing has fallen by about 50% since 2002. Tibolone, a selective tissue estrogenic activity regulator, is prescribed much less commonly than hormone therapy but shows a similar pattern. Prescribing of bisphosphonates increased rapidly throughout the study period, particularly in women aged 70 years and older, with the pattern of prescribing reflecting to some extent, the availability of new weekly formulations. Trends in the prescribing of hormone therapy in the UK appear to closely reflect new epidemiological evidence and prescribing advice. It is likely that the substantial fall in hormone therapy and tibolone prescribing seen since 2002 is a direct consequence of the publication of Women's Health Initiative trial results and subsequent changes in advice given by the Committee on Safety of Medicines. The 1997 publication of results from the Collaborative Group on Hormonal Factors in Breast Cancer and 2003 publication of the Million Women Study findings may also have impacted on trends, particularly within certain age groups. The substantial and continuing increase in prescribing prevalence of bisphosphonates reinforces the need for research into the long-term risks and benefits of these therapies.


Differential activity of interferon-α8 promoter is regulated by Oct-1 and a SNP that dictates prognosis of glioma.
We have previously reported that the single nucleotide polymorphism (SNP) rs12553612 in IFNA8 is associated with better overall survival of glioma patients with the AA-genotype compared with patients with the AC-genotype. As rs12553612 is located in the IFNA8 promoter, we hypothesized that the A-allele allows for an enhanced IFNA8 promoter activity compared with the C-allele. Reporter assays in the human monocyte derived THP-1 cell line demonstrated a superior promoter activity of the A-allele compared with the C-allele. Electrophoretic mobility shift assays (EMSA) further demonstrated that the A-genotype specifically binds to more nuclear proteins than the C-genotype, including the transcription factor Oct-1. Further, co-transfection of plasmids encoding Oct-1 and the reporter constructs revealed that Oct-1 enhanced the promoter activity with the A- but not the C-allele. Taken together, our data demonstrate that the A-allele in the rs12553612 SNP, which is associated with better glioma patient survival, allows for IFNA8 transcription by allowing for Oct-1 binding, which is absent in patients with C allele, and suggests a molecular mechanism of IFNA8 mediated immune-surveillance of glioma progression.


Point of care ultrasound in thoracic malignancy.
Ultrasonography is a safe, efficient and cost-effective mode of imaging that can assist clinicians with important treatment decisions and provide procedural guidance. Today, point of care ultrasound plays an essential role in the assessment of benign and malignant conditions of chest, both in the outpatient and inpatient setting. Small, ultra-portable, affordable units can now be carried in the coat pocket. Advanced lung cancer, metastatic diseases to the lungs or thoracic malignancies can present with pleural effusion, pulmonary edema, post-obstructive pneumonia, or ascites that can be assessed by the clinician with ultrasound. It can be used to evaluate the extent of thoracic tumors beyond the parenchyma to the parietal pleura or chest wall, assess cervical, supraclavicular lymphadenopathy prior to fine needle aspiration or to determine venous thromboembolism (VTE) associated with malignancy. Thoracic ultrasound is currently being practiced by the pulmonologists, thoracic surgeons and intensivists to provide guidance during placement of pleural catheters, chest tubes or to evaluate the pleural cavity before thoracoscopy. Point of care ultrasound can improve efficiency in procedures by decreasing complications, increasing success and reducing financial strain on the health care system.


Enzymatic cleavage of nucleic acids on gold nanoparticles: a generic platform for facile colorimetric biosensors.
The enzymatic cleavage of nucleic acids (DNA or DNA with a single RNA linkage) on well-dispersed gold nanoparticles (AuNPs) is exploited in the design of facile colorimetric biosensors. The assays are performed at salt concentrations such that DNA-modified AuNPs are barely stabilized by the electrostatic and steric stabilization. Enzymatic cleavage of DNA chains on the AuNP surface destabilizes the AuNPs, resulting in a rapid aggregation driven by van der Waals attraction, and a red-to-purple color change. Two different systems are chosen, DNase I (a DNA endonuclease) and 8-17 (a Pb(2+)-depedent RNA-cleaving DNAzyme), to demonstrate the utility of our assay for the detection of metal ions and sensing enzyme activities. Compared with previous studies in which AuNP aggregates are converted into dispersed AuNPs by enzymatic cleavage of DNA crosslinkers, the present assay is technically simpler. Moreover, the accessibility of DNA to biomolecular recognition elements (e.g. enzymes) on well-dispersed AuNPs in our assay appears to be higher than that embedded inside aggregates. This biosensing system should be readily adaptable to other enzymes or substrates for detection of analytes such as small molecules, proteases and their inhibitors.


Intentional mixed buccal cell reference sample in a paternity case.
We report a case where an alleged father (AF) attempted to substitute someone else's saliva sample for his reference sample in a paternity analysis. Buccal cells were collected from the AF and the child, and DNA analysis was performed using an autosomal STR loci (Identifiler). The profile from the AF showed extra peaks in some loci, as well as a much higher "X" allele peak relative to the "Y" allele peak at the amelogenin locus. After conducting reanalysis by another technician with another set of positive and negative controls, it was concluded that the only source of the mixed profile was by intentional introduction by the AF, at the time of sampling, of some foreign human biological material, most likely saliva from a woman. Owing to the inconclusive results, when the AF was called back to the lab and the peculiar results were explained to him, he admitted that he had introduced into his mouth saliva from another person in an attempt to be excluded as the father of the child. Although tampering with DNA reference samples is not common, some individuals may attempt to contaminate or otherwise adulterate specimens before DNA tests. Personnel responsible for sampling should be aware of this possibility and should try to establish procedures to avoid the problem.


High-sensitivity temperature sensor based on a droplet-like fiber circle.
A low-cost yet high-sensitivity temperature fiber sensor is proposed and demonstrated in this paper. A single-mode fiber with coating is simply bent in a droplet-like circle with a radius of several millimeters. The strong bending induces mode interferences between the silica core mode and the excited modes propagating in the polymer coating. Many resonant dips were observed in the transmission spectra and are found to shift to a shorter wavelength with the increase of environmental temperature. Our linear fitting result of the experimental data shows that the proposed sensor presents high temperature sensitivity up to -3.102 nm/°C, which is even comparable with sensors based on selective liquid-filled photonic crystal fibers. Such high temperature sensitivity results from the large thermo-optical coefficient difference between the silica core and the polymer coating. The influence of a circle radius to the sensitivities is also discussed.


Prediction of phosphorylation sites based on the integration of multiple classifiers.
Phosphorylation is an important part of post-translational modifications of proteins, and is essential for many biological activities. Phosphorylation and dephosphorylation can regulate signal transduction, gene expression, and cell cycle regulation in many cellular processes. Phosphorylation is extremely important for both basic research and drug discovery to rapidly and correctly identify the attributes of a new protein phosphorylation sites. Moreover, abnormal phosphorylation can be used as a key medical feature related to a disease in some cases. The using of computational methods could improve the accuracy of detection of phosphorylation sites, which can provide predictive guidance for the prevention of the occurrence and/or the best course of treatment for certain diseases. Furthermore, this approach can effectively reduce the costs of biological experiments. In this study, a flexible neural tree (FNT), particle swarm optimization, and support vector machine algorithms were used to classify data with secondary encoding according to the physical and chemical properties of amino acids for feature extraction. Comparison of the classification results obtained from the three classifiers showed that the classification of the FNT was the best. The three classifiers were then integrated in the form of a minority subordinate to the majority vote to obtain the results. The performance of the integrated model showed improvement in sensitivity (87.41%), specificity (87.60%), and accuracy (87.50%).


Standard operating procedures for neurophysiologic assessment of male sexual dysfunction.
Can neurophysiological testing in male patients with sexual dysfunction benefit the decision-making process? The answer remains unclear. To provide standard operating procedures for the neurophysiologic assessment of male sexual dysfunction. Medical literature was reviewed and combined with expert opinion of the authors. Bulbocavernosus reflex latency time, pudendal somatosensory evoked potentials, and sympathetic skin responses have been considered as potential candidates for the diagnosis and assessment of erectile dysfunction (ED). Currently, there is no consensus on a standardized methodology for these neurophysiological investigations in the overall assessment of ED. These procedures are unable to assess the integrity of the efferent parasympathetic proerectile penile innervation; accordingly, none of these assessment procedures is recommended for ED patients. Corpus cavernosum electromyography (CC-EMG) can detect abnormalities in cavernous smooth muscle although these alterations can be attributed both to damage to autonomic penile innervation and to degenerative processes of the cavernous smooth muscle. CC-EMG is still considered experimental. Evidence does not support that men with premature ejaculation (PE) are consistently characterized by penile hypersensitivity; accordingly, penile threshold determination is not recommended to in the diagnosis of PE. Neurophysiological investigation of other components of the penile sensory pathways in PE patients has not provided any definitive contribution to the diagnosis. No neurophysiological assessment procedures yield additional information that consistently aids in the assessment of PE and ED.


In situ cross-linking of elastin-like polypeptide block copolymers for tissue repair.
Rapid cross-linking of elastin-like polypeptides (ELPs) with hydroxymethylphosphines (HMPs) in aqueous solution is attractive for minimally invasive in vivo implantation of biomaterials and tissue engineering scaffolds. In order to examine the independent effect of the location and number of reactive sites on the chemical cross-linking kinetics of ELPs and the mechanical properties of the resulting hydrogels, we have designed ELP block copolymers comprised of cross-linkable, hydrophobic ELP blocks with periodic Lys residues (A block) and aliphatic, hydrophilic ELP blocks with no cross-linking sites (B block); three different block architectures, A, ABA, and BABA were synthesized in this study. All ELP block copolymers were rapidly cross-linked with HMPs within several minutes under physiological conditions. The inclusion of the un-cross-linked hydrophilic block, its length relative to the cross-linkable hydrophobic block, and the block copolymer architecture all had a significant effect on swelling ratios of the cross-linked hydrogels, their microstructure, and mechanical properties. Fibroblasts embedded in the ELP hydrogels survived the cross-linking process and remained viable for at least 3 days in vitro when the gels were formed from an equimolar ratio of HMPs and Lys residues of ELPs. DNA quantification of the embedded cells indicated that the cell viability within triblock ELP hydrogels was statistically greater than that in the monoblock gels at day 3. These results suggest that the mechanical properties of ELP hydrogels and the microenvironment that they present to cells can be tuned by the design of the block copolymer architecture.


A carbazole alkaloid deactivates mTOR through the suppression of rictor and that induces apoptosis in lung cancer cells.
Non-small cell lung cancer (NSCLC) is known to be a difficult cancer to treat because of its poor prognosis, limited option for surgery, and resistance to chemo or radiotherapy. In this study, we have demonstrated that suppression of rictor expression in A549 and H1299 NSCLC cells by mahanine, a carbazole alkaloid, disrupted constitutive activation of mTOR and Akt. Mahanine suppression of rictor gene expression and consequent attenuation of its protein expression affected the inhibition of mTOR (Ser-2481) and Akt (Ser-473) phosphorylation. Since mahanine treatment revealed this new insight of rictor-mTOR relationship, we examined an association between mTOR activation with rictor expression. Interestingly, in rictor knockdown (KD) NSCLC cells, mTOR activation was significantly impaired. Transfection of rictor over-expression vector into the NSCLC cells reversed this situation. In fact, both rictor KD and mahanine treated cells showed considerably depleted phospho-mTOR level. These results indicate that rictor is required to maintain constitutive activation of mTOR in lung cancer cells. When mTOR kinase activity in rictor KD cells was examined with Akt as substrate, a significant reduction of Akt phosphorylation indicated impairment of mTOR kinase potentiality. Disruption of mTOR and Akt activation caused drastic mortality of NSCLC cancer cells through apoptosis. Hence, our study reveals a new dimension in mTOR-rictor relationship, where rictor stands to be a suitable therapeutic target for lung cancer.


Cannabis: a self-medication drug for weight management? The never ending story.
In a society highly focused on physical appearance, people are increasingly using the so-called performance and image-enhancing drugs (PIEDs) or life-style drugs as an easy way to control weight. Preliminary data from online sources (e.g. websites, drug forums, e-newsletters) suggest an increased use of cannabis amongst the general population as a PIED due to its putative weight-loss properties. The use of cannabis and/or cannabis-related products to lose weight may represent a new substance-use trend that should be carefully monitored and adequately investigated, especially in light of the well-known adverse psychiatric and somatic effects of cannabis, its possible interaction with other medications/drugs and the unknown and potentially dangerous composition of synthetic cannabimimetics preparations.


Phase space analysis of networks based on biologically realistic parameters.
We study cortical network dynamics for a spatially embedded network model. It represents, in terms of spatial scale, a large piece of cortex allowing for long-range connections, resulting in a rather sparse connectivity. The spatial embedding also permits us to include distance-dependent conduction delays. We use two different types of conductance-based I&F neurons as excitatory and inhibitory units, as well as specific connection probabilities. In order to remain computationally tractable, we reduce neuron density, modelling part of the missing internal input via external poissonian spike trains. Compared to previous studies, we observe significant changes in the dynamical phase space: Altered activity patterns require another regularity measures than the coefficient of variation. Hence, we compare three different regularity measure on the basis of artificial inter-spike-interval distributions. We identify two types of mixed states, where different phases coexist in certain regions of the phase space. More notably, our boundary between high and low activity states depends predominantly on the relation between excitatory and inhibitory synaptic strength instead of the input rate.


Genome-wide analysis of differential RNA editing in epilepsy.
The recoding of genetic information through RNA editing contributes to proteomic diversity, but the extent and significance of RNA editing in disease is poorly understood. In particular, few studies have investigated the relationship between RNA editing and disease at a genome-wide level. Here, we developed a framework for the genome-wide detection of RNA sites that are differentially edited in disease. Using RNA-sequencing data from 100 hippocampi from mice with epilepsy (pilocarpine-temporal lobe epilepsy model) and 100 healthy control hippocampi, we identified 256 RNA sites (overlapping with 87 genes) that were significantly differentially edited between epileptic cases and controls. The degree of differential RNA editing in epileptic mice correlated with frequency of seizures, and the set of genes differentially RNA-edited between case and control mice were enriched for functional terms highly relevant to epilepsy, including "neuron projection" and "seizures." Genes with differential RNA editing were preferentially enriched for genes with a genetic association to epilepsy. Indeed, we found that they are significantly enriched for genes that harbor nonsynonymous de novo mutations in patients with epileptic encephalopathy and for common susceptibility variants associated with generalized epilepsy. These analyses reveal a functional convergence between genes that are differentially RNA-edited in acquired symptomatic epilepsy and those that contribute risk for genetic epilepsy. Taken together, our results suggest a potential role for RNA editing in the epileptic hippocampus in the occurrence and severity of epileptic seizures.


Phylogeography of the catfish Hatcheria macraei reveals a negligible role of drainage divides in structuring populations.
Southern South America provides a set of unusual geographic features that make it particularly interesting for studying phylogeography. The Andes Mountains run along a north-to-south axis and act as a barrier to gene flow for much of the biota of this region, with southern portions experiencing extensive historical glaciation. Geological data reveal a series of drainage reversals, shifting from Pacific Ocean outlets to Atlantic Ocean outlets because of glacier formation that dammed and reversed rivers. Once glaciers melted around 13 000 years ago, drainages returned to the Pacific Ocean. This geologic history predicts that aquatic organisms in Pacific rivers should have their closest relationships to their counterparts in Atlantic rivers immediately to their east. We tested this prediction in the trichomycterid catfish Hatcheria macraei from 38 locations using the mitochondrial cytochrome b gene. Our results show that most populations found in Pacific rivers were closely related to fish found in the adjacent Atlantic draining Río Chubut. Surprisingly, one documented drainage reversal (from Río Deseado into Río Baker) did not result in movement of H. macraei. Overall, we found the lowest levels of genetic structure between most Pacific rivers that are adjacent to the Atlantic draining Río Chubut. We also found low levels of population structuring among three of four contemporary river basins that drain to the Atlantic Ocean. Our findings suggest that drainage basin boundaries have historically not played an important long-term role in structuring between nine of 11 drainages, an unusual finding in freshwater biogeography.


Occupational risk and the development of premalignant skin lesions among paraquat manufacturers.
The objective of this study was to determine the prevalence rate and possible aetiological factors of premalignant skin lesions observed among paraquat manufacturers. A total of 228 workers in 28 factories were interviewed and independently examined by a dermatologist during site inspection in 1985. Information concerning past working experience, current toxic exposures, other risk factors of hyperpigmented macules and keratosis, and the past and present manufacturing processes of each factory was collected. Sixty nine cases of hyperpigmented macules and 17 of hyperkeratosis were found. Typical macules were irregular in shape, pin head size, hyperpigmented, with or without hyperkeratosis, and usually distributed symmetrically over the forearms, hands, neck, and upper chest, where exposure to sunlight was maximal. Six patients with hyperkeratotic lesions subsequently had biopsies performed and two showed Bowenoid changes. Eighty per cent (28 cases) and 67% (38 cases) of workers developed hyperpigmented macules if they had ever been engaged in bipyridine centrifugation and crystallisation, respectively; there were three workers 3% with such lesions among those who performed packaging or administrative jobs, or both. There was a significant trend (p less than 0.0001) for workers to develop hyperpigmented macules and hyperkeratosis the longer they had been exposed to centrifugation or crystallisation, or both, independent of age and the duration of exposure to sunlight. Evidence is presented to suggest that sunlight is a necessary cofactor and that the aetiological agent was produced during high temperature sodium process of bipyridine synthesis, and possibly bipyridine isomer(s).


High-valent nitridorhenium(v) complexes containing PNP ligands: implications of ligand flexibility.
The synthesis of (PNP)Re(N)X (PNP = [2-P(CHMe2)2-4-MeC6H3]2N, X = Cl and Me) complexes is described. The methylnitridorhenium complex 3 was found to react differently with CO and isocyanides, leading to the isolation of a Re(v) acyl complex 4 and an isocyanide adduct 6. Two parallel pathways were observed for the reaction of 3 with CO: (1) CO inserts into the Re-Me bond to afford 4, and (2) 3 isomerizes by distortion of the aryl backbone of the PNP ligand to afford the isomer 3'. This is followed by the reaction of 3' with CO to afford the tricarbonyl complex 5, which was fully characterized. The contrasting reaction of 3 with 2,6-dimethylphenyl isocyanide lends further support for the proposed isomerization pathway. DFT (M06) calculations suggest that insertion of CNR into the Re-Me bond (27.2 kcal mol-1) is inaccessible at room temperature. Instead the substrate adds to the metal center via the most accessible face i.e. syn to the rhenium-nitrido bond, to afford 6. The addition of CO to isomer 3' is proposed to proceed with a similar mechanism to 2,6-dimethylphenyl isocyanide.


Long-term exposure to traffic-related air pollution and lung cancer risk.
Most studies on the association between lung cancer and air pollution have investigated mortality. There have been few studies of lung cancer incidence. We used data from the ongoing Netherlands Cohort Study on Diet and Cancer for 114,378 subjects with follow-up from September 1986 to December 1997. Exposure to black smoke, nitrogen dioxide (NO2), sulfur dioxide (SO2), and particulate matter < or =2.5 microm (PM2.5) and traffic intensity variables (intensity on nearest road, intensity in a 100 m buffer, and an indicator variable for living close to a major road) were estimated at the home address. We conducted Cox proportional hazard analyses in the full cohort adjusting for age, sex, smoking status, and area-level socioeconomic status. We also carried out case-cohort analyses using more potential confounders on a subset of study participants for whom complete information from the baseline questionnaire had been processed. Adjusted analyses included 1940 cases for the full cohort and 1295 cases for the case-cohort analysis. Relative risks (RRs) for the overall air pollution concentrations were slightly below unity, and for the traffic variables RRs were slightly elevated. Risk was elevated among people who never smoked cigarettes (40,114 participants; 252 cases), with RRs of 1.47 (95% confidence interval = 1.01-2.16) for overall black smoke concentration, 1.11 (0.88-1.41) for traffic intensity on nearest road, and 1.55 (0.98-2.43) for living near a major road. We found evidence for an association of exposure to black smoke and traffic with lung cancer incidence in people who had never smoked. No associations were found for the full cohort, or for other categories of smoking.


Computed tomographic features of feline nasopharyngeal polyps.
The computed tomographic (CT) findings of histopathologically confirmed nasopharyngeal polyps are described in 13 cats. Most polyps were mildly hypoattenuating to adjacent muscles and isoattenuating to soft-tissue (n= 13), homogeneous (n = 12) and with ill-defined borders (n = 10) on precontrast images. After contrast medium administration, the polyps were homogeneous (n = 11), with well-defined borders (n = 13), oval (n = 13), and had rim enhancement (n = 13). Nasopharyngeal polyps were pedunculated in 11 cats with a stalk-like structure connecting the polyp through the auditory tube to an affected tympanic bulla. All cats had at least one tympanic bulla severely affected, with CT images identifying: (1) complete (n = 12) or partial (n = 1) obliteration of either the dorsal or ventral compartments with soft-tissue attenuating material; (2) pathologic expansion (n = 13) with wall thickening (n = 10) that was asymmetric in nine cats; and (3) identification of a polyp-associated stalk-like structure (n = 11). Nine cats had unilateral tympanic bulla disease ipsilateral to the polyp, and four cats had bilateral tympanic bulla disease, most severe ipsilateral to the polyp with milder contralateral pathologic changes. Two cats had minimal osteolysis of the tympanic bulla. Enlargement of the medial retropharyngeal lymph node was seen commonly (n = 8), and in all cats it was ipsilateral to the most affected tympanic bulla. One cat had bilateral lymphadenopathy. CT is an excellent imaging tool for the supportive diagnosis of nasopharyngeal polyps in cats. CT findings of a well-defined mass with strong rim enhancement, mass-associated stalk-like structure, and asymmetric tympanic bulla wall thickening with pathologic expansion of the tympanic bullae are highly indicative of an inflammatory polyp.


Sephin1, which prolongs the integrated stress response, is a promising therapeutic for multiple sclerosis.
Multiple sclerosis is a chronic autoimmune demyelinating disorder of the CNS. Immune-mediated oligodendrocyte cell loss contributes to multiple sclerosis pathogenesis, such that oligodendrocyte-protective strategies represent a promising therapeutic approach. The integrated stress response, which is an innate cellular protective signalling pathway, reduces the cytotoxic impact of inflammation on oligodendrocytes. This response is initiated by phosphorylation of eIF2α to diminish global protein translation and selectively allow for the synthesis of protective proteins. The integrated stress response is terminated by dephosphorylation of eIF2α. The small molecule Sephin1 inhibits eIF2α dephosphorylation, thereby prolonging the protective response. Herein, we tested the effectiveness of Sephin1 in shielding oligodendrocytes against inflammatory stress. We confirmed that Sephin1 prolonged eIF2α phosphorylation in stressed primary oligodendrocyte cultures. Moreover, by using a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis, we demonstrated that Sephin1 delayed the onset of clinical symptoms, which correlated with a prolonged integrated stress response, reduced oligodendrocyte and axon loss, as well as diminished T cell presence in the CNS. Sephin1 is reportedly a selective inhibitor of GADD34 (PPP1R15A), which is a stress-induced regulatory subunit of protein phosphatase 1 complex that dephosphorylates eIF2α. Consistent with this possibility, GADD34 mutant mice presented with a similar ameliorated experimental autoimmune encephalomyelitis phenotype as Sephin1-treated mice, and Sephin1 did not provide additional therapeutic benefit to the GADD34 mutant animals. Results presented from the adoptive transfer of encephalitogenic T cells between wild-type and GADD34 mutant mice further indicate that the beneficial effects of Sephin1 are mediated through a direct protective effect on the CNS. Of particular therapeutic relevance, Sephin1 provided additive therapeutic benefit when combined with the first line multiple sclerosis drug, interferon β. Together, our results suggest that a neuroprotective treatment based on the enhancement of the integrated stress response would likely have significant therapeutic value for multiple sclerosis patients.


Long-term clinical outcomes after a percutaneous coronary intervention with a drug-eluting stent in patients with unprotected left main coronary artery disease excluded from clinical trials.
Major randomized clinical trials assessing clinical outcomes in patients who underwent a percutaneous coronary intervention (PCI) for left main coronary artery disease excluded some high-risk subsets. Whether the effectiveness and safety of a percutaneous approach in this group of patients are comparable with those observed in clinical trials is unclear. We aimed to explore the long-term outcomes of contemporary drug-eluting stent (DES)-based revascularization for left main coronary artery disease in patients presenting with one or more clinical or angiographic characteristics who would have precluded inclusion in randomized trials. Between April 2003 and December 2011, 340 consecutive patients with unprotected left main coronary artery stenosis of at least 50% who underwent successful PCI with DES at Sejong General Hospital (Bucheon, Republic of Korea) were included in this retrospective study. Patients were classified into the exclusion group (group E; n=120) and the inclusion group (group I; n=220) according to the prespecified inclusion and exclusion criteria utilized in clinical trials. During the median follow-up of 86 (52-114) months, major adverse cardiac or cerebrovascular events occurred in 69 (31.4%) patients in group I and 46 (38.3%) patients in group E (P=0.155). In the propensity score-matched population, group E was not associated with a higher incidence of major adverse cardiac or cerebrovascular events (hazard ratio: 1.42, 95% confidence interval: 0.76-2.65, P=0.758). Definite or probable stent thrombosis occurred in five patients of group I, with no cases in group E. In our real-world registry, about a third of patients who underwent PCI for unprotected left main coronary artery stenosis had one or more high-risk characteristics or comorbid conditions that represent exclusion criteria of previous randomized trials. PCI using DES is feasible in these patients.


Well-being of professional older adults' caregivers in Alberta's assisted living and long-term care facilities: a cross-sectional study.
For the care need of older adults, long-term care (LTC) and assisted living (AL) facilities are expanding in Alberta, but little is known about the caregivers' well-being. The purpose of the study was to investigate the physical health conditions, mental and emotional health (MEH), health behaviour, stress levels, quality of life (QOL), and turnover and absenteeism (TAA) among professional caregivers in Alberta's LTC and AL facilities. This cross-sectional survey involved 933 conveniently selected caregivers working in Alberta's LTC and AL facilities. Standardised questions were selected from the Canadian Community Health Survey, Patient Health Questionnaire-9, and Short Form-36 QOL survey revalidated and administered to the participants. The new questionnaire was used to assess the caregivers' general health condition (GHC), physical health, health behaviour, stress level, QOL, and TAA. Data were analysed using descriptive statistics, Cronbach alpha, Pearson's correlation, one-way analysis of variance, and multiple linear regression. Of 1385 surveys sent to 39 facilities, 933 valid responses were received (response rate = 67.4%). The majority of the caregivers were females (90.8%) who were ≥ 35 years (73.6%), worked between 20 to 40 h weekly (67.3%), and were satisfied with their GHC (68.1%). The Registered Nurses had better GHC (mean difference [MD] = 0.18, p = 0.004) and higher TAA than the Health Care Aides (MD = 0.24, p = 0.005). There were correlations between caregivers' TAA and each of MEH (r = 0.398), QOL (r = 0.308), and stress (r = 0.251); p < 0.001. The most significant predictors of TAA were the propensity to quit a workplace or the profession, illness, job stress, and work-related injury, F (5, 551) = 76.62, p < 0.001, adjusted R2 = 0.998. Reducing the caregivers' job stressors such as work overload, inflexible schedule, and poor remuneration, and improving their quality of life, health behaviour, and mental, emotional, and physical health conditions may increase their job satisfaction and reduce turnover and absenteeism.


The neuropeptide neuromedin U activates eosinophils and is involved in allergen-induced eosinophilia.
Neuromedin U (NMU) is a neuropeptide expressed not only in the central nervous system but also in various organs, including the gastrointestinal tract and lungs. NMU interacts with two G protein-coupled receptors, NMU-R1 and NMU-R2. Although NMU-R2 is expressed in a specific region of the brain, NMU-R1 is expressed in various peripheral tissues, including immune and hematopoietic cells. Our recent study demonstrated an important role of NMU in mast cell-mediated inflammation. In this study, we showed that airway eosinophilia was reduced in NMU-deficient mice in an allergen-induced asthma model. There were no differences in the antigen-induced Th2 responses between wild-type and NMU knockout mice. NMU-R1 was highly expressed in the eosinophil cell line, and NMU directly induced Ca(2+) mobilization and extracellular/signal-regulated kinase phosphorylation. NMU also induced cell adhesion to components of the extracellular matrix (fibronectin and collagen type I), and chemotaxis in vitro. Furthermore, NMU-R1 was also expressed in human peripheral blood eosinophils, and NMU induced cell adhesion in a dose-dependent manner. These data indicate that NMU promotes eosinophil infiltration into inflammatory sites by directly activating eosinophils. Our study suggests that NMU receptor antagonists could be novel targets for pharmacological inhibition of allergic inflammatory diseases, including asthma.


Hypertension in Reproductive-Aged Women With Polycystic Ovary Syndrome and Association With Obesity.
Polycystic ovary syndrome (PCOS) is a common disorder with metabolic complications, yet the prevalence of hypertension is unclear. We aim to assess hypertension prevalence and the impact of obesity in women reporting PCOS compared to those not reporting PCOS. This is a cross-sectional analysis of data from a large longitudinal study, the Australian Longitudinal Study on Women's Health (ALSWH). Women from the general community were randomly selected from the national health insurance database. Standardized data collection occurred at 6 survey time points. Data from Survey 4 in 2006 (n = 8,612, age: 28-33 years) were examined for this study. The main outcome measures studied were self-reported PCOS and hypertension. Reported PCOS prevalence was 5.8% (95% confidence interval (CI): 5.3%-6.4%). Women with PCOS had higher body mass index (BMI). Hypertension prevalence was 5.5% (95% CI: 3.3-7.7) in women reporting PCOS and 2.0% (95% CI: 1.6-2.3) in women not reporting PCOS (P < 0.001). Hypertension was associated with BMI (odds ratio: 1.07, 95% CI: 1.05-1.10, P < 0.001) with a trend towards an association with PCOS (P = 0.09). On subgroup analysis, hypertension was not associated with BMI in women reporting PCOS but was associated in those not reporting PCOS. In this large community-based cohort, we note increased prevalence of hypertension and higher BMI in young women reporting PCOS. BMI association with hypertension appeared clear in women not reporting PCOS. Yet in women with PCOS, hypertension appeared to not be associated with BMI, akin to observations on diabetes risk in PCOS, suggesting that metabolic abnormalities in PCOS may be independent of BMI.


A Randomized Crossover Study to Assess the Usability of Two New Vision Tests in Patients with Low Vision.
Well-established charts such as Early Treatment Diabetic Retinopathy Study are able to quantify visual acuity (VA) with a low cutoff of 1.6 logMAR. Below this point, nonquantitative measures, such as count fingers, hand movements, and light perception, are used. There is a need for more reproducible, comparable, and reliable ways to measure VA changes in this patient cohort. The purpose of this study was to examine and compare the ability of the Berkeley Rudimentary Vision Test (BRVT) and the Freiburg Acuity Test (FrACT) to quantify VA in low-vision patients who score nonnumerical VAs in standard charts. Fifty adult participants with VA ≤1.0 logMAR in both eyes were recruited from the Oxford Eye Hospital, Oxford, United Kingdom. Correlation between FrACT and BRVT results and the correlation between VA and daily living activities were analyzed statistically. Potential predictors of differences were investigated. The BRVT was significantly faster to conduct (P = .002), but FrACT was able to quantify vision numerically in a greater proportion of eyes. The κ agreement between tests was 0.26. The difference increased systematically with the VA reduction (P < .0001). The Bland-Altman analysis showed a skew to measurement of lower logMAR VA indicating better vision measured on the FrACT. The only significant predictor of difference between the tests was binocular VA (coefficient, -0.445; P = .001). Both tests are suitable for a very low-vision population. The BRVT is a faster test to administer, but FrACT provides a numerical result in more eyes. The poor intertest repeatability indicates that they cannot be used interchangeably. The BRVT generally reported poorer vision than did the FrACT. The medium of presentation, such as a computer screen or externally lit print medium, is likely to be the biggest factor in these differences and warrants further investigation.


Post-Daubert admissibility of scientific evidence on malingering of cognitive deficits.
In Daubert v. Merrell Dow Pharmaceuticals, Inc. (1993) the Supreme Court held that evidence must be "reliable" to be admissible and for scientific evidence "evidentiary reliability" is based on scientific validity. This article addresses the question "Do the Rey 15-Item Test ('FIT'), the Test of Memory Malingering ('TOMM'), and the Validity Indicator Profile ('VIP') likely meet the Daubert standard for admissibility of scientific evidence?" Sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively), and base rates of 30 and 15 percent were calculated for each test. Given the existing literature on malingering and the implications of a misclassification of malingering, we discuss the findings for each of the three tests using a PPV > or = 80 percent with a base rate of malingering of < or = 30. Our analyses indicate that the Rey 15-FIT fails to meet this standard of scientific validity. In contrast, the TOMM shows high specificity and PPV, and our findings suggest cautious optimism regarding the VIP. These results are discussed within the context of the courts' guidelines for the Daubert standard.


Preventing dental caries in children <5 years: systematic review updating USPSTF recommendation.
Screening and preventive interventions by primary care providers could improve outcomes related to early childhood caries. The objective of this study was to update the 2004 US Preventive Services Task Force systematic review on prevention of caries in children younger than 5 years of age. Searching Medline and the Cochrane Library (through March 2013) and reference lists, we included trials and controlled observational studies on the effectiveness and harms of screening and treatments. One author extracted study characteristics and results, which were checked for accuracy by a second author. Two authors independently assessed study quality. No study evaluated effects of screening by primary care providers on clinical outcomes. One good-quality cohort study found pediatrician examination associated with a sensitivity of 0.76 for identifying a child with cavities. No new trials evaluated oral fluoride supplementation. Three new randomized trials were consistent with previous studies in finding fluoride varnish more effective than no varnish (reduction in caries increment 18% to 59%). Three trials of xylitol were inconclusive regarding effects on caries. New observational studies were consistent with previous evidence showing an association between early childhood fluoride use and enamel fluorosis. Evidence on the accuracy of risk prediction instruments in primary care settings is not available. There is no direct evidence that screening by primary care clinicians reduces early childhood caries. Evidence previously reviewed by the US Preventive Services Task Force found oral fluoride supplementation effective at reducing caries incidence, and new evidence supports the effectiveness of fluoride varnish in higher-risk children.


An analysis of ophthalmology services in Finland - has the time come for a Public-Private Partnership?
We studied the prerequisites for Public-Private Partnership (PPP) in the context of the Finnish health care system and more specifically in the field of ophthalmology. PPP can be defined as a more or less permanent cooperation between public and private actors, through which the joint products or services are developed and in which the risks, costs and profits are shared.The Finnish eye care services system is heterogeneous with several different providers and can be regarded as sub-optimal in terms of overall resource use. What is more, the public sector is suffering from a shortage of ophthalmologists, which further decreases its possibilities to meet the present needs. As ophthalmology has traditionally been a medical specialty with a substantial private sector involvement in service provision, PPP could be a feasible policy to be used in the field. We thus ask the following research question: Is there, and to what extent, an open window of opportunity for PPP? In addition to the previously published literature, the research data consisted of 17 thematic interviews with public and private experts in the field of ophthalmology. The analysis was conducted in two stages. First, a literature-based content analysis was used to explore the prerequisites for PPP. Second, Kingdon's (1995) multiple streams theory was used to study the opening of the window of opportunity for PPP. Public and private parties reported similar problems in the current situation but defined them differently. Also, there is no consensus on policy alternatives. Public opinion seems to be somewhat uncertain as to the attitudes towards private service providers. The analysis thus showed that although there are prerequisites for PPP, the time has not yet come for a Public-Private Partnership. Should the window open fully, the emergence of policy entrepreneurs and an opportunity for a win-win situation between public and private organizations are required.


Spatiotemporal dynamics of Toxoplasma gondii infection in Canadian lynx (Lynx canadensis) in western Québec, Canada.
Toxoplasma gondii, one of the more common zoonotic parasites in the world, can cause serious illness in humans and other animals worldwide. Felids are the only known host that can shed T. gondii oocysts, which are essential to the perpetuation of the parasite. In much of boreal Canada, the Canadian lynx (Lynx canadensis) is the only wild felid host that could contribute to environmental contamination with T. gondii oocysts. We estimated the prevalence of T. gondii antibodies in Canadian lynx from western Québec and compared our results with earlier findings in the same region 12 yr earlier. We investigated factors associated with seroconversion, including age, sex, geographic location, and possible co-occurrence with domestic cats (Felis catus), and we assessed the proportion of lynx shedding T. gondii oocysts. Blood and fecal samples were collected from 84 lynx harvested by trappers in the eastern part of the study area during winter 2009-2010. Sera were tested for antibodies to T. gondii by the modified agglutination test (cutoff titer 1:50) and fecal samples for parasite eggs by fecal flotation. Antibodies to T. gondii were detected in sera of 14% of 84 lynx. Numerous helminth ova and coccidian oocysts were found in feces, whereas T. gondii-like oocysts were not detected. Antibody prevalence increased with age class (odds ratio [OR]=4.33, 95% confidence interval [CI]=1.57-11.99, P<0.01). Antibody prevalence (14%) in our study was significantly lower than in 84 lynx (36%) trapped in the western part of the study area during winter 1997-1998 (OR=0.18, 95% CI=0.08-0.44, P<0.001). Our results suggest there may be significant spatiotemporal dynamics of T. gondii infection in lynx in Canada, and we review possible abiotic and biotic ecologic factors supporting these findings.


Inhibitory effects of glycolipids fraction from spinach on mammalian DNA polymerase activity and human cancer cell proliferation.
We succeeded in purifying the fraction containing the major glycolipids in monogalactosyl diacylglycerol, digalactosyl diacylglycerol and sulfoquinovosyl diacylglycerol (SQDG) from dried vegetables. This glycolipids fraction was an inhibitor of DNA polymerase alpha (pol alpha) in vitro and also the proliferation of human cancer cells. In this study, eight common vegetables were investigated in terms of the glycolipids fraction, the amounts of major glycolipids, mammalian DNA polymerase inhibitory activity and antiproliferative activity toward human cancer cells. Green tea possessed the largest amount of glycolipids overall. Spinach contained the largest amount of SQDG, followed by parsley, green onion, chive, sweet pepper, green tea, carrot and garlic. Spinach had the strongest inhibitory effect on pol alpha activity and human cancer cell proliferation. A significant correlation was found between SQDG content and inhibition of DNA polymerase. Therefore, the inhibition of pol alpha activity by SQDG may lead to cell growth suppression. Of the six subspecies of spinach (Spinacia oleracea) tested, "Anna" had the largest amount of SQDG, strongest inhibitory activity toward DNA polymerase and greatest effect on human cancer cell proliferation. Based on these results, the glycolipids fraction from spinach is potentially a source of food material for a novel anticancer activity.


Metabolic effects of L-carnitine on type 2 diabetes mellitus: systematic review and meta-analysis.
Carnitine is an endogenous metabolite and exogenous nutrient with a pivotal role in lipid metabolism. Plasma levels of carnitine are reduced in type 2 Diabetes Mellitus (T2DM). The aim was to evaluate the metabolic effects of the administration of L-carnitine in T2DM. A systematic review was performed. Relevant randomized, controlled-trials trials were searched in Pubmed, Trip Database and Cochrane Library, and selected when they had enough methodological quality assessed with the Jadad scale. Article search strategy included "Carnitine" OR "L-carnitine" AND "Diabetes -Mellitus" OR "Diabetes mellitus, type 2" OR "Noninsulindependent-diabetes mellitus". Meta-analysis was performed, and the difference of means calculated with a 95% confidence interval. Heterogeneity was evaluated with the Q statistic. The systematic review included 4 trials with 284 patients. Oral L-carnitine lowered fasting plasma glucose [-14.3 mg/dl (CI95% - 23.2 to -5.4); p=0,002], total cholesterol [-7.8 mg/dL (95%CI -15.5 to -0.1); p=0.09], low density lipoprotein [-8.8 mg/dl (CI95% -12.2 to -8.5), p<0.0001], apolipoprotein-B100 [-7.6 mg/dl (CI95% -13.6 to -1.6); p=0.013] and apolipoprotein-A1 [-6.0 mg/dl (CI95% -10.5 a -1.5); p=0.523]. There was no significant heterogeneity. The changes in triglycerides, lipoprotein (a) or HbA(1c) were not significant. The administration of L-carnitine in type 2 diabetes mellitus is associated with an improvement in glycaemia and plasma lipids.


Treatment Outcome of Ovulation-inducing Agents in Patients with Anovulatory Infertility: A Prospective, Observational Study.
To compare different treatment regimens on pregnancy rate and outcome in patients with anovulatory infertility. A prospective observational study was conducted on patients with infertility due to anovulation. Patients treated with clomiphene citrate (CC) 50/100 mg/day from 2nd to 6th day of menstrual cycle (MC) (n = 38), short gonadotropin-releasing hormone (GnRH) agonist regimen (leuprolide [0.5 mg subcutaneous] + recombinant follicle-stimulating hormone [rFSH] [225 IU intramuscular [IM] from 2nd to 10th day of MC [n = 32]), long GnRH agonist regimen (leuprolide from 21st day followed by leuprolide + rFSH from 2nd to 10th day of MC [n = 19]), and antagonist regimen (human menopausal gonadotropin [hMG] [150 IU IM] from 2nd day followed by hMG + cetrorelix from 7th to 10th day of MC) (n = 6) were recruited and followed up for follicular size, endometrial thickness, and pregnancy test. Data were analyzed using appropriate statistical test andP < 0.05 was considered statistically significant. A significant increase in follicular diameter and endometrial thickness was observed in patients treated with gonadotropin regimens as compared to CC alone (P < 0.0001). The highest number of positive pregnancy test with ultrasonographic evidence of gestational sac was observed with leuprolide + rFSH (long regimen) (10/19, 52.6%) followed by leuprolide + rFSH (short regimen) (13/32, 40.6%) while least in antagonist regimen (2/6, 33.3%) and CC (1/38, 2.63%). All regimens were well tolerated. Treatment outcome was better with long agonist regimen.


Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial.
The current recommendation is for at least 12 months of dual antiplatelet therapy after implantation of a drug-eluting stent. However, the optimal duration of dual antiplatelet therapy with specific types of drug-eluting stents remains unknown. To assess the clinical noninferiority of 3 months (short-term) vs 12 months (long-term) of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) with zotarolimus-eluting stents. The OPTIMIZE trial was an open-label, active-controlled, 1:1 randomized noninferiority study including 3119 patients in 33 sites in Brazil between April 2010 and March 2012. Clinical follow-up was performed at 1, 3, 6, and 12 months. Eligible patients were those with stable coronary artery disease or history of low-risk acute coronary syndrome (ACS) undergoing PCI with zotarolimus-eluting stents. After PCI with zotarolimus-eluting stents, patients were prescribed aspirin (100-200 mg daily) and clopidogrel (75 mg daily) for 3 months (n = 1563) or 12 months (n = 1556), unless contraindicated because of occurrence of an end point. The primary end point was net adverse clinical and cerebral events (NACCE; a composite of all-cause death, myocardial infarction [MI], stroke, or major bleeding); the expected event rate at 1 year was 9%, with a noninferiority margin of 2.7%. Secondary end points were major adverse cardiac events (MACE; a composite of all-cause death, MI, emergent coronary artery bypass graft surgery, or target lesion revascularization) and Academic Research Consortium definite or probable stent thrombosis. NACCE occurred in 93 patients receiving short-term and 90 patients receiving long-term therapy (6.0% vs 5.8%, respectively; risk difference, 0.17 [95% CI, -1.52 to 1.86]; P = .002 for noninferiority). Kaplan-Meier estimates demonstrated MACE rates at 1 year of 8.3% (128) in the short-term group and 7.4% (114) in the long-term group (HR, 1.12 [95% CI, 0.87-1.45]). Between 91 and 360 days, no statistically significant association was observed for NACCE (39 [2.6%] vs 38 [2.6%] for the short- and long-term groups, respectively; HR, 1.03 [95% CI, 0.66-1.60]), MACE (78 [5.3%] vs 64 [4.3%]; HR, 1.22 [95% CI, 0.88-1.70]), or stent thrombosis (4 [0.3%] vs 1 [0.1%]; HR, 3.97 [95% CI, 0.44-35.49]). In patients with stable coronary artery disease or low-risk ACS treated with zotarolimus-eluting stents, 3 months of dual antiplatelet therapy was noninferior to 12 months for NACCE, without significantly increasing the risk of stent thrombosis. clinicaltrials.gov Identifier: NCT01113372.


Real-time high resolution laser speckle imaging of cerebral vascular changes in a rodent photothrombosis model.
The study of hemodynamic and vascular changes following ischemic stroke is of great importance in the understanding of physiological and pathological processes during the thrombus formation. The photothrombosis model is preferred by researchers in stroke study for its minimal invasiveness, controllable infarct volume and lesion location. Nevertheless, there is a lack in high spatiotemporal resolution techniques for real time monitoring of cerebral blood flow (CBF) changes in 2D-profile. In this study, we implemented a microscopic laser speckle imaging (LSI) system to detect CBF and other vascular changes in the rodent model of photothrombotic stroke. Using a high resolution and high speed CCD (640 × 480 pixels, 60 fps), online image registration technique, and automatic parabolic curve fitting, we obtained real time CBF and blood velocity profile (BVP) changes in cortical vessels. Real time CBF and BVP monitoring has been shown to reveal details of vascular disturbances and the stages of blood coagulation in photothrombotic stroke. Moreover, LSI also provides information on additional parameters including vessel morphologic size, blood flow centerline velocity and CBF spatiotemporal fluctuations, which are very important for understanding the physiology and neurovascular pathology in the photothrombosis model.