Comparison of grey water treatment performance by a cascading sand filter and a constructed wetland.
A novel unplanted vertical flow subsurface constructed wetland technology comprising three shallow beds (0.6 m length, 0.45 m width and 0.2 m depth) arranged in a cascading series and a standard single-pass Vertical Flow Planted Constructed Wetland (VFPCW, 6 m² and 0.7 m depth) were tested for grey water treatment. Particular focus was on meeting consent for published wastewater reuse parameters and removal of anionic surfactants. Treatment performance at two hydraulic loading rates (HLR) of 0.08, and 0.17 m³ m⁻² d⁻¹ were compared. Both technologies effectively removed more than 90% turbidity and more than 96% for organics with the prototype meeting the most stringent reuse standard of < 2 NTU and <10 mg/L. However, surfactant removal in the VFPCW was higher (76-85%) than in the prototype which only achieved more than 50% removal at higher loading rate. Generally, the prototype performed consistently better than the VFPCW except for surfactant removal. However, at higher loading rates, both systems did not meet the reuse standard of <1 mg L⁻¹ for anionic surfactants. This observation confirms that shallow beds provide a more oxidised environment leading to higher BOD₅ and COD removals. Presence of plants in the VFPCW led to higher anionic surfactant removal, through increased microbial and sorption processes.


Paired maxillary and smaller mandibular mouthguard for rugby player with malalignment.
A rugby player who had frequently experienced soft tissue injuries while playing rugby and wearing a conventional custom-made mouthguard came to the hospital clinic. The patient had suffered traumatic soft tissue injuries such as lip lacerations and bite trauma. Severe crowding due to ectopic maxillary and mandibular canines was observed. In response to the patient's request for better protection, a set of maxillary and mandibular mouthguards was designed: one covering the entire maxillary dentition and the other the mandibular front teeth only. The mouthguards were to be worn simultaneously. In this paper, we describe how these mouthguards were fabricated and discuss the results. The patient has experienced no injury to the stomatognathic system, including the lips, for five seasons since he began wearing this set of mouthguards. This new pairing of mouthguards appears to offer sufficient protection against injury, despite severe malalignment. We believe that this new type of paired maxillary and mandibular mouthguards has the potential to reduce sports-related dental injuries.


Primary intestinal lymphoma: clinical and therapeutic features of 32 patients.
Lymphomas of the gastrointestinal tract are the most common type of primary extranodal lymphomas, accounting for 5 to 10% of all non-Hodgkin's lymphomas. In particular, primary intestinal lymphomas represent about 15-20% of gastrointestinal lymphomas. New multimodal therapeutic approaches have improved the prognosis of this once deadly disease: we report a retrospective analysis of our experience with 32 cases of primary western intestinal lymphomas, presenting clinical, therapeutical and prognostic data. From March 1989 to November 1995, 32 patients with untreated primary western intestinal lymphomas were submitted to radical surgery plus polychemotherapy (early stages, I and II; 22 patients), or polychemotherapy alone (advanced stage, III and IV; 10 patients). The most frequent symptoms were abdominal pain, nausea, vomiting and weight loss. The tumor was located in the jejunum in 2 cases (6.2%), in the proximal small bowel in 15 cases (46.9%), in the distal and terminal ileum in 8 cases (25%), in the colon and rectum in 4 cases (12.5%), and multiple sites were found in 3 cases (9.4%). According to histology, 26 patients had high-grade and 6 low-grade non-Hodgkin's lymphoma. Stage I-II patients underwent radical resection of the tumor and chemotherapy; advanced (III-IV) stage patients were treated with chemotherapy alone as first-line approach. Of the 32 patients, 24 (75%) achieved a complete response (CR); according to stage, all stage I-II patients had CR, while only 2 of the 10 stage III-IV patients reached CR. The risk of a lower response rate was significantly correlated with the presence of advanced stage (III-IV) (p = 0.000001). The overall 5-year survival rate was 59%, with a relapse-free survival rate of 72% among the 24 complete responders. Intestinal lymphomas differ significantly from their gastric counterpart, not only in pathology, but also with regard to clinical features, management and prognosis. Our experience confirm the efficacy of the surgery-chemotherapy combination in obtaining a good remission rate for localized early primary intestinal lymphoma and indicates that this combination represents the only means for managing complications.


Locally advanced versus metastatic pancreatic cancer: two different diseases with two different treatment approaches?
The results of the SCALOP trial were reviewed and interpreted at the light of previous trials and of the more recent LAP-07 trial. In this latter trial the role of radiotherapy after an induction chmeotherapy has been questioned. Based on these findings data from the SCALOP trial loose most of their value. In fact, while it showed that capecitabine may be combined with radiotherapy more safely than gemcitabine and it could be a standard regimen as a consolidation regimen after an induction chemotherapy, the LAP-07 trial showed that radiotherapy in combination with chemotherapy does not add any valuable effect to chemotherapy alone.


Development of novel therapeutic strategies for lung cancer: targeting the cholinergic system.
One of the earliest descriptions of non-neuronal ACh synthesis was by Morris who reported that ACh was synthesized in the placenta [1]; furthermore, Falugi et al. showed the presence of AChE in human fibrosarcoma cells [2]. Afterward, the expression of ACh, AChE, and cholinergic receptors in non-neuronal cells was reported in several studies [3-16]. Indeed, recent data reported that SCLC expresses a cholinergic autocrine loop that can regulate cell growth. Such work demonstrates that SCLC cells have a cholinergic phenotype and that ACh exerts as an autocrine growth factor in human lung tumours [16]. Moreover, it has been recently reported that nicotine in lung adenocarcinoma A549 cells, potently induces Bad phosphorylation at serine (S)112, S136 and S155 in a mechanism involving activation of MAPKs, ERK1/2, PI3K/AKT and PKA through the linking to alpha7-receptors [9]. Bad phosphorylation results in sequestering Bad from mitochondria and subsequently interacting with 14-3-3 in the cytosol [9]. We have recently reported that human malignant pleural mesothelioma expresses a cholinergic system, involved in cell growth regulation. Hence, mesothelioma cells growth is modulated by the cholinergic system in which agonists (i.e. nicotine) have a proliferative effect and antagonists (i.e. curare or alpha-cobratoxin) have an inhibitory effect. Furthermore apoptosis mechanisms are under the control of the cholinergic system (nicotine antiapoptotic via induction of NF-kappaB complexes and phosphorylation of Bad at S112, curare proapoptotic via G0-G1 arrest p21waf-1-dependent, but p53-independent) [16]. The involvement of the non-neuronal cholinergic system in lung cancer and mesothelioma appears reasonable and opens up new translational research strategies.


Modelling the propagation of terahertz radiation through a tissue simulating phantom.
Terahertz (THz) frequency radiation, 0.1 THz to 20 THz, is being investigated for biomedical imaging applications following the introduction of pulsed THz sources that produce picosecond pulses and function at room temperature. Owing to the broadband nature of the radiation, spectral and temporal information is available from radiation that has interacted with a sample; this information is exploited in the development of biomedical imaging tools and sensors. In this work, models to aid interpretation of broadband THz spectra were developed and evaluated. THz radiation lies on the boundary between regions best considered using a deterministic electromagnetic approach and those better analysed using a stochastic approach incorporating quantum mechanical effects, so two computational models to simulate the propagation of THz radiation in an absorbing medium were compared. The first was a thin film analysis and the second a stochastic Monte Carlo model. The Cole-Cole model was used to predict the variation with frequency of the physical properties of the sample and scattering was neglected. The two models were compared with measurements from a highly absorbing water-based phantom. The Monte Carlo model gave a prediction closer to experiment over 0.1 to 3 THz. Knowledge of the frequency-dependent physical properties, including the scattering characteristics, of the absorbing media is necessary. The thin film model is computationally simple to implement but is restricted by the geometry of the sample it can describe. The Monte Carlo framework, despite being initially more complex, provides greater flexibility to investigate more complicated sample geometries.


Optimizing the representation of orientation preference maps in visual cortex.
The colorful representation of orientation preference maps in primary visual cortex has become iconic. However, the standard representation is misleading because it uses a color mapping to indicate orientations based on the HSV (hue, saturation, value) color space, for which important perceptual features such as brightness, and not just hue, vary among orientations. This means that some orientations stand out more than others, conveying a distorted visual impression. This is particularly problematic for visualizing subtle biases caused by slight overrepresentation of some orientations due to, for example, stripe rearing. We show that displaying orientation maps with a color mapping based on a slightly modified version of the HCL (hue, chroma, lightness) color space, so that primarily only hue varies between orientations, leads to a more balanced visual impression. This makes it easier to perceive the true structure of this seminal example of functional brain architecture.


Microbial mechanisms of carbon removal in subsurface flow wetlands.
The microbial mechanisms of carbon removal in subsurface flow wetlands were studied, in one wetland with plants and one without plants. Particular emphasis was given to the influence of plants in the treatment process. Wetlands without plants showed higher carbon removal than those with plants, 63% and 51%, respectively (p < 0.05). Molecular analysis of the bacterial diversity, growth rates and specific microbial activities showed that the two wetlands were different, especially towards the outlet of the two systems. Sulphate reducers and methanogens were found in both wetlands, and they are thought to be the main removers of soluble organic carbon in these two systems.


Design of the Dutch Obesity Intervention in Teenagers (NRG-DOiT): systematic development, implementation and evaluation of a school-based intervention aimed at the prevention of excessive weight gain in adolescents.
Only limited data are available on the development, implementation, and evaluation processes of weight gain prevention programs in adolescents. To be able to learn from successes and failures of such interventions, integral written and published reports are needed. Applying the Intervention Mapping (IM) protocol, this paper describes the development, implementation, and evaluation of the Dutch Obesity Intervention in Teenagers (DOiT), a school-based intervention program aimed at the prevention of excessive weight gain. The intervention focussed on the following health behaviours: (1) reduction of the consumption of sugar-sweetened beverages, (2) reduction of energy intake derived from snacks, (3) decrease of levels of sedentary behaviour, and (4) increase of levels of physical activity (i.e. active transport behaviour and sports participation). The intervention program consisted of an individual classroom-based component (i.e. an educational program, covering 11 lessons of both biology and physical education classes), and an environmental component (i.e. encouraging and supporting changes at the school canteens, as well as offering additional physical education classes). We evaluated the effectiveness of the intervention program using a randomised controlled trial design. We assessed the effects of the intervention on body composition (primary outcome measure), as well as on behaviour, behavioural determinants, and aerobic fitness (secondary outcome measures). Furthermore, we conducted a process evaluation. The development of the DOiT-intervention resulted in a comprehensive school-based weight gain prevention program, tailored to the needs of Dutch adolescents from low socio-economic background.


An evaluation of the use of remotely sensed parameters for prediction of incidence and risk associated with Vibrio parahaemolyticus in Gulf Coast oysters (Crassostrea virginica).
The U.S. Food and Drug Administration recently published a Vibrio parahaemolyticus risk assessment for consumption of raw oysters that predicts V. parahaemolyticus densities at harvest based on water temperature. We retrospectively compared archived remotely sensed measurements (sea surface temperature, chlorophyll, and turbidity) with previously published data from an environmental study of V. parahaemolyticus in Alabama oysters to assess the utility of the former data for predicting V. parahaemolyticus densities in oysters. Remotely sensed sea surface temperature correlated well with previous in situ measurements (R(2) = 0.86) of bottom water temperature, supporting the notion that remotely sensed sea surface temperature data are a sufficiently accurate substitute for direct measurement. Turbidity and chlorophyll levels were not determined in the previous study, but in comparison with the V. parahaemolyticus data, remotely sensed values for these parameters may explain some of the variation in V. parahaemolyticus levels. More accurate determination of these effects and the temporal and spatial variability of these parameters may further improve the accuracy of prediction models. To illustrate the utility of remotely sensed data as a basis for risk management, predictions based on the U.S. Food and Drug Administration V. parahaemolyticus risk assessment model were integrated with remotely sensed sea surface temperature data to display graphically variations in V. parahaemolyticus density in oysters associated with spatial variations in water temperature. We believe images such as these could be posted in near real time, and that the availability of such information in a user-friendly format could be the basis for timely and informed risk management decisions.


A Cell-Based Assay Reveals Nuclear Translocation of Intracellular Domains Released by SPPL Proteases.
During regulated intramembrane proteolysis (RIP) a membrane-spanning substrate protein is cleaved by an ectodomain sheddase and an intramembrane cleaving protease. A cytoplasmic intracellular domain (ICD) is liberated, which can migrate to the nucleus thereby influencing transcriptional regulation. Signal peptide peptidase-like (SPPL) 2a and 2b have been implicated in RIP of type II transmembrane proteins. Even though SPPL2a might represent a potential pharmacological target for treatment of B-cell-mediated autoimmunity, no specific and potent inhibitors for this enzyme are currently available. We report here on the first quantitative cell-based assay for measurement of SPPL2a/b activity. Demonstrating the failure of standard Gal4/VP16 reporter assays for SPPL2a/b analysis, we have devised a novel system employing β-galactosidase (βGal) complementation. This is based on detecting nuclear translocation of the proteolytically released substrate ICDs, which results in specific restoration of βGal activity. Utilizing this potentially high-throughput compatible new setup, we demonstrate nuclear translocation of the ICDs from integral membrane protein 2B (ITM2B), tumor necrosis factor (TNF) and CD74 and identify secreted frizzled-related protein 2 (SFRP2) as potential transcriptional downstream target of the CD74 ICD. We show that the presented assay is easily adaptable to other intramembrane proteases and therefore represents a valuable tool for the functional analysis and development of new inhibitors of this class of enzymes.


Preventing risk for significant behavior problems through a cognitive-behavioral intervention: effects of the tools for getting along curriculum at one-year follow-up.
Efficient and effective social-emotional learning programs increase the likelihood of success in school for all students, and particularly for those who may develop emotional or behavior problems. In this study, we followed a sub-sample of students 1 year after their participation in a randomized controlled trial of the effects of the Tools for Getting Along (TFGA) curriculum. TFGA is a universally delivered, preventive cognitive-behavioral curricular intervention designed to improve upper elementary school students' emotional and behavioral self-regulation. To determine effects at 1-year follow-up, we assessed 720 out of the 1,296 original students across TFGA and control conditions on measures of curricular knowledge, teacher-rated executive function and behavior, and student-reported anger and social problem solving. Findings indicated a continued positive effect on curricular knowledge for students taught TFGA relative to controls. We also found significant pretest by condition interaction effects on teacher reports of skills associated with executive function, including inhibitory control and shift (cognitive flexibility), and on teacher reported internalizing and externalizing behavior. Specifically, students with poorer scores on these measures at pretest benefited from TFGA at follow-up relative to comparable students in the control condition. Finally, we found marginally significant pretest by condition interaction effects on proactive aggression, outward expressions of anger, and the executive function related skills of initiating activities and using working memory. Counter to expectations, we found negative TFGA effects on student-reported trait anger and anger control.


Refractive state following retinal reattachment and silicone oil tamponade in dogs.
To evaluate the refractive error induced by intraocular administration of silicone oil (SiO) in dogs. 47 client-owned dogs evaluated for blindness secondary to retinal detachment. -3-port pars plana vitrectomy with perfluoro-octane and SiO exchange (1,000- or 5,000-centistoke SiO) was performed in 1 or both eyes for all dogs (n = 63 eyes), depending on which eye or eyes were affected. Dogs were normotensive, had complete oil filling of the eyes, and were examined in a standing position for retinoscopic examination of both eyes (including healthy eyes). The mean refractive error for SiO-filled phakic and pseudophakic eyes was 2.67 and 3.24 D, respectively. The mean refractive error for SiO-filled aphakic eyes was 6.50 D. Dogs in which 5,000-centistoke SiO was used had consistently greater positive refractive errors (mean, 3.45 D), compared with dogs in which 1,000-centistoke SiO was used (mean, 2.10 D); however, the difference was nonsignificant. There was no significant linear relationship between refractive error and the number of days between surgery and retinoscopy. Hyperopia was observed in all dogs that underwent SiO tamponade, regardless of lens status (phakic, pseudophakic, or aphakic). Aphakic eyes underwent a myopic shift when filled with SiO. Pseudophakic eyes appeared to be more hyperopic than phakic eyes when filled with SiO; however, additional investigation is needed to confirm the study findings.


Substance use disorders in Arab countries: research activity and bibliometric analysis.
Substance use disorders, which include substance abuse and substance dependence, are present in all regions of the world including Middle Eastern Arab countries. Bibliometric analysis is an increasingly used tool for research assessment. The main objective of this study was to assess research productivity in the field of substance use disorders in Arab countries using bibliometric indicators. Original or review research articles authored or co-authored by investigators from Arab countries about substance use disorders during the period 1900-2013 were retrieved using the ISI Web of Science database. Research activity was assessed by analyzing the annual research productivity, contribution of each Arab country, names of journals, citations, and types of abused substances. Four hundred and thirteen documents in substance use disorders were retrieved. Annual research productivity was low but showed a significant increase in the last few years. In terms of quantity, Kingdom of Saudi Arabia (83 documents) ranked first in research about substance use disorders while Lebanon (17.4 documents per million) ranked first in terms of number of documents published per million inhabitants. Retrieved documents were found in different journal titles and categories, mostly in Drug and Alcohol Dependence Journal. Authors from USA appeared in 117 documents published by investigators from Arab countries. Citation analysis of retrieved documents showed that the average citation per document was 10.76 and the h - index was 35. The majority of retrieved documents were about tobacco and smoking (175 documents) field while alcohol consumption and abuse research was the least with 69 documents. The results obtained suggest that research in this field was largely neglected in the past. However, recent research interest was observed. Research output on tobacco and smoking was relatively high compared to other substances of abuse like illicit drugs and medicinal agents. Governmental funding for academics and mental health graduate programs to do research in the field of substance use disorders is highly recommended.


Ungulate predation and ecological roles of wolves and coyotes in eastern North America.
Understanding the ecological roles of species that influence ecosystem processes is a central goal of ecology and conservation biology. Eastern coyotes (Canis latrans) have ascended to the role of apex predator across much of eastern North America since the extirpation of wolves (Canis spp.) and there has been considerable confusion regarding their ability to prey on ungulates and their ecological niche relative to wolves. Eastern wolves (C. lycaon) are thought to have been the historical top predator in eastern deciduous forests and have previously been characterized as deer specialists that are inefficient predators of moose because of their smaller size relative to gray wolves (C. lupus). We investigated intrinsic and extrinsic influences on per capita kill rates of white-tailed deer (Odocoileus virginianus) and moose (Alces alces) during winter by sympatric packs of eastern coyotes, eastern wolves, and admixed canids in Ontario, Canada to clarify the predatory ability and ecological roles of the different canid top predators of eastern North America. Eastern coyote ancestry within packs negatively influenced per capita total ungulate (deer and moose combined) and moose kill rates. Furthermore, canids in packs dominated by eastern coyote ancestry consumed significantly less ungulate biomass and more anthropogenic food than packs dominated by wolf ancestry. Similar to gray wolves in previous studies, eastern wolves preyed on deer where they were available. However, in areas were deer were scarce, eastern wolves killed moose at rates similar to those previously documented for gray wolves at comparable moose densities across North America. Eastern coyotes are effective deer predators, but their dietary flexibility and low kill rates on moose suggest they have not replaced the ecological role of wolves in eastern North America.


Micro RNA-126 coordinates cell behavior and signaling cascades according to characteristics of breast cancer cells.
Micro RNA-126 is known to enhance apoptotic processes and also plays a role in vascular growth through the regulation of vascular endothelial growth factor-mediated signaling, angiogenesis, and vascular integrity. We aimed to determine the role of miR-126 in breast cancer cell lines with a variety of different characteristics to evaluate its interaction with certain cancer-related molecules and mechanisms. To determine the effect of presence and absence of miR-126 in MCF-7 and MDA-MB-231 breast cancer cells, miR-126 mimics and inhibitor were transfected. miRNA and gene expressions were observed by using RT-PCR. Viability, proliferation, adhesion, invasion and lateral motility assays were performed to determine cell behavior changes. miR-126 is more effective on MDA-MB-231 cells on cell behavior. We observed an increase in miR-126 expression when miR-126 mimics was transfected to MCF-7 and MDA-MB-231 cells. Also, there was a decrease in miR-126 expression when MCF-7 and MDA-MB-231 cells were transfected with miR-126 inhibitor. Furthermore, presence and absence of miR-126 modulated the gene expressions of VEGF/PI3K/AKT and MAPK signaling in MCF-7 and MDA-MB-231. Our study showed that miR-126 is in a state of interaction with a multitude molecules playing a role in breast cancer. According to obtained data, we can say that miR-126 may be more effective in inhibition of metastatic breast cancer (Tab. 4, Fig. 3, Ref. 46).


Thalidomide and analogues: potential for immunomodulation of inflammatory and neoplastic dermatologic disorders.
Thalidomide and analogues are a class of immunomodulatory drugs or IMiDS. Thalidomide was initially approved by the U.S. Food and Drug Administation for treatment of erythema nodosum in leprosy and is now approved for multiple myeloma as well. A second generation IMiD, lenalidomide, is also approved for multiple myeloma and refractory myelodysplastic syndrome. Discovery of this class of drugs has been serendipitous and empirical, as the drug targets have been unknown. In this review, the authors integrate recent identification of drug targets of IMiDS, which include the inducible form of nitric oxide synthase (iNOS), Rho GTPase and caspase-1, with the developments in the understanding of the molecular biology of human inflammatory, infectious and neoplastic skin disorders. Because thalidomide reemerged through leprosy, the original disease classified by the T cell, the authors have also emphasized advances in the understanding of T-cell subsets in human skin disorders.


Clinical effects and pharmacokinetics of the fusion protein PIXY321 in children receiving myelosuppressive chemotherapy.
A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited, and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels. To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with myelosuppressive chemotherapy. A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered once or twice daily by subcutaneous injection in total doses of 500 to 1000 microg/m2 per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule only). Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose studied (1000 microg/m2 per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m2 (range 77 1804 ml/min per m2) and the median half-life was 3.7 h (range 2.1-20.8 h). On day 14, clearance increased in all patients studied (median increase 63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were < 1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent activity in vitro. The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients.


True-lumen collapse in aortic dissection: part I. Evaluation of causative factors in phantoms with pulsatile flow.
To investigate the causative factors in true-lumen collapse in a model of aortic dissection. Phantoms with an aortic arch, true and false lumina with abdominal branch vessels, and a distal bifurcation were used to model a Stanford type B aortic dissection. The effects of anatomic factors (entry-tear size, branch-vessel flow distribution, fenestrations, distal reentry communication) and physiologic factors (peripheral resistance in the branch vessels, pump output and rate, vascular compliance) on true-lumen collapse were investigated. The morphology of the true lumen was observed. Branch pressures and flow rates were measured. True-lumen collapse was induced and was exacerbated by an increase in the size of the entry tear, a decrease in the false-lumen outflow caused by occluding the false-lumen branch vessels, and an increase in the true-lumen outflow caused by lowering the peripheral resistance in true-lumen branch vessels. Two kinds of true-lumen collapse depended on pump output. With low pump output and low outflow resistance from the true lumen, the true lumen collapsed. With high pump output and low inflow resistance in the false lumen, the true lumen was compressed. Distal reentry communication between the true and false limbs was more effective than aortic fenestrations in preventing true-lumen collapse. True-lumen collapse in this dissection model strongly depends on the difference in the ratios of inflow capacity to outflow capacity in the true and false lumina. Both anatomic and physiologic factors can affect true-lumen collapse.


Calcium alginate gels as stem cell matrix-making paracrine stem cell activity available for enhanced healing after surgery.
Regeneration after surgery can be improved by the administration of anabolic growth factors. However, to locally maintain these factors at the site of regeneration is problematic. The aim of this study was to develop a matrix system containing human mesenchymal stem cells (MSCs) which can be applied to the surgical site and allows the secretion of endogenous healing factors from the cells. Calcium alginate gels were prepared by a combination of internal and external gelation. The gelling behaviour, mechanical stability, surface adhesive properties and injectability of the gels were investigated. The permeability of the gels for growth factors was analysed using bovine serum albumin and lysozyme as model proteins. Human MSCs were isolated, cultivated and seeded into the alginate gels. Cell viability was determined by AlamarBlue assay and fluorescence microscopy. The release of human VEGF and bFGF from the cells was determined using an enzyme-linked immunoassay. Gels with sufficient mechanical properties were prepared which remained injectable through a syringe and solidified in a sufficient time frame after application. Surface adhesion was improved by the addition of polyethylene glycol 300,000 and hyaluronic acid. Humans MSCs remained viable for the duration of 6 weeks within the gels. Human VEGF and bFGF was found in quantifiable concentrations in cell culture supernatants of gels loaded with MSCs and incubated for a period of 6 weeks. This work shows that calcium alginate gels can function as immobilization matrices for human MSCs.


Modern diet and metabolic variance--a recipe for disaster?
Recently, a positive correlation between alanine transaminase activity and body mass was established among healthy young individuals of normal weight. Here we explore further this relationship and propose a physiological rationale for this link. Cross-sectional statistical analysis of adiposity across large samples of adults differing by age, diet and lifestyle. 46,684 19-20 years old Swiss male conscripts and published data on 1000 Eskimos, 518 Toronto residents and 97,000 North American Adventists. Serum concentrations of the alanine transaminase, post-prandial glucose levels, cholesterol, body height and weight, blood pressure and routine blood analysis (thrombocytes and leukocytes) for Swiss conscripts. Adiposity measures and dietary information for other groups were also obtained. Stepwise multiple regression after correction for random errors of physiological tests showed that 28% of the total variance in body mass is associated with ALT concentrations. This relationship remained significant when only metabolically healthy (as defined by the American Heart Association) Swiss conscripts were selected. The data indicated that high protein only or high carbohydrate only diets are associated with lower levels of obesity than a diet combining proteins and carbohydrates. Elevated levels of alanine transaminase, and likely other transaminases, may result in overactivity of the alanine cycle that produces pyruvate from protein. When a mixed meal of protein, carbohydrate and fat is consumed, carbohydrates and fats are digested faster and metabolised to satisfy body's energetic needs while slower digested protein is ultimately converted to malonyl CoA and stored as fat. Chronicity of this sequence is proposed to cause accumulation of somatic fat stores and thus obesity.


The Clinical Application of MicroRNAs in Infectious Disease.
MicroRNAs (miRNAs) are short single-stranded non-coding RNA sequences that posttranscriptionally regulate up to 60% of protein encoding genes. Evidence is emerging that miRNAs are key mediators of the host response to infection, predominantly by regulating proteins involved in innate and adaptive immune pathways. miRNAs can govern the cellular tropism of some viruses, are implicated in the resistance of some individuals to infections like HIV, and are associated with impaired vaccine response in older people. Not surprisingly, pathogens have evolved ways to undermine the effects of miRNAs on immunity. Recognition of this has led to new experimental treatments, RG-101 and Miravirsen-hepatitis C treatments which target host miRNA. miRNAs are being investigated as novel infection biomarkers, and they are being used to design attenuated vaccines, e.g., against Dengue virus. This comprehensive review synthesizes current knowledge of miRNA in host response to infection with emphasis on potential clinical applications, along with an evaluation of the challenges still to be overcome.


Trauma hemorrhagic shock-induced lung injury involves a gut-lymph-induced TLR4 pathway in mice.
Injurious non-microbial factors released from the stressed gut during shocked states contribute to the development of acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS). Since Toll-like receptors (TLR) act as sensors of tissue injury as well as microbial invasion and TLR4 signaling occurs in both sepsis and noninfectious models of ischemia/reperfusion (I/R) injury, we hypothesized that factors in the intestinal mesenteric lymph after trauma hemorrhagic shock (T/HS) mediate gut-induced lung injury via TLR4 activation. The concept that factors in T/HS lymph exiting the gut recreates ALI is evidenced by our findings that the infusion of porcine lymph, collected from animals subjected to global T/HS injury, into naïve wildtype (WT) mice induced lung injury. Using C3H/HeJ mice that harbor a TLR4 mutation, we found that TLR4 activation was necessary for the development of T/HS porcine lymph-induced lung injury as determined by Evan's blue dye (EBD) lung permeability and myeloperoxidase (MPO) levels as well as the induction of the injurious pulmonary iNOS response. TRIF and Myd88 deficiency fully and partially attenuated T/HS lymph-induced increases in lung permeability respectively. Additional studies in TLR2 deficient mice showed that TLR2 activation was not involved in the pathology of T/HS lymph-induced lung injury. Lastly, the lymph samples were devoid of bacteria, endotoxin and bacterial DNA and passage of lymph through an endotoxin removal column did not abrogate the ability of T/HS lymph to cause lung injury in naïve mice. Our findings suggest that non-microbial factors in the intestinal mesenteric lymph after T/HS are capable of recreating T/HS-induced lung injury via TLR4 activation.


Reduced insulin exocytosis in human pancreatic β-cells with gene variants linked to type 2 diabetes.
The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet function remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features in relation to genetic risk profiles in diabetic and nondiabetic donors. Islets from donors with T2D exhibited impaired insulin secretion, which was more pronounced in lean than obese diabetic donors. We assessed the impact of 14 disease susceptibility variants on measures of glucose sensing, exocytosis, and structure. Variants near TCF7L2 and ADRA2A were associated with reduced glucose-induced insulin secretion, whereas susceptibility variants near ADRA2A, KCNJ11, KCNQ1, and TCF7L2 were associated with reduced depolarization-evoked insulin exocytosis. KCNQ1, ADRA2A, KCNJ11, HHEX/IDE, and SLC2A2 variants affected granule docking. We combined our results to create a novel genetic risk score for β-cell dysfunction that includes aberrant granule docking, decreased Ca(2+) sensitivity of exocytosis, and reduced insulin release. Individuals with a high risk score displayed an impaired response to intravenous glucose and deteriorating insulin secretion over time. Our results underscore the importance of defects in β-cell exocytosis in T2D and demonstrate the potential of cellular phenotypic characterization in the elucidation of complex genetic disorders.


Life Course Transitions and Changes in Alcohol Consumption Among Older Irish Adults: Results From The Irish Longitudinal Study on Ageing (TILDA).
Objective: The objective of this study was to determine whether trajectories of older adults' alcohol consumption are influenced by the following life course transitions, relationship status, employment status, and self-rated health. Method: Volume and frequency of drinking were harmonized across first three waves of The Irish Longitudinal Study on Ageing (TILDA; N = 4,295). Multilevel regression models were used to model frequency, average weekly consumption, and heavy episodic drinking. Results: Men and women drank more frequently over time, with frequency decreasing with age for women. Average weekly consumption decreased over time and with increasing age. Transitions in self-rated health, particularly those reflecting poorer health, were associated with lower frequency and weekly consumption. Heavy episodic drinking decreased with age. Men who were retired across all waves were more likely to engage in heavy episodic drinking at baseline. Discussion: Despite the decline in average weekly consumption and heavy episodic drinking, the observed quantities consumed and the increase in frequency of consumption suggest that older Irish adults remain vulnerable to alcohol-related harms.


A revitalized biopsychosocial model: core theory, research paradigms, and clinical implications.
The biopsychosocial model (BPSM) was proposed by George Engel in 1977 as an improvement to the biomedical model (BMM), to take account of psychological and social as well as biological factors relevant to health and disease. Since then the BPSM has had a mixed reputation, as the overarching framework for psychiatry, perhaps for medicine generally, while also being criticized for being theoretically and empirically vacuous. Over the past few decades, substantial evidence has accumulated supporting the BPSM but its theory remains less clear. The first part of this paper reviews recent well-known, general theories in the relevant sciences that can provide a theoretical framework of the model, constituting a revitalized BPSM capable of theorizing causal interactions within and between biological, psychological, and social domains. Fundamental concepts in this new framework include causation as regulation and dysfunction as dysregulation. Associated research paradigms are outlined in Part 2. Research in psychological therapies and social epidemiology are major examples of programs that have produced results anomalous for the BMM and consistent with the BPSM. Theorized models of causal mechanisms enrich empirical data and two biopsychosocial examples are models of chronic stress and pain perception. Clinical implications are reviewed in Part 3. The BPSM accommodates psychological and social as well as biological treatment effects evident in the clinical trials literature. Personal, interpersonal, and institutional aspects of clinical care are out of the scope of the BMM, assigned to the art of healthcare rather than the science, but can be accommodated and theorized in the BPSM.


Smoking characteristics among lesbian, gay, and bisexual adults.
Cigarette smoking is the leading preventable cause of death and disease in the United States. Sexual minorities (lesbians, gay men, and bisexuals), smoke at higher rates than the general population. However, little else is known about sexual minority smokers. Furthermore, the sexual minority population is diverse and little research exists to determine whether subgroups, such as lesbians, gay men, and female and male bisexuals, differ on smoker characteristics. We examine differences in smoking characteristics (advertising receptivity, age of first cigarette, non-daily smoking, cigarettes per day, nicotine dependence, desire to quit and past quit attempts) among lesbians, gay men, and female and male bisexual adults in the United States. Secondary analysis of the CDC's (Centers for Disease Control and Prevention) 2009-2010 National Adult Tobacco Survey (N=118,590). Controlling for age, race, socioeconomic status and geographic region, identifying as a female bisexual was associated with fewer past quit attempts, lower age at first cigarette, and higher nicotine dependence when compared to heterosexual women. There were no differences in desire to quit between male or female sexual minorities and their heterosexual counterparts. Sexual minority individuals smoke at higher rates than heterosexuals and yet similarly desire to quit. Tailored efforts may be needed to address smoking among bisexual women.


Clonal genotype and population structure inference from single-cell tumor sequencing.
Single-cell DNA sequencing has great potential to reveal the clonal genotypes and population structure of human cancers. However, single-cell data suffer from missing values and biased allelic counts as well as false genotype measurements owing to the sequencing of multiple cells. We describe the Single Cell Genotyper (https://bitbucket.org/aroth85/scg), an open-source software based on a statistical model coupled with a mean-field variational inference method, which can be used to address these problems and robustly infer clonal genotypes.


Ginsenoside Rg1 Regulates Liver Lipid Factor Metabolism in NAFLD Model Rats.
To establish the molecular mechanism of ginsenoside Rg1 in nonalcoholic fatty liver disease (NAFLD), Sprague Dawley (SD) rats (180-220 g) were randomly divided into a control group, model group, ginsenoside Rg1 low-dose group (30 mg/(kg day)), high-dose (60 mg/(kg day)) group, and simvastatin group (1 mg/(kg day)), with 10 SD rats in each group. The control group was given a normal diet. The model group rats were given high-sugar and high-fat diets for 14 weeks. After the model of NAFLD was established successfully, ginsenoside Rg1 was administered orally for 4 or 8 weeks. The results showed that ginsenoside Rg1 decreased the levels of glucose (GLU), insulin (INS), triglyceride (TG), and total cholesterol (TC) and improved liver function. Meanwhile, ginsenoside Rg1 inhibited the secretion of interleukin-1 (IL-1), IL-6, IL-8, IL-18, and tumor necrosis factor-α (TNF-α) and improved hepatocyte morphology and lipid accumulation in the liver. Furthermore, ginsenoside Rg1 promoted the expression of peroxisome proliferator-activated receptor-α (PPAR-α), carnitine palmitoyl transferase 1α (CPT1A), carnitine palmitoyl transferase 2 (CPT2), and cholesterol 7α-hydroxylase (CYP-7A) and inhibited the expression of sterol regulatory element binding proteins-1C (SREBP-1C). In conclusion, ginsenoside Rg1 can inhibit inflammatory reaction, regulate lipid metabolism, and alleviate liver injury in NAFLD model rats.


Male and female reproductive fitness costs of an immune response in natural populations.
Parasites can mediate host fitness both directly, via effects on survival and reproduction, or indirectly by inducing host immune defense with costly side-effects. The evolution of immune defense is determined by a complex interplay of costs and benefits of parasite infection and immune response, all of which may differ for male and female hosts in sexual lineages. Here, we examine fitness costs associated with an inducible immune defense in a fish-cestode host-parasite system. Cestode infection induces peritoneal fibrosis in threespine stickleback (Gasterosteus aculeatus), constraining cestode growth and sometimes encasing and killing the parasite. Surveying two wild populations of stickleback, we confirm that the presence of fibrosis scar tissue is associated with reduced parasite burden in both male and female fish. However, fibrotic fish had lower foraging success and reproductive fitness (reduced female egg production and male nesting success), indicating strong costs of the lingering immunopathology. Consistent with substantial sexually concordant fitness effects of immune response, we find alignment of multivariate selection across the sexes despite sexual antagonism over morphological shape. Although both sexes experienced costs of fibrosis, the net impacts are unequal because in the two study populations females had higher cestode exposure. To evaluate whether this difference in risk should drive sex-specific immune strategies, we analyze a quantitative genetic model of host immune response to a trophically transmitted parasite. The model and empirical data illustrate how shared costs and benefits of immune response lead to shared evolutionary interests of male and female hosts, despite unequal infection risks across the sexes.


Imputation-based population genetics analysis of Plasmodium falciparum malaria parasites.
Whole-genome sequencing technologies are being increasingly applied to Plasmodium falciparum clinical isolates to identify genetic determinants of malaria pathogenesis. However, genome-wide discovery methods, such as haplotype scans for signatures of natural selection, are hindered by missing genotypes in sequence data. Poor correlation between single nucleotide polymorphisms (SNPs) in the P. falciparum genome complicates efforts to apply established missing-genotype imputation methods that leverage off patterns of linkage disequilibrium (LD). The accuracy of state-of-the-art, LD-based imputation methods (IMPUTE, Beagle) was assessed by measuring allelic r2 for 459 P. falciparum samples from malaria patients in 4 countries: Thailand, Cambodia, Gambia, and Malawi. In restricting our analysis to 86 k high-quality SNPs across the populations, we found that the complete-case analysis was restricted to 21k SNPs (24.5%), despite no single SNP having more than 10% missing genotypes. The accuracy of Beagle in filling in missing genotypes was consistently high across all populations (allelic r2, 0.87-0.96), but the performance of IMPUTE was mixed (allelic r2, 0.34-0.99) depending on reference haplotypes and population. Positive selection analysis using Beagle-imputed haplotypes identified loci involved in resistance to chloroquine (crt) in Thailand, Cambodia, and Gambia, sulfadoxine-pyrimethamine (dhfr, dhps) in Cambodia, and artemisinin (kelch13) in Cambodia. Tajima's D-based analysis identified genes under balancing selection that encode well-characterized vaccine candidates: apical merozoite antigen 1 (ama1) and merozoite surface protein 1 (msp1). In contrast, the complete-case analysis failed to identify any well-validated drug resistance or candidate vaccine loci, except kelch13. In a setting of low LD and modest levels of missing genotypes, using Beagle to impute P. falciparum genotypes is a viable strategy for conducting accurate large-scale population genetics and association analyses, and supporting global surveillance for drug resistance markers and candidate vaccine antigens.


Effects of a self-guided, web-based activity programme for patients with persistent musculoskeletal pain in primary healthcare: A randomized controlled trial.
Web-based interventions for pain management are increasingly used with possible benefits, but never used in addition to multimodal rehabilitation (MMR). MMR is recommended treatment for persistent pain in Sweden. The aim was to evaluate the effects of a self-guided, web-based programme added to MMR for work ability, pain, disability and health-related quality of life. We included 99 participants with persistent musculoskeletal pain in a randomized study with two intervention arms: (1) MMR and web-based intervention, and (2) MMR. Data was collected at baseline, 4 and 12 months. Outcome measures were work ability, working percentage, average pain intensity, pain-related disability, and health-related quality of life. There were no significant effects of adding the web-based intervention to MMR regarding any of the outcome variables. This trial provides no support for adding a self-guided, web-based activity programme to MMR for patients with persistent musculoskeletal pain. The comprehensive self-guided, web-based programme for activity, Web-BCPA, added to multimodal treatment in primary health care had no effect on work ability, pain, disability or health-related quality of life. Future web-based interventions should be tailored to patients' individual needs and expectations.


Peptide bond detection via graphene nanogaps: a proof of principle study.
Solid-state nanopores and nanogaps are emerging as promising tools for single molecule analysis. 2D materials, such as graphene, can potentially reach the spatial resolution needed for nucleic acid and protein sequencing. In the context of the density functional theory, atomistic modeling and non-equilibrium Green's function calculation, we show that glycine based polypeptide chains translocating across a nano-gap between two semi-infinite graphene nano-ribbons leave a specific transverse current signature for each peptide bond. The projected density of states and bond current analyses reveal a complex scenario with a role played by the adjacent α-carbons and side chains and by the orbitals of the partially resonant double bond involving C, N and O atoms of the peptide bond. In this context, specific fingerprints of the atoms involved in the peptide bonds are found. The same scenario is evidenced also for peptides involving alanine residues. The signal measured can be considered as a specific fingerprint of peptide bonds between small and neutral amino acids with no polar/charge effects. On this basis, a newly conceived nano-device made of a graphene based array of nano-gap is proposed as a possible route to approach peptide sequencing with atomic resolution.


Mood disorders and complementary and alternative medicine: a literature review.
Mood disorders are a major public health problem and are associated with considerable burden of disease, suicides, physical comorbidities, high economic costs, and poor quality of life. Approximately 30%-40% of patients with major depression have only a partial response to available pharmacological and psychotherapeutic interventions. Complementary and alternative medicine (CAM) has been used either alone or in combination with conventional therapies in patients with mood disorders. This review of the literature examines evidence-based data on the use of CAM in mood disorders. A search of the PubMed, Medline, Google Scholar, and Quertile databases using keywords was conducted, and relevant articles published in the English language in the peer-reviewed journals over the past two decades were retrieved. Evidence-based data suggest that light therapy, St John's wort, Rhodiola rosea, omega-3 fatty acids, yoga, acupuncture, mindfulness therapies, exercise, sleep deprivation, and S-adenosylmethionine are effective in the treatment of mood disorders. Clinical trials of vitamin B complex, vitamin D, and methylfolate found that, while these were useful in physical illness, results were equivocal in patients with mood disorders. Studies support the adjunctive role of omega-3 fatty acids, eicosapentaenoic acid, and docosahexaenoic acid in unipolar and bipolar depression, although manic symptoms are not affected and higher doses are required in patients with resistant bipolar depression and rapid cycling. Omega-3 fatty acids are useful in pregnant women with major depression, and have no adverse effects on the fetus. Choline, inositol, 5-hydroxy-L-tryptophan, and N-acetylcysteine are effective adjuncts in bipolar patients. Dehydroepiandrosterone is effective both in bipolar depression and depression in the setting of comorbid physical disease, although doses should be titrated to avoid adverse effects. Ayurvedic and homeopathic therapies have the potential to improve symptoms of depression, although larger controlled trials are needed. Mind-body-spirit and integrative medicine approaches can be used effectively in mild to moderate depression and in treatment-resistant depression. Currently, although CAM therapies are not the primary treatment of mood disorders, level 1 evidence could emerge in the future showing that such treatments are effective.


Regulation of Proinflammatory Enzymes by Peroxisome Proliferator-Activated Receptor Gamma in Astroglia Infected with Toxoplasma gondii.
Peroxisome proliferator-activated receptor gamma (PPARγ) regulates neuroinflammation, and its agonists act as neuroprotective agents. This study aims to investigate the correlation between PPARγ and proinflammatory enzyme expression in astroglia infected with Toxoplasma gondii tachyzoite in vitro. Our results showed that matrix metalloprotease (MMP)-2, MMP-9, cyclooxygenase-2 (COX-2), prostaglandin (PGE)-2, inducible nitric-oxide synthase (iNOS), and nitric oxide (NO) were significantly increased in T. gondii-infected astroglia. Furthermore, the expression levels of MMP-2, MMP-9, COX-2, PGE-2, iNOS, and NO were significantly decreased by rosiglitazone-a PPARγ agonist. By contrast, the treatment with GW9662, a PPARγ antagonist, efficiently increased the expression levels of MMP-2, MMP-9, COX-2, PGE-2, iNOS, and NO. These results suggested that the treatment with rosiglitazone offers a potential strategy for controlling the inflammatory factors in T. gondii infection.


Clinical relevance of cagA and vacA gene polymorphisms in Helicobacter pylori isolates from Senegalese patients.
The molecular epidemiology of Helicobacter pylori in Africa is poorly documented. From January 2007 to December 2008, we investigated 187 patients with gastric symptoms in one of the main tertiary hospitals in Dakar, Senegal. One hundred and seventeen patients were culture-positive for H. pylori. Polymorphisms in vacA and cagA status were investigated by PCR; the 3'-region of cagA was sequenced, and EPIYA motifs were identified. Bacterial heterogeneity within individuals was extensively assessed by using an approach based on vacA and cagA heterogeneity. Fourteen per cent of H. pylori-positive patients displayed evidence of mixed infection, which may affect disease outcome. Patients with multiple vacA alleles were excluded from subsequent analyses. Among the final study population of 105 patients, 29 had gastritis only, 61 had ulcerated lesions, and 15 had suspicion of neoplasia based on endoscopic findings. All cases of suspected neoplasia were histologically confirmed as gastric cancer (GC). The cagA gene was present in 73.3% of isolates. CagA proteins contained zero (3.7%), one (93.9%) or two (2.4%) EPIYA-C segments, and all were western CagA. Most of the isolates possessed presumed high-vacuolization isotypes (s1i1m1 (57.1%) or s1i1m2 (21.9%)). Despite the small number of cases, GC was associated with cagA (p 0.03), two EPIYA-C segments in the C-terminal region of CagA (p 0.03), and the s1 vacA allele (p 0.002). Multiple EPIYA-C segments were less frequent than reported in other countries, possibly contributing to the low incidence of GC in Senegal.


A pitfall in diagnosis of human prion diseases using detection of protease-resistant prion protein in urine. Contamination with bacterial outer membrane proteins.
Because a definite diagnosis of prion diseases relies on the detection of the abnormal isoform of prion protein (PrPSc), it has been urgently necessary to establish a non-invasive diagnostic test to detect PrPSc in human prion diseases. To evaluate diagnostic usefulness and reliability of the detection of protease-resistant prion protein in urine, we extensively analyzed proteinase K (PK)-resistant proteins in patients affected with prion diseases and control subjects by Western blot, a coupled liquid chromatography and mass spectrometry analysis, and N-terminal sequence analysis. The PK-resistant signal migrating around 32 kDa previously reported by Shaked et al. (Shaked, G. M., Shaked, Y., Kariv-Inbal, Z., Halimi, M., Avraham, I., and Gabizon, R. (2001) J. Biol. Chem. 276, 31479-31482) was not observed in this study. Instead, discrete protein bands with an apparent molecular mass of approximately 37 kDa were detected in the urine of many patients affected with prion diseases and two diseased controls. Although these proteins also gave strong signals in the Western blot using a variety of anti-PrP antibodies as a primary antibody, we found that the signals were still detectable by incubation of secondary antibodies alone, i.e. in the absence of the primary anti-PrP antibodies. Mass spectrometry and N-terminal protein sequencing analysis revealed that the majority of the PK-resistant 37-kDa proteins in the urine of patients were outer membrane proteins (OMPs) of the Enterobacterial species. OMPs isolated from these bacteria were resistant to PK and the PK-resistant OMPs from the Enterobacterial species migrated around 37 kDa on SDS-PAGE. Furthermore, nonspecific binding of OMPs to antibodies could be mistaken for PrPSc. These findings caution that bacterial contamination can affect the immunological detection of prion protein. Therefore, the presence of Enterobacterial species should be excluded in the immunological tests for PrPSc in clinical samples, in particular, urine.


Using Robson's Ten-Group Classification System for comparing caesarean section rates in Europe: an analysis of routine data from the Euro-Peristat study.
Robson's Ten Group Classification System (TGCS) creates clinically relevant sub-groups for monitoring caesarean birth rates. This study assesses whether this classification can be derived from routine data in Europe and uses it to analyse national caesarean rates. Observational study using routine data. Twenty-seven EU member states plus Iceland, Norway, Switzerland and the UK. All births at ≥22 weeks of gestational age in 2015. National statistical offices and medical birth registers derived numbers of caesarean births in TGCS groups. Overall caesarean rate, prevalence and caesarean rates in each of the TGCS groups. Of 31 countries, 18 were able to provide data on the TGCS groups, with UK data available only from Northern Ireland. Caesarean birth rates ranged from 16.1 to 56.9%. Countries providing TGCS data had lower caesarean rates than countries without data (25.8% versus 32.9%, P = 0.04). Countries with higher caesarean rates tended to have higher rates in all TGCS groups. Substantial heterogeneity was observed, however, especially for groups 5 (previous caesarean section), 6, 7 (nulliparous/multiparous breech) and 10 (singleton cephalic preterm). The differences in percentages of abnormal lies, group 9, illustrate potential misclassification arising from unstandardised definitions. Although further validation of data quality is needed, using TGCS in Europe provides valuable comparator and baseline data for benchmarking and surveillance. Higher caesarean rates in countries unable to construct the TGCS suggest that effective routine information systems may be an indicator of a country's investment in implementing evidence-based caesarean policies. Many European countries can provide Robson's Ten-Group Classification to improve caesarean rate comparisons.


The public's perceptions about cognitive health and Alzheimer's disease among the U.S. population: a national review.
The present review assesses the public's perceptions about cognitive health and Alzheimer's disease among adults in the United States. We searched the published literature and Internet, and contacted experts in the field to locate surveys assessing the public's perceptions about cognition. We found 10 eligible surveys and abstracted data concerning the public's knowledge, beliefs, concerns, and sources of information. Most of the surveys were conducted in the 2000s and focused on Alzheimer's disease rather then cognitive health. Based on the findings from the surveys, most adults were found to be aware of Alzheimer's disease but lacked specific information about the disease and its treatments. Most respondents did not perceive themselves as being very knowledgeable about Alzheimer's disease. Although we could classify the findings into several overarching domains, such as knowledge, we found considerable variability among surveys in the questions asked. Additional work is needed to understand the public's perceptions about cognitive health. Moreover, we also lack studies that help us understand perceptions about cognition across diverse demographic and cultural groups. Only by addressing these gaps can we develop targeted and effective strategies to enhance knowledge and beliefs about cognitive impairment and health.


Dopamine transporter genotype is associated with a lateralized resistance to distraction during attention selection.
Although lateral asymmetries in orienting behavior are evident across species and have been linked to interhemispheric asymmetries in dopamine signaling, the relative contribution of attentional versus motoric processes remains unclear. Here we took a cognitive genetic approach to adjudicate between roles for dopamine in attentional versus response selection. A sample of nonclinical adult humans (N = 518) performed three cognitive tasks (spatial attentional competition, spatial cueing, and flanker tasks) that varied in the degree to which they required participants to resolve attentional or response competition. All participants were genotyped for two putatively functional tandem repeat polymorphisms of the dopamine transporter gene (DAT1; SLC6A3), which are argued to influence the level of available synaptic dopamine and confer risk to disorders of inattention. DAT1 genotype modulated the task-specific effects of the various task-irrelevant stimuli across both the spatial competition and spatial cueing but not flanker tasks. Specifically, compared with individuals carrying one or two copies of the 10-repeat DAT1 allele, individuals without this allele demonstrated an immunity to distraction, such that response times were unaffected by increases in the number of distractor stimuli, particularly when these were presented predominantly in the left hemifield. All three genotype groups exhibited uniform costs of resolving leftward response selection in a standard flanker task. None of these significant effects could be explained by speed-accuracy trade-offs, suggesting that participants without the 10-repeat allele of the DAT1 tandem repeat polymorphism possess an enhanced attentional ability to suppress task-irrelevant stimuli in the left hemifield.


Prevalence of amblyopia in children undergoing nasolacrimal duct irrigation and probing.
To investigate ambylopia and amblyopia risk factors of children who underwent nasolacrimal duct (NLD) irrigation and probing for congenital nasolacrimal duct obstruction (CNLDO). The medical records of patients who had undergone NLD irrigation and probing for CNLDO at an age of 3 years or younger were reviewed, and 51 of the patients were recalled between October 1 and December 31, 2011 for a detailed ophthalmic examination to determinate amblyopia or amblyopia risk factors. Amblyopia was accepted as difference in visual acuity of two or more Snellen lines between the two eyes or visual acuity of 20/30 or worse in either eye. The median age of the 51 patients to whom NLD irrigation and probing were attempted for CNLDO was 23 months. CNLDO affected a total of 70 eyes. All patients were reviewed for best-corrected visual acuity, refractive errors, and strabismus at a median age of 70.5 months (range 31-95 months). Amblyopia or amblyopia risk factors were identified in 14 patients (27.5%). One child (7.15%) had only strabismus, six children (42.8%) had only amblyogenic refractive errors, two (14.3%) had a combination of two, one child (7.15%) had a family history for amblyopia, but four children (28.6%) had no amblyopia risk factors but had amblyopia. Amblyogenic risk factors are found higher in patients with CNLDO and patients undergoing NLD irrigation and probing in comparison to normal population. Therefore, we recommend these children to routinely undergo cycloplegic refractions and full ophthalmic examinations.


Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review.
The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin derivatives been used but mostly in south east Asia. Experience has shown that resistance eventually curtails the life-span of antimalarial drugs. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. Current efforts focus on research into new compounds with novel mechanisms of action, and on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and costly ventures. Antimalarial drug development has traditionally been slow but now various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial development pipeline is looking reasonably healthy. Most development relies on the quinoline, antifolate and artemisinin compounds. There is a pressing need to have effective, easy to use, affordable drugs that will last a long time. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focused on the use of artesunate combined with currently used standard drugs, namely, mefloquine, amodiaquine, sulfadoxine/pyrimethamine, and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and depend on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. This review will summarise current antimalarial drug developments and outline recent clinical research that aims to bring artemisinin based combinations to those that need them most.


Degenerative disease in lumbar spine of military parachuting instructors.
Parachuting, be it static line or skydiving, places enormous stresses on the human spine. It is, therefore, important to determine the prevalence and severity of degenerative changes in the lumbar spine of subjects who practice this sport activity. Seventy four parachuting instructors, mean age 33 years and with an average of 410 static line and skydiving jumps, were included in the study. Past radiographs were examined and compared to current anterolateral and lateral views of the lumbar spine, in order to determine the prevalence of degenerative changes and document possible progression. Doubtful radiographic changes in the lumbar spine were identified in 47.4 percent of the parachuting instructors, mild degeneration in 9.6 percent, moderate degenerative disease in 10.9 percent and severe radiographic changes in 5.5 percent. Schmorll nodes were found in 8.1 percent of the subjects. Traction spurs--osteophytes were identified in 6.8 percent. The degenerative changes correlated with age and the number of jumps. Spondylolysis of L5-S1 and L3-L4 segments were observed in 12.2 and 1.4 percent respectively. Progressive spondylolisthesis was found in 2 subjects. No correlation was found between the severity of radiographic changes and either the prevalence and the severity of low back pain. The present findings provide a rational for considering repeated sheer stress as an etiology of degenerative changes in the spinal cord, and as a possible contributing factor to the pathogenesis of spondylolysis. Further study has to be done comparing parachuting instructors to a non-parachuting group, or equivalent physically active individuals, in order to assess the effect of sport-background on the development of degenerative changes.


Patterns of Sexual Risk Behavior, HIV Infection, and Use of Health Services Among Sub-Saharan African Migrants in Portugal.
This study identified patterns of sexual risk behavior among a sub-Saharan African migrant (SAM) population in Portugal and examined its associations with human immunodeficiency virus (HIV) prevalence, sociodemographics, use of sexual health services, and HIV testing. A cross-sectional biobehavioral survey was conducted with a venue-based sample of 790 SAMs. Data were collected using questionnaires and rapid HIV tests. Cluster analysis identified five subgroups with differing levels of HIV infection (2.5% to 11.3%). In Cluster 1, most participants reported sexual abstinence over the past year and the remaining used condoms consistently; this cluster had the highest HIV prevalence (11.3%). In Cluster 2, most reported one sexual partner and all reported unprotected sex; all HIV-positive participants in this cluster were unaware of their HIV-positive status. In Clusters 3 and 4, most had four or more partners, yet all used condoms. In Cluster 3, 56.5% reported both regular and occasional partners. In Cluster 4, 74% had only occasional partners; all engaged in commercial sex. In Cluster 5, all reported four or more partners and condomless sex. In all subgroups we found low rates of HIV testing and high unawareness of HIV serostatus. Targeted prevention interventions are needed to reduce unprotected sexual relations and undiagnosed infection, as well as improve linkage to sexual health services.


Developing a conceptual model of pediatric inpatient safety accidents: A mixed methods approach.
Given that injuries to children during periods of hospitalization can lead to more serious health conditions in vulnerable children, preventing pediatric inpatient injuries should be a priority for the pediatric health care profession. This study was conducted to develop a conceptual model of factors affecting pediatric inpatient safety, including all injuries, not just fall injuries, in pediatric units. An explorative sequential mixed methods design was used. Qualitative interviews were conducted with 13 nurses working in pediatrics units and 17 parents of hospitalized children, and then 200 nurses in pediatrics units and parents of hospitalized children completed a self-report questionnaire. Based on the integration of both qualitative and quantitative data using building and weaving narrative integration, the Pediatric Inpatient Safety Accidents (PISA) model was proposed. The PISA model contains two main domains, the immediate and mediating domain and encompasses the six factors explain of the elements affecting the occurrence and prevention of pediatric inpatient safety accidents. The PISA model can serve as a model to understand child accidents in hospitals as well as to plan customized nursing interventions to prevent child accidents.


Hepatitis B and C virus infection and the risk of biliary tract cancer: a population-based study in China.
Emerging data suggest that chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections may also play a role in extrahepatic bile duct cancers. To test the HBV hypothesis, we examined the relationship of HBV/HCV infection with risks of biliary tract cancer and biliary stones in a population-based case-control study conducted in Shanghai, China. Standard assays were used to detect HBV surface antigen (HBsAg) and antibodies against HBV core antigen (anti-HBc) and hepatitis C virus (anti-HCV) in sera from 417 patients with biliary tract cancers, 517 with biliary stones, and 762 healthy controls randomly selected from the population. Unconditional logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for each disease type. HBsAg seroprevalence was 7.3% among population controls and 14.2% among patients with extrahepatic bile duct cancer, resulting in a 2.4-fold risk of extrahepatic bile duct cancer (95% CI 1.2-4.5). No association was found for cancers of the gallbladder (prevalence 8.2%) or the ampulla of Vater (6.1%), or for stones in the gallbladder (10.1%) or bile duct (9.3%). Further adjustment for education, smoking, body mass index, diabetes and gallstones did not materially change the results. Prevalence of HCV infection in this population was low (2%), limiting our ability to detect an association with biliary diseases. In Shanghai, an HBV endemic area, chronic HBV infection was associated with a 2.4-fold risk of extrahepatic bile duct cancer. These results should be confirmed in other populations with varying risks of HBV and HCV infection.


Antenatal corticosteroids for women at risk of imminent preterm birth in low-resource countries: the case for equipoise and the need for efficacy trials.
The scientific basis for antenatal corticosteroids (ACS) for women at risk of preterm birth has rapidly changed in recent years. Two landmark trials-the Antenatal Corticosteroid Trial and the Antenatal Late Preterm Steroids Trial-have challenged the long-held assumptions on the comparative health benefits and harms regarding the use of ACS for preterm birth across all levels of care and contexts, including resource-limited settings. Researchers, clinicians, programme managers, policymakers and donors working in low-income and middle-income countries now face challenging questions of whether, where and how ACS can be used to optimise outcomes for both women and preterm newborns. In this article, we briefly present an appraisal of the current evidence around ACS, how these findings informed WHO's current recommendations on ACS use, and the knowledge gaps that have emerged in the light of new trial evidence. Critical considerations in the generalisability of the available evidence demonstrate that a true state of clinical equipoise exists for this treatment option in low-resource settings. An expert group convened by WHO concluded that there is a clear need for more efficacy trials of ACS in these settings to inform clinical practice.


Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B.
One year of treatment with entecavir (0.5 mg daily) in nucleoside-naive patients with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B (CHB) resulted in significantly improved liver histology and virological and biochemical endpoints in comparison with lamivudine. Patients who received at least 3 years of cumulative entecavir therapy in phase 3 studies and a long-term rollover study and underwent long-term liver biopsy were evaluated for improvements in histological appearance. Sixty-nine patients [50 HBeAg-positive and 19 HBeAg-negative] receiving entecavir therapy underwent long-term liver biopsy (median time of biopsy = 6 years, range = 3-7 years). Histological improvement was analyzed for 57 patients who had adequate baseline biopsy samples, baseline Knodell necroinflammatory scores > or =2, and adequate long-term biopsy samples. At the time of long-term biopsy, all patients in the cohort had a hepatitis B virus DNA level <300 copies/mL, and 86% had a normalized alanine aminotransferase level. Histological improvement (> or =2-point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) was observed in 96% of patients, and a > or =1-point improvement in the Ishak fibrosis score was found in 88% of patients, including all 10 patients with advanced fibrosis or cirrhosis at the phase 3 baseline. The majority of nucleoside-naive patients with CHB who were treated with entecavir in this long-term cohort achieved substantial histological improvement and regression of fibrosis or cirrhosis.


The prevalence of three species of feline haemoplasmas in samples submitted to a diagnostics service as determined by three novel real-time duplex PCR assays.
Three distinct species of feline haemoplasmas are recognised: Mycoplasma haemofelis (Mhf), Candidatus Mycoplasma haemominutum (CMhm) and Candidatus Mycoplasma turicensis (CMt). These species differ in pathogenicity as Mhf and CMt can be associated with anaemia whereas CMhm usually results in few clinical signs. The purpose of this study was to develop quantitative real-time PCR assays for the detection of all three feline haemoplasma species combined with an endogenous internal control and to determine the prevalence of infection, using these assays, in 1592 EDTA blood samples submitted to Langford Veterinary Diagnostics, University of Bristol for haemoplasma testing. Primers and TaqMan probes were designed against published 16S rDNA sequences. These assays were combined with a feline 28S rDNA-specific assay to produce three duplex assays. The assays detected 1-10 copies of a sequence-specific plasmid per PCR. None of the assays showed cross-reactivity with 10(6) copies of a sequence-specific plasmid from the non-target haemoplasma species. Real-time PCR was performed on all samples using the three assays. Seven samples were negative for feline 28S rDNA and were excluded from the study. Of the remaining 1585 samples, 45 (2.8%), 177 (11.2%) and 27 (1.7%) samples were positive for Mhf, CMhm and CMt, respectively, including 11 Mhf/CMhm, 10 CMhm/CMt and two Mhf/CMt dual infections and two triple infections. The results of this study demonstrate the utility of these new duplex PCR assays for the detection of haemoplasma infections. CMhm was the most common infection and CMt infections were often associated with co-infection with other haemoplasma species, especially CMhm.


Unsolved problems in biology--The state of current thinking.
Many outstanding problems have been solved in biology and medicine for which scientists have been awarded prestigious prizes including the Nobel Prize, Lasker Award and Breakthrough Prizes in life sciences. These have been the fruits of years of basic research. From time to time, publications have appeared listing "unsolved" problems in biology. In this article, I ask the question whether it is possible to have such a list, if not a unique one, at least one that is analogous to the Millennium Prize in mathematics. My approach to finding an answer to this question was to gather views of leading biologists. I have also included my own views. Analysis of all the responses received over several years has convinced me that it is difficult, but not impossible, to have such a prize. Biology is complex and very interdisciplinary these days at times involving large numbers of teams, unlike mathematics, where Andrew Wiles spent seven years in complete isolation and secrecy solving Fermat's last theorem. Such an approach is simply not possible in biology. Still I would like to suggest that a similar prize can be established by a panel of distinguished scientists. It would be awarded to those who solved one of the listed problems in biology that warrant a verifiable solution. Despite many different opinions, I found that there is some commonality in the responses I received - I go on to discuss what these are and how they may impact future thinking.


Localisation of lymphatic vessels and vascular endothelial growth factors-C and -D in human and mouse skeletal muscle with immunohistochemistry.
The present study was aimed to localise lymphatic vessels and their growth factors in human and mouse skeletal muscle with immunohistochemistry and specific antibodies (VEGFR-3, LYVE-1, VEGF-C and VEGF-D). The largest lymphatic vessels were found in perimysial connective tissue next to the arteries and veins, as has been shown earlier with electron microscopy. As a new finding, we also found small LYVE-1 positive vessels in the capillary bed between muscle fibres. These vessels were located next to CD31 positive blood capillaries and were of the same size, but fewer in number. In addition, we described the localisation of the two main lymphangiogenic growth factor proteins, vascular endothelial growth factor-C and -D. Both proteins were expressed in skeletal muscle at mRNA and protein levels. VEGF-D was located under the sarcolemma in some of the muscle fibres, in the endothelia of larger blood vessels and in fibroblasts. VEGF-C protein was localised to the nerves and muscle spindles, to fibroblasts and surrounding connective tissue, but was not found in muscle fibres or endothelial cells. Our results are the first to suggest the presence of lymphatic capillaries throughout the skeletal muscle, and to present the localisation of VEGF-C and -D in the muscles.


Integrated transcriptomic and proteomic analyses of P. falciparum gametocytes: molecular insight into sex-specific processes and translational repression.
Sexual differentiation of malaria parasites into gametocytes in the vertebrate host and subsequent gamete fertilization in mosquitoes is essential for the spreading of the disease. The molecular processes orchestrating these transitions are far from fully understood. Here, we report the first transcriptome analysis of male and female Plasmodium falciparum gametocytes coupled with a comprehensive proteome analysis. In male gametocytes there is an enrichment of proteins involved in the formation of flagellated gametes; proteins involved in DNA replication, chromatin organization and axoneme formation. On the other hand, female gametocytes are enriched in proteins required for zygote formation and functions after fertilization; protein-, lipid- and energy-metabolism. Integration of transcriptome and proteome data revealed 512 highly expressed maternal transcripts without corresponding protein expression indicating large scale translational repression in P. falciparum female gametocytes for the first time. Despite a high degree of conservation between Plasmodium species, 260 of these 'repressed transcripts' have not been previously described. Moreover, for some of these genes, protein expression is only reported in oocysts and sporozoites indicating that repressed transcripts can be partitioned into short- and long-term storage. Finally, these data sets provide an essential resource for identification of vaccine/drug targets and for further mechanistic studies.


Differential effect of genetic burden on disease phenotypes in Crohn's disease and ulcerative colitis: analysis of a North American cohort.
Crohn's disease (CD) and ulcerative colitis (UC) are chronic immunologically mediated diseases with a progressive relapsing remitting course. There is considerable heterogeneity in disease course and accurate prediction of natural history has been challenging. The phenotypic implication of increasing genetic predisposition to CD or UC is unknown. The data source for our study was a prospective cohort of CD and UC patients recruited from a tertiary referral center. All patients underwent genotyping on the Illumina Immunochip. A genetic risk score (GRS) incorporating strength of association (log odds ratio) and allele dose for each of the 163 inflammatory bowel disease (IBD) risk loci was calculated and phenotypic associations examined across GRS quartiles. Our study cohort included 1,105 patients (697 CD, 408 UC). Increasing genetic burden was associated with earlier age of diagnosis of CD (Ptrend=0.008). Patients in the highest GRS quartile were likely to develop disease 5 years earlier than those in the lowest quartile. Increasing genetic burden was also associated with ileal involvement in CD (Ptrend <0.0001). The effect of genetic burden was independent of the NOD2 locus and was stronger among those with no NOD2 variants, and in never smokers. UC patients with an involved first-degree relative had a higher genetic burden, but GRS was not associated with disease phenotype in UC. Increasing genetic burden is associated with early age of diagnosis in CD, but not UC. The expanded panel of IBD risk loci explains only a fraction of variance of disease phenotype, suggesting limited clinical utility of genetics in predicting natural history.


The Timed Swallowing Proficiency for Eating and Drinking (SPEAD) Test: Development and Initial Validation of an Instrument to Objectify (Impaired) Swallowing Capacity in Head and Neck Cancer Patients.
Objective swallowing outcomes measure the physical swallowing function, while subjective outcomes measure swallowing perception. A test for swallowing capacity, measuring the ingestion of all consistencies is currently not available. Therefore, the Swallowing Proficiency for Eating And Drinking (SPEAD) test was developed. It entails the timed ingestion of thin liquid, thick liquid and solid. In this study, its feasibility, reliability and validity were evaluated in patients with dysphagia after treatment for head and neck cancer (HNC) and healthy participants. Thirty-eight HNC patients and forty healthy participants were enrolled in this study and performed the SPEAD test three times. Video recordings of the test were evaluated three times by one observer, and once by three additional observers, to assess test-retest, intra-rater and inter-rater reliability. Validity was assessed by calculating effect sizes for the difference between results of patients and healthy participants and by evaluating correlations with objective (e.g., videofluoroscopy and functional oral intake scale) and subjective (e.g., SWAL-QOL) swallowing outcomes. Test-retest, intra-rater and inter-rater reliability of ingestion duration was good to excellent. All hypotheses with regard to magnitude and direction of correlations were confirmed, supporting construct validity of the test. Our initial results suggest that the SPEAD test reliably measures the transport capacity of the upper digestive tract (in grams per second) and that this test can be useful to objectively evaluate and monitor the (safe) swallowing capacity in HNC patients, in both research as well as daily clinical practice.


'If you start thinking positively, you won't miss sex': narratives of sexual (in)activity among people living with HIV in Nairobi's informal settlements.
Drawing on qualitative data, this paper examines narratives of sexual activity (or the lack thereof) among people living with HIV in two urban poor contexts in Kenya and the ways in which these narratives intersect with the discourse of a ubiquitous HIV-prevention strategy - the 'ABC' (Abstinence, Be Faithful, Condom Use) approach. The exploration of these narratives gives insight into the ways that the notions and meanings around sexual activity are informed and re-shaped by the experience of living with HIV in urban poor settings and into the complex ways in which the components of the ABC approach feature in the lives of PLHIV in these contexts. As the sexuality of people living with HIV in sub-Saharan Africa is an under-researched area, this paper sheds light on the realities of living with HIV in urban poor settings and illuminates the context that informs constructions of sexuality in this milieui.


Quantitative Gross and CT measurements of Cadaveric Cervical Vertebrae (C3 - C6) as Guidelines for the Lateral mass screw fixation.
Lateral mass screw fixation is the treatment of choice for posterior cervical stabilization. Long or misdirected screws carry a risk of injury to spinal nerve roots or vertebral artery. This study was aimed to assess the gross anatomic and CT measurements of typical cervical vertebrae for the selection of lateral mass screws. Dimensions of the articular pillars were measured on 1) Dry cervical vertebrae with Vernier calipers and 2) Multiplanar reformations of CT scans of the same vertebrae with Viewer software package. The data was statistically evaluated. The transverse diameter of the articular pillars with Vernier calipers varied from 6.0 to 15.4 mm (mean=10.5 mm ± 1.5) and on CT scans ranged from 8.2 - 16.1 mm (mean=11.6 mm ± 1.4). The antero-posterior diameter, an estimate of the screw length by Roy-Camille technique varied from 3.9 to 12.7 mm (mean=8.6 mm ± 1.6) by Vernier calipers and from 6.4 to 13.3 mm (mean=9.1 ± 1.2) on CT scans. The oblique AP diameter, an estimate of screw length by Magerl method varied from 10.8 to 20.3 mm (mean=14.9 mm ± 1.8) by Vernier calipers and from 11.4 to 19.3 mm (mean=14.5 mm ± 1.7) on CT. The CT measurements for height, transverse and AP diameter of the articular pillars were 0.5 - 1.0 mm larger than dimensions by Vernier calipers. No statistically significant difference was observed between the caliper and CT measurements for the oblique AP diameter. CT measurements of the articular pillars may slightly overestimate the desired screw length selected by spine surgeons when compared to actual anatomy. Although means of the articular pillars correspond to the screw lengths used, substantial number of observations below 10 mm for Roy-Camille trajectory and below 14 mm for Magerl trajectory requires careful preoperative planning and intra-operative confirmation to avoid long/misdirected lateral mass screws.


Metagenomic-based study of the phylogenetic and functional gene diversity in Galápagos land and marine iguanas.
In this study, a metagenome-based analysis of the fecal samples from the macrophytic algae-consuming marine iguana (MI; Amblyrhynchus cristatus) and terrestrial biomass-consuming land iguanas (LI; Conolophus spp.) was conducted. Phylogenetic affiliations of the fecal microbiome were more similar between both iguanas than to other mammalian herbivorous hosts. However, functional gene diversities in both MI and LI iguana hosts differed in relation to the diet, where the MI fecal microbiota had a functional diversity that clustered apart from the other terrestrial-biomass consuming reptilian and mammalian hosts. A further examination of the carbohydrate-degrading genes revealed that several of the prevalent glycosyl hydrolases (GH), glycosyl transferases (GT), carbohydrate binding modules (CBM), and carbohydrate esterases (CE) gene classes were conserved among all examined herbivorous hosts, reiterating the important roles these genes play in the breakdown and metabolism of herbivorous diets. Genes encoding some classes of carbohydrate-degrading families, including GH2, GH13, GT2, GT4, CBM50, CBM48, CE4, and CE11, as well as genes associated with sulfur metabolism and dehalogenation, were highly enriched or unique to the MI. In contrast, gene sequences that relate to archaeal methanogenesis were detected only in LI fecal microbiome, and genes coding for GH13, GH66, GT2, GT4, CBM50, CBM13, CE4, and CE8 carbohydrate active enzymes were highly abundant in the LI. Bacterial populations were enriched on various carbohydrates substrates (e.g., glucose, arabinose, xylose). The majority of the enriched bacterial populations belong to genera Clostridium spp. and Enterococcus spp. that likely accounted for the high prevalence of GH13 and GH2, as well as the GT families (e.g., GT2, GT4, GT28, GT35, and GT51) that were ubiquitously present in the fecal microbiota of all herbivorous hosts.


Arsenic carcinogenesis in the skin.
Chronic arsenic poisoning is a world public health issue. Long-term exposure to inorganic arsenic (As) from drinking water has been documented to induce cancers in lung, urinary bladder, kidney, liver and skin in a dose-response relationship. Oxidative stress, chromosomal abnormality and altered growth factors are possible modes of action in arsenic carcinogenesis. Arsenic tends to accumulate in the skin. Skin hyperpigmentation and hyperkeratosis have long been known to be the hallmark signs of chronic As exposure. There are significant associations between these dermatological lesions and risk of skin cancer. The most common arsenic-induced skin cancers are Bowen's disease (carcinoma in situ), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Arsenic-induced Bowen's disease (As-BD) is able to transform into invasive BCC and SCC. Individuals with As-BD are considered for more aggressive cancer screening in the lung and urinary bladder. As-BD provides an excellent model for studying the early stages of chemical carcinogenesis in human beings. Arsenic exposure is associated with G2/M cell cycle arrest and DNA aneuploidy in both cultured keratinocytes and As-BD lesions. These cellular abnormalities relate to the p53 dysfunction induced by arsenic. The characteristic clinical figures of arsenic-induced skin cancer are: (i) occurrence on sun-protected areas of the body; (ii) multiple and recrudescent lesions. Both As and UVB are able to induce skin cancer. Arsenic treatment enhances the cytotoxicity, mutagenicity and clastogenicity of UV in mammalian cells. Both As and UVB induce apoptosis in keratinocytes by caspase-9 and caspase-8 signaling, respectively. Combined UVB and As treatments resulted in the antiproliferative and proapoptotic effects by stimulating both caspase pathways in the keratinocytes. UVB irradiation inhibited mutant p53 and ki-67 expression, as well as increased in the number of apoptotic cells in As-BD lesions which resulted in an inhibitory effect on proliferation. As-UVB interaction provides a reasonable explanation for the rare occurrences of arsenical cancer in the sun-exposed skin. The multiple and recurrent skin lesions are associated with cellular immune dysfunction in chronic arsenism. A decrease in peripheral CD4+ cells was noticed in the inhabitants of arsenic exposure areas. There was a decrease in the number of Langerhans cells in As-BD lesion which results in an impaired immune function on the lesional sites. Since CD4+ cells are the target cell affected by As, the interaction between CD4+ cells and epidermal keratinocytes under As affection might be closely linked to the pathogenesis of multiple occurrence of arsenic-induced skin cancer. In this review, we provide and discuss the pathomechanisms of arsenic skin cancer and the relationship to its characteristic figures. Such information is critical for understanding the molecular mechanism for arsenic carcinogenesis in other internal organs.


Amyloid aggregation on lipid bilayers and its impact on membrane permeability.
Fibrillar protein aggregates (amyloids) are involved in several common pathologies, e.g., Alzheimer's disease and type II diabetes. Accumulating evidence suggests that toxicity in amyloid-related diseases originates from the deposition of protein aggregates on the cell membrane, which results in bilayer disruption and cell leakage. The molecular mechanism of damage to the membrane, however, is still obscure. To shed light on it we have performed coarse-grained molecular dynamics simulations of fibril-forming amphipathic peptides in the presence of lipid vesicles. The simulation results show that highly amyloidogenic peptides fibrillate on the surface of the vesicle, damaging the bilayer and promoting leakage. In contrast, the ordered aggregation of peptides with low amyloidogenicity is hindered by the vesicles. Remarkably, leakage from the vesicle is caused by growing aggregates, but not mature fibrils. The simulation results provide a basis for understanding the range of aggregation behavior that is observed in experiments with fibril-forming (poly)peptides.