Obesity modifies the energetic phenotype of dilated cardiomyopathy.
We sought to determine if myocardial energetics could distinguish obesity cardiomyopathy as a distinct entity from dilated cardiomyopathy. Sixteen normal weight participants with dilated cardiomyopathy (DCMNW), and 27 with DCM and obesity (DCMOB), were compared to 26 normal weight controls (CTLNW). All underwent cardiac magnetic resonance imaging and 31P spectroscopy to assess function and energetics. Nineteen DCMOB underwent repeat assessment after a dietary weight loss intervention. Adenosine triphosphate (ATP) delivery through creatine kinase (CK flux) was 55% lower in DCMNW than in CTLNW (P = 0.004), correlating with left ventricular ejection fraction (LVEF, r = 0.4, P = 0.015). In contrast, despite similar LVEF (DCMOB 41 ± 7%, DCMNW 38 ± 6%, P = 0.14), CK flux was two-fold higher in DCMOB (P < 0.001), due to higher rate through CK [median kf 0.21 (0.14) vs. 0.11 (0.12) s-1, P = 0.002]. During increased workload, the CTLNW heart increased CK flux by 97% (P < 0.001). In contrast, CK flux was unchanged in DCMNW and fell in DCMOB (by >50%, P < 0.001). Intentional weight loss was associated with positive left ventricular remodelling, with reduced left ventricular end-diastolic volume (by 8%, P < 0.001) and a change in LVEF (40 ± 9% vs. 45 ± 10%, P = 0.002). This occurred alongside a fall in ATP delivery rate with weight loss (by 7%, P = 0.049). In normal weight, DCM is associated with reduced resting ATP delivery. In obese DCM, ATP demand through CK is greater, suggesting reduced efficiency of energy utilization. Dietary weight loss is associated with significant improvement in myocardial contractility, and a fall in ATP delivery, suggesting improved metabolic efficiency. This highlights distinct energetic pathways in obesity cardiomyopathy, which are both different from dilated cardiomyopathy, and may be reversible with weight loss.


Innovations in gene and growth factor delivery systems for diabetic wound healing.
The rise in lower extremity amputations due to nonhealing of foot ulcers in diabetic patients calls for rapid improvement in effective treatment regimens. Administration of growth factors (GFs) are thought to offer an off-the-shelf treatment; however, the dose- and time-dependent efficacy of the GFs together with the hostile environment of diabetic wound beds impose a major hindrance in the selection of an ideal route for GF delivery. As an alternative, the delivery of therapeutic genes using viral and nonviral vectors, capable of transiently expressing the genes until the recovery of the wounded tissue offers promise. The development of implantable biomaterial dressings capable of modulating the release of either single or combinatorial GFs/genes may offer solutions to this overgrowing problem. This article reviews the state of the art on gene and protein delivery and the strategic optimization of clinically adopted delivery strategies for the healing of diabetic wounds.


Expression and function of P2 receptors in hematopoietic stem and progenitor cells.
Nucleotides have unambiguously emerged as a family of mediators of intercellular communication, which bind to a class of plasma membrane receptors, P2 receptors, to trigger intercellular signaling. P2 receptors can be further divided into P2X and P2Y subfamilies based on structure and function. Different hematopoietic cells express diverse spectrums of P2 receptors at different levels, including hematopoietic stem and progenitor cells (HSPCs). Extracellular adenosine triphosphate (ATP) exerts different effects on HSPCs, regulating cell proliferation, differentiation, migration, and chemotaxis, release of cytokines or lysosomal constituents, and generation of reactive oxygen or nitrogen species. The relationship between abnormal P2 receptor function and human diseases attracts more and more attention. This review summarizes the expression and function of P2 receptors in HSPCs and the relationship to hematopoietic diseases.


Vulnerability of islets in the immediate posttransplantation period. Dynamic changes in structure and function.
To learn more about islet vulnerability in the immediate posttransplant period, 400 syngeneic islets were transplanted under the kidney capsule of B6AF1 mice. Three groups of recipients were used: normal mice (normal), streptozotocin (STZ)-diabetic (diabetic), and STZ-diabetic kept hypo- or normoglycemic with insulin pellets (diabetic-normalized). Normoglycemia was achieved in all three groups 14 days after transplantation; however, in the diabetic and diabetic-normalized groups, blood glucose levels throughout the posttransplantation period were respectively higher and lower than in the normal group. Grafts were harvested 1, 3, 7, and 14 days after transplantation and analyzed for morphology, beta-cell death, beta-cell mass, insulin content, and insulin mRNA expression. In all groups, substantial damage in islet grafts was found on days 1 and 3 with apoptotic nuclei and necrotic cores; on day 3, beta-cell death was significantly higher in the diabetic group than in the other groups. Tissue remodelling occurred in all groups with stable graft appearance on day 14; the actual beta-cell mass of the grafts was lowest in the diabetic group. Graft insulin content decreased in all groups on day 1 and fell even further on days 3 and 7. Insulin mRNA levels of grafts retrieved from both the diabetic and diabetic-normalized group were lower than those from the normal group already by day 1 and remained lower on day 14. In conclusion, the first few days of islet transplantation, even under the most advantageous circumstances of excellent metabolic control, are characterized by dynamic changes, with substantial islet cell dysfunction and death followed by tissue remodelling and then stable engraftment.


Loading Effect of Prosthetic Feet's Anthropomorphicity on Transtibial Osseointegrated Implant.
Osseointegrated implants for direct skeletal attachment of transtibial prosthesis carry risks that are yet to be fully resolved, such as early loosening, mechanical failure of percutaneous and medullar parts of implant, periprosthetic issues, and infections. Underloading could lead to early loosening and infection. Overloading might compromise the bone-implant interface. Therefore, Goldilocks loading regimen applied by transtibial bone-anchored prostheses is critical for safe and efficient development of osseointegration around the implant during rehabilitation and beyond. We hypothesized that Goldilocks loading could be achieved when ambulating with a so-called anthropomorphic prosthetic ankle showing moment-angle relationship similar to a sound ankle. Quantitative characteristics of the moment-angle curve of the sound ankle during dorsiflexion phase of a free-pace walking were extracted for 4 able-bodied participants (experiment 1). A slope of the moment-angle curve (stiffness) was calculated twice: for the first half and for the second half of the moment-angle curve. The difference of stiffnesses (those at the second half minus at the first half) was called the index of anthropomorphicity (IA). By definition, positive IA is associated with concave shape of the moment-angle curve, and the negative IA is associated with convex shape. In experiment 2, the same recordings and calculations were performed for 3 participants fitted with transtibial osseointegrated fixation during walking with their usual feet and the Free-Flow Foot (Ohio Willow Wood). The Free-Flow Foot was selected for its anthropomorphicity demonstrated in the previous studies with amputees using traditional socket attachment. The IA was 5.88 ± 0.93 for the able-bodied participants, indicating that the stiffness during the first part of the dorsiflexion phase was substantially fewer than during the second parts, as the calf muscles resisted to angulation in ankle substantially less than during the second part of dorsiflexion phase. For amputees fitted with Free-Flow Foot, IA was 2.68 ± 1.09 and -2.97 ± 2.37 for the same amputees fitted with their usual feet. Indexes of anthropomorphicity, while of different magnitude, were positive in control able-bodied group and in the amputee group wearing Free-Flow Foot, which was qualitatively associated with concave shape of their moment-angle curves. The 3 usual feet worn by the participants were classified as nonanthropomorphic as their individual moment-angle curves were convex and the corresponding IAs were negative. Furthermore, this study showed that a foot with anthropomorphic characteristics tends to decrease maximal loads at the bone-implant interface as compared to the nonanthropomorphic feet and possibly may minimize the risks to compromise the integrity of this interface.


The use of methylphenidate among students: the future of enhancement?
During the past few years considerable debate has arisen within academic journals with respect to the use of smart drugs or cognitive enhancement pharmaceuticals. The following paper seeks to examine the foundations of this cognitive enhancement debate using the example of methylphenidate use among college students. The argument taken is that much of the enhancement debate rests upon inflated assumptions about the ability of such drugs to enhance and over-estimations of either the size of the current market for such drugs or the rise in popularity as drugs for enhancing cognitive abilities. This article provides an overview of the empirical evidence that methylphenidate has the ability to significantly improve cognitive abilities in healthy individuals, and examines whether the presumed uptake of the drug is either as socially significant as implied or growing to the extent that it requires urgent regulatory attention. In addition, it reviews the evidence of side-effects for the use of methylphenidate which may be an influential factor in whether an individual decides to use such drugs. The primary conclusions are that neither drug efficacy, nor the benefit-to-risk balance, nor indicators of current or growing demand provide sufficient evidence that methylphenidate is a suitable example of a cognitive enhancer with mass appeal. In light of these empirically based conclusions, the article discusses why methylphenidate might have become seen as a smart drug or cognitive enhancer.


A laser ablation method for the synthesis of crystalline semiconductor nanowires
A method combining laser ablation cluster formation and vapor-liquid-solid (VLS) growth was developed for the synthesis of semiconductor nanowires. In this process, laser ablation was used to prepare nanometer-diameter catalyst clusters that define the size of wires produced by VLS growth. This approach was used to prepare bulk quantities of uniform single-crystal silicon and germanium nanowires with diameters of 6 to 20 and 3 to 9 nanometers, respectively, and lengths ranging from 1 to 30 micrometers. Studies carried out with different conditions and catalyst materials confirmed the central details of the growth mechanism and suggest that well-established phase diagrams can be used to predict rationally catalyst materials and growth conditions for the preparation of nanowires.


Human papillomavirus type 16 DNA in anal cancers from six different countries.
An association between anal squamous cell carcinoma and human papillomavirus (HPV) type 16 DNA has been documented in the UK. If HPV type 16 is an important aetiological factor in the development of this tumour it would be expected to occur in anal cancer tissues from other parts of the world. In this study a series of 173 anal squamous cell carcinoma tissue samples from five centres around the world have been examined by DNA hybridisation for HPV type 16 DNA sequences. HPV type 16 DNA was found in 50 of 173 (29%) of these. The prevalence of HPV associated anal squamous cell carcinoma was significantly lower in tissue from India and South Africa than in the Swiss, Polish, or Brazilian samples. HPV associated anal squamous cell carcinoma does occur in other countries and further investigations of the prevalence of these tumours in association with other HPV types are required.


Relations of Fish Community Composition to Environmental Variables in Streams of Central Nebraska, USA
Nine sites on streams in the Platte River Basin in central Nebraska were sampled as part of the US Geological Survey's National Water-Quality Assessment Program during 1993-1994. A combination of canonical correspondence analysis and an index of biotic integrity determined from fish community data produced complementary evaluations of water-quality conditions. Results of the canonical correspondence analysis were useful in showing which environmental variables were significant in differentiating fish communities at the nine sites. Five environmental variables were statistically significant in the analysis. Median specific conductance of water samples collected at a site accounted for the largest amount of variability in the species data. Although the percentage of the basin as cropland was not the first variable chosen in a forward selection process, it was the most strongly correlated with the first ordination axis. A rangeland-dominated site was distinguished from all others along that axis. Median orthophosphate concentration of samples collected in the year up to the time of fish sampling was most strongly correlated with the second ordination axis. The index of biotic integrity produced results that could be interpreted in terms of the relative water quality between sites. Sites draining nearly 100% cropland had the lowest scores for two individual metrics of the index of biotic integrity that were related to species tolerance. Effective monitoring of water quality could be achieved by coupling methods that address both the ecological components of fish communities and their statistical relationships to environmental factors.KEY WORDS: Canonical correspondence analysis; Fish communities; Environmental variables; Index of biotic integrity; National Water-Quality Assessment Program; Nebraska


Effects of vitamin a supplementation on immune responses and correlation with clinical outcomes.
Vitamin A supplementation to preschool children is known to decrease the risks of mortality and morbidity from some forms of diarrhea, measles, human immunodeficiency virus (HIV) infection, and malaria. These effects are likely to be the result of the actions of vitamin A on immunity. Some of the immunomodulatory mechanisms of vitamin A have been described in clinical trials and can be correlated with clinical outcomes of supplementation. The effects on morbidity from measles are related to enhanced antibody production and lymphocyte proliferation. Benefits for severe diarrhea could be attributable to the functions of vitamin A in sustaining the integrity of mucosal epithelia in the gut, whereas positive effects among HIV-infected children could also be related to increased T-cell lymphopoiesis. There is no conclusive evidence for a direct effect of vitamin A supplementation on cytokine production or lymphocyte activation. Under certain circumstances, vitamin A supplementation to infants has the potential to improve the antibody response to some vaccines, including tetanus and diphtheria toxoids and measles. There is limited research on the effects of vitamin A supplementation to adults and the elderly on their immune function; currently available data provide no consistent evidence for beneficial effects. Additional studies with these age groups are needed.


Scoring relevancy of features based on combinatorial analysis of Lasso with application to lymphoma diagnosis.
One challenge in applying bioinformatic tools to clinical or biological data is high number of features that might be provided to the learning algorithm without any prior knowledge on which ones should be used. In such applications, the number of features can drastically exceed the number of training instances which is often limited by the number of available samples for the study. The Lasso is one of many regularization methods that have been developed to prevent overfitting and improve prediction performance in high-dimensional settings. In this paper, we propose a novel algorithm for feature selection based on the Lasso and our hypothesis is that defining a scoring scheme that measures the "quality" of each feature can provide a more robust feature selection method. Our approach is to generate several samples from the training data by bootstrapping, determine the best relevance-ordering of the features for each sample, and finally combine these relevance-orderings to select highly relevant features. In addition to the theoretical analysis of our feature scoring scheme, we provided empirical evaluations on six real datasets from different fields to confirm the superiority of our method in exploratory data analysis and prediction performance. For example, we applied FeaLect, our feature scoring algorithm, to a lymphoma dataset, and according to a human expert, our method led to selecting more meaningful features than those commonly used in the clinics. This case study built a basis for discovering interesting new criteria for lymphoma diagnosis. Furthermore, to facilitate the use of our algorithm in other applications, the source code that implements our algorithm was released as FeaLect, a documented R package in CRAN.


Medullary thyroid carcinoma and biomarkers: past, present and future.
The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.


Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β.
The K(+) channel KCa3.1 is required for Ca(2+) influx and the subsequent activation of CD4 T cells. The class II phosphatidylinositol 3 kinase C2β (PI3KC2β) is activated by the T-cell receptor (TCR) and is critical for KCa3.1 channel activation. Tripartite motif containing protein 27 (TRIM27) is a member of a large family of proteins that function as Really Interesting New Gene (RING) E3 ubiquitin ligases. We now show that TRIM27 functions as an E3 ligase and mediates lysine 48 polyubiquitination of PI3KC2β, leading to a decrease in PI3K enzyme activity. By inhibiting PI3KC2β, TRIM27 also functions to negatively regulate CD4 T cells by inhibiting KCa3.1 channel activity and TCR-stimulated Ca(2+) influx and cytokine production in Jurkat, primary human CD4 T cells, and Th0, Th1, and Th2 CD4 T cells generated from TRIM27(-/-) mice. These findings provide a unique mechanism for regulating class II PI3Ks, and identify TRIM27 as a previously undescribed negative regulator of CD4 T cells.


Korean clinical practice guideline for perioperative red blood cell transfusion from Korean Society of Anesthesiologists.
Considering the functional role of red blood cells (RBC) in maintaining oxygen supply to tissues, RBC transfusion can be a life-saving intervention in situations of severe bleeding or anemia. RBC transfusion is often inevitable to address intraoperative massive bleeding; it is a key component in safe perioperative patient management. Unlike general medical resources, packed RBCs (pRBCs) have limited availability because their supply relies entirely on voluntary donations. Additionally, excessive utilization of pRBCs may aggravate prognosis or increase the risk of developing infectious diseases. Appropriate perioperative RBC transfusion is, therefore, crucial for the management of patient safety and medical resource conservation. These concerns motivated us to develop the present clinical practice guideline for evidence-based efficient and safe perioperative RBC transfusion management considering the current clinical landscape. This guideline was obtained after the revision and refinement of exemplary clinical practice guidelines developed in advanced countries. This was followed by rigorous evidence-based reassessment considering the healthcare environment of the country. This guideline covers all important aspects of perioperative RBC transfusion, such as preoperative anemia management, appropriate RBC storage period, and leukoreduction (removal of white blood cells using filters), reversal of perioperative bleeding tendency, strategies for perioperative RBC transfusion, appropriate blood management protocols, efforts to reduce blood transfusion requirements, and patient monitoring during a perioperative transfusion. This guideline will aid decisions related to RBC transfusion in healthcare settings and minimize patient risk associated with unnecessary pRBC transfusion.


Validation of the flow-through chamber (FTC) and steady-state (SS) methods for clearance rate measurements in bivalves.
To obtain precise and reliable laboratory clearance rate (filtration rate) measurements with the 'flow-through chamber method' (FTC) the design must ensure that only inflow water reaches the bivalve's inhalant aperture and that exit flow is fully mixed. As earlier recommended these prerequisites can be checked by a plot of clearance rate (CR) versus increasing through-flow (Fl) to reach a plateau, which is the true CR, but we also recommend to plot percent particles cleared versus reciprocal through-flow where the plateau becomes the straight line CR/Fl, and we emphasize that the percent of particles cleared is in itself neither a criterion for valid CR measurement, nor an indicator of appropriate 'chamber geometry' as hitherto adapted in many studies. For the 'steady-state method' (SS), the design must ensure that inflow water becomes fully mixed with the bivalve's excurrent flow to establish a uniform chamber concentration prevailing at its incurrent flow and at the chamber outlet. These prerequisites can be checked by a plot of CR versus increasing Fl, which should give the true CR at all through-flows. Theoretically, the experimental uncertainty of CR for a given accuracy of concentration measurements depends on the percent reduction in particle concentration (100×P) from inlet to outlet of the ideal 'chamber geomety'. For FTC, it decreases with increasing values of P while for SS it first decreases but then increases again, suggesting the use of an intermediate value of P. In practice, the optimal value of P may depend on the given 'chamber geometry'. The fundamental differences between the FTC and the SS methods and practical guidelines for their use are pointed out, and new data on CR for the blue mussel, Mytilus edulis, illustrate a design and use of the SS method which may be employed in e.g. long-term growth experiments at constant algal concentrations.


Use of indicators of standards of care to improve tuberculosis program management in Ethiopia.
Systematic monitoring of health programs and on-site mentoring of health workers are essential for the success of health care. This operations research was designed to measure the effectiveness of a new mentorship and supervisory tool for supervisors. In 2011 the Help Ethiopia Address the Low TB Performance (HEAL TB) Project used WHO or national TB indicators as standards of care (SOC) for baseline assessment, progress monitoring, gap identification, assessment of health workers' capacity-building needs, and data quality assurance. Cut-off points were selected for poor, average, and best performers for each indicator. In this analysis we present results from 10 zones (of 28) in which 1,165 health facilities were supported from 2011 through 2015. Other zones were excluded from the analysis because they entered the project later. The data were collected by trained mentors/supervisors and entered into Microsoft Excel. We used rates and ratios to show the impact of the intervention. The improvement in the median composite score of 13 selected major indicators (out of 22) over four years was significant (p = 0.000). The proportion of health facilities with 100% data accuracy for all forms of TB was 55.1% at baseline and reached 96.5%. In terms of program performance, the TB cure rate improved from 71% to 91.1%, while the treatment success rate increased from 88% to 95.3%. In the laboratory area, where there was previously no external quality assurance (EQA) for sputum microscopy, 1,165 health facilities now have quarterly EQA, and 96.1% of the facilities achieved a ≥ 95% concordance rate in blinded rechecking. The SOC approach for supervision was effective for measuring progress, enhancing quality of services, identifying capacity needs, and serving as a mentorship and an operational research tool.


Dermal and ocular irritation studies of honeybee (Apis mellifera L.) venom.
The aim of this study was to access the irritant properties of bee venom (BV) after its application to skin and eye mucous membranes of the rabbit. The animals were also observed for clinical signs and mortality after the application of the test material. Six animals were used for the skin irritation test and nine rabbits for the eye irritation test. The acute BV application to the rabbit skin revealed no appreciable clinical signs throughout the observation period of 72 h and there was no mortality seen. In the eye irritation test, eye reactions were read and graded 24, 48, 72, 96 and 168 h after BV treatment. No changes in the cornea, iris or conjunctivae were observed at all time points of observations. Based on the present findings, it can be concluded that the irritation potential of BV is negligible.


MDS clinical diagnostic criteria for Parkinson's disease.
This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances.


Effects of activation on lipoprotein lipase secretion by macrophages. Evidence for autoregulation.
Lipoprotein lipase (LPL) activity was measured in the media of cultured mouse peritoneal macrophages that were isolated after the intraperitoneal injection of inflammatory agents in order to yield a variety of states of activation. Fully activated macrophages obtained from Corynebacterium parvum-injected mice secreted very low levels of LPL when compared to unstimulated macrophages, while inflammatory and primed macrophages had increased LPL secretion. When inflammatory macrophages were incubated with conditioned medium obtained from fully activated macrophages, LPL secretion decreased in a time- and dose-dependent fashion. The factor(s) secreted by fully activated macrophages that inhibited LPL secretion was shown to be thermolabile and distinct from tumor necrosis factor. These results demonstrate that activation dramatically alters macrophage LPL secretion.


Gene Therapy for Retinal Disease: What Lies Ahead.
Gene therapy in simple terms can be defined as a medical treatment that exerts its effects using molecules of DNA or RNA within cells. Most traditional drugs act by mechanisms that include binding to cell surface receptors, inhibiting enzymes in intracellular pathways or by modifying transcription. These approaches rely to some extent on a normal genetic make-up of the cell in the final common pathway, which raises significant challenges in diseases that are caused by specific gene mutations. An alternative gene therapy approach to change the behaviour of cells at the most fundamental level by one single genetic modification is therefore potentially very powerful and wide ranging. This paper presents an overview of retinal gene therapy at the current time and highlights the future therapeutic potential for a number of diseases that are currently incurable.


Preparation, characterization, and in vivo evaluation of cyclosporine cationic liposomes for the treatment of psoriasis.
Cyclosporine (CYC), a calcineurin inhibitor acts specifically on T-cells and is one of the most effective treatment options for psoriasis. Systemic administration of the drug has been associated with dose-dependent toxic effects, while its topical delivery is a challenging task due to unfavourable physicochemical properties of drug. The aim of the present study is to develop and evaluate the efficacy of topical liposomal gel containing CYC loaded cationic liposomal nanocarriers in imiquimod induced psoriatic plaque model. Liposomes composed of DOTAP and cholesterol was formulated by different liposomal preparation techniques. Optimized liposomal carriers prepared by ethanol injection method were characterized with respect to size, zeta potential, entrapment efficiency, stability, in vitro drug release and in vivo studies. Cationic liposomes with particle size of 111 ± 1.62 nm, PDI of 0.27 ± 0.08, entrapment efficiency of 93 ± 2.12%, and zeta potential of 41.12 ± 3.56 mV were obtained. Drug loaded liposomal gels showed shear thinning behaviour, which is suitable for topical application. Topical application of CYC liposomal gels on imiquimod induced psoriatic plaque model reduced the symptoms of psoriasis and levels of key psoriatic cytokines such as tumour necrosis factor-α, IL-17, and IL-22. In conclusion, the developed liposomal carrier of CYC was found to be effective and can find application in treatment of psoriasis.


Ketones and lactate "fuel" tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism.
Previously, we proposed a new model for understanding the "Warburg effect" in tumor metabolism. In this scheme, cancer-associated fibroblasts undergo aerobic glycolysis and the resulting energy-rich metabolites are then transferred to epithelial cancer cells, where they enter the TCA cycle, resulting in high ATP production via oxidative phosphorylation. We have termed this new paradigm "The Reverse Warburg Effect." Here, we directly evaluate whether the end-products of aerobic glycolysis (3-hydroxy-butyrate and L-lactate) can stimulate tumor growth and metastasis, using MDA-MB-231 breast cancer xenografts as a model system. More specifically, we show that administration of 3-hydroxy-butyrate (a ketone body) increases tumor growth by ∼2.5-fold, without any measurable increases in tumor vascularization/angiogenesis. Both 3-hydroxy-butyrate and L-lactate functioned as chemo-attractants, stimulating the migration of epithelial cancer cells. Although L-lactate did not increase primary tumor growth, it stimulated the formation of lung metastases by ∼10-fold. Thus, we conclude that ketones and lactate fuel tumor growth and metastasis, providing functional evidence to support the "Reverse Warburg Effect". Moreover, we discuss the possibility that it may be unwise to use lactate-containing i.v. solutions (such as Lactated Ringer's or Hartmann's solution) in cancer patients, given the dramatic metastasis-promoting properties of L-lactate. Also, we provide evidence for the up-regulation of oxidative mitochondrial metabolism and the TCA cycle in human breast cancer cells in vivo, via an informatics analysis of the existing raw transcriptional profiles of epithelial breast cancer cells and adjacent stromal cells. Lastly, our findings may explain why diabetic patients have an increased incidence of cancer, due to increased ketone production, and a tendency towards autophagy/mitophagy in their adipose tissue.


The structure of Mordacia mordax insulin supports the monophyly of the Petromyzontiformes and an ancient divergence of Mordaciidae and Geotriidae.
The phylogenetic relationships between the two southern hemisphere lamprey families (Geotriidae and Mordaciidae) and their northern hemisphere counterparts (Petromyzontidae) are unresolved. Insulin was isolated from an extract of islet-containing intestinal tissue from ammocoetes of the Australian lamprey, Mordacia mordax. Its primary structure was established as A-chain: GIVEQCCHRK10CSIYDMENYC20N and B-chain: SALMGTGGTH10LCGSHLVEAL20YVVCGQRGFF30 YTP[SKG]. Although the residues in parentheses are only tentatively assigned, mass spectrometry supports the proposed sequence and demonstrates that Mordacia proinsulin, unlike proinsulin from Geotria australis, is fully processed to mature insulin. Insulins from M. mordax and G. australis and from the northern hemisphere lampreys Petromyzon marinus and Lampetra fluviatilis share a pentapeptide extension to N-terminus of the B-chain (Ser-Ala-Leu-Xaa-Gly) that has never been found in the insulins of any other vertebrate class. This observation provides support for the claim that the Petromyzontiformes constitute a monophyletic group. M. mordax insulin differs from that of G. australis by 18 amino acid residues but by only four residues from the common sequence of P. marinus and L. fluviatilis insulin. These data are consistent with the view that Geotriidae and Mordaciidae have been separated for a long period and suggest that G. australis insulin has undergone an accelerated rate of molecular evolution.


DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A): a gene with dosage effect during development and neurogenesis.
DYRKs (dual-specificity tyrosine-regulated kinases) are an emerging family of evolutionarily conserved dual-specificity kinases that play key roles in cell proliferation, survival, and development. The research in the last years suggests a relevant conserved function during neuronal development, related to proliferation and/or differentiation for DYRK1A. It is expressed in neural progenitor cells and has been proposed to participate in the signaling mechanisms that regulate dendrite differentiation. In Drosophila, disruption of the homolog minibrain gene results in flies with reduced neuroblast proliferation, decreased numbers of central brain neurons, and learning/memory deficits. Knockout DYRK1A mice are embryonic lethal, and heterozygotes show decreased viability and region-specific reductions in brain size. In humans, DYRK1A has been proposed to be involved in the neurodevelopmental alterations associated with Down syndrome. The large number of protein interaction and putative substrates described for DYRK1A suggest multiple pathways and functions to be involved in its developmental function. This review focuses on the functional role that DYRK1A plays in brain development.


Is part-night lighting an effective measure to limit the impacts of artificial lighting on bats?
As light pollution is currently considered to be a major threat to biodiversity, different lighting management options are being explored to mitigate the impact of artificial lighting on wildlife. Although part-night lighting schemes have been adopted by many local authorities across Europe to reduce the carbon footprint and save energy, their effects on biodiversity are unknown. Through a paired, in situ experiment, we compared the activity levels of 8 bat species under unlit, part-night, and full-night lighting treatments in a rural area located 60 km south of Paris, France. We selected 36 study locations composed of 1 lit site and a paired unlit control site; 24 of these sites were located in areas subject to part-night lighting schemes, and 12 sites were in areas under standard, full-night lighting. There was significantly more activity on part-night lighting sites compared to full-night lighting sites for the late-emerging, light-sensitive Plecotus spp., and a similar pattern was observable for Myotis spp., although not significant. In contrast, part-night lighting did not influence the activity of early emerging bat species around streetlights, except for Pipistrellus pipistrellus for which there was significantly less activity on part-night lighting sites than on full-night lighting sites. Overall, no significant difference in activity between part- and full-night lighting sites were observed in 5 of the 8 species studied, suggesting that current part-night lighting schemes fail to encompass the range of activity of most bat species. We recommend that such schemes start earlier at night to effectively mitigate the adverse effects of artificial lighting on light-sensitive species, particularly along ecological corridors that are especially important to the persistence of biodiversity in urban landscapes.


Significantly elevated concentration of plasma monocyte chemotactic protein 1 of patients with pelvic inflammatory disease.
Our goal was to compare the expression of plasma monocyte chemotactic protein 1 (MCP-1) and the gene polymorphism in patients with pelvic inflammatory disease (PID) and healthy controls. The enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were, respectively, used to measure the plasma MCP-1 level and MCP-1 polymorphism in 70 healthy controls and in 64 patients with PID before and after they received routine treatment protocols. We found plasma MCP-1 was significantly elevated in patients with PID compared to that in normal controls and decreased significantly compared to that in patients with PID after they received treatment. The increased expression of plasma MCP-1 was significantly correlated with the cell counts of white blood cells (WBCs) in blood and the level of plasma C-reactive protein (CRP) of patients with PID before they received treatment. There was no association between MCP-1 -2518G/A SNP and its gene expression levels and PID susceptibility. Elevated plasma MCP-1 could be a biological marker for the diagnosis and to be a new strategy for target therapy of pelvic inflammatory disease.


The U.S. Health Care Crisis Five Years After Passage of the Affordable Care Act: A Data Snapshot.
Despite passage of the Affordable Care Act in 2010, the U.S. health care crisis continues. While coverage has been expanded, the reform will leave 27 million people uninsured in 2024, according to the Congressional Budget Office. Much of the new coverage is of low actuarial value with high cost-sharing requirements, creating barriers to access. Choice of physician is restricted to narrow networks of providers. Recent measures of uninsurance, underinsurance, access to care, and health care costs are given. Changes in Medicare, particularly privatization and the rise of specialty drug tiers that limit access to medically necessary medications, are reviewed. Data on a new wave of consolidation among hospitals, medical groups, insurers, and drug companies are presented. The rise of ultra-high-price drugs, such as Solvadi, is raising pharmaceutical costs, particularly in Medicaid, the program for low-income Americans. International health comparisons continue to show the United States performing poorly in relation to other countries. Recent polling data are presented, showing support for more fundamental reform.


Metal-free ferromagnetic metal and intrinsic spin semiconductor: two different kinds of SWCNT functionalized BN nanoribbons.
Two different kinds of SWCNT functionalized zigzag edge BN nanoribbons with n chains (n-ZBNNRs), namely, (a) B-edge functionalized by (m,m)SWCNT and N-edge modified with H (nZBNNR-B-(m,m)SWCNTs); and (b) the B-edge modified with H and the N-edge functionalized by (m,m)SWCNT (nZBNNR-N-(m,m)SWCNTs), have been predicted. Amazingly, we find that unlike the semiconducting and nonmagnetic H-modified n-ZBNNRs, the nZBNNR-B-(m,m)SWCNTs are intrinsic ferromagnetic metals, regardless of ribbon widths n and tube diameters (m,m). At a given (m,m), their local magnetic moments, at first, exhibit oscillation with increasing n, whereas when n is larger than 5, they are independent of n. In contrast, unlike the metallic and nonmagnetic (m,m)SWCNTs, the nZBNNR-N-(m,m)SWCNTs are ferromagnetic intrinsic spin-semiconductors with direct band gaps, regardless of n and (m,m). Their local magnetic moments and band gaps are independent of n and (m,m). The DFT calculations reveal that the process of SWCNT functionalization of the n-ZBNNRs does not need any activation energy. Moreover, the formation energies of the SWCNT functionalized n-ZBNNRs are always less than zero. Therefore, the SWCNT functionalized n-ZBNNRs are not only stable, but can also be spontaneously formed. Furthermore, compared with n-ZBNNRs, the SWCNT functionalized n-ZBNNRs show significant improvements in their thermal and mechanical stabilities. Thus, (m,m)SWCNT functionalization of n-ZBNNRs may open new routes toward practical nanoelectronic and optoelectronic as well as spintronic devices based on BNC-based materials.


[Effect of age on the pharmacokinetic parameters of digoxin].
Digoxin pharmacokinetics was studied in 40 virtually healthy subjects aged 60-89 years and 10 subjects aged 20-29 years injected with a single dose (0.5 mg) of digoxin. The pharmacokinetic data were interpreted in terms of a two-compartmental model. The constant of digoxin transfer rate from the peripheral compartment to the central one appreciably increased, whereas the elimination constant and the magnitude of the total clearance was decreased with aging. The values of the apparent volume of the drug distribution in the central compartment, as well as those of the stationary and kinetic volumes of distribution got reduced. In elderly and senile subjects, the pharmacokinetic curve area increased. The half-life of digoxin in young, elderly and senile subjects was equal to 51, 54 and 57 h, respectively.


In silico proteome analysis to facilitate proteomics experiments using mass spectrometry.
Proteomics experiments typically involve protein or peptide separation steps coupled to the identification of many hundreds to thousands of peptides by mass spectrometry. Development of methodology and instrumentation in this field is proceeding rapidly, and effective software is needed to link the different stages of proteomic analysis. We have developed an application, proteogest, written in Perl that generates descriptive and statistical analyses of the biophysical properties of multiple (e.g. thousands) protein sequences submitted by the user, for instance protein sequences inferred from the complete genome sequence of a model organism. The application also carries out in silico proteolytic digestion of the submitted proteomes, or subsets thereof, and the distribution of biophysical properties of the resulting peptides is presented. proteogest is customizable, the user being able to select many options, for instance the cleavage pattern of the digestion treatment or the presence of modifications to specific amino acid residues. We show how proteogest can be used to compare the proteomes and digested proteome products of model organisms, to examine the added complexity generated by modification of residues, and to facilitate the design of proteomics experiments for optimal representation of component proteins.


On-chip sample preparation for complete blood count from raw blood.
This paper describes a monolithic microfluidic device capable of on-chip sample preparation for both RBC and WBC measurements from whole blood. For the first time, on-chip sample processing (e.g. dilution, lysis, and filtration) and downstream single cell measurement were fully integrated to enable sample preparation and single cell analysis from whole blood on a single device. The device consists of two parallel sub-systems that perform sample processing and electrical measurements for measuring RBC and WBC parameters. The system provides a modular environment capable of handling solutions of various viscosities by adjusting the length of channels and precisely controlling mixing ratios, and features a new 'offset' filter configuration for increased duration of device operation. RBC concentration, mean corpuscular volume (MCV), cell distribution width, WBC concentration and differential are determined by electrical impedance measurement. Experimental characterization of over 100,000 cells from 10 patient blood samples validated the system's capability for performing on-chip raw blood processing and measurement.


Disparities in Adherence to Pediatric Sepsis Guidelines across a Spectrum of Emergency Departments: A Multicenter, Cross-Sectional Observational In Situ Simulation Study.
Each year in the United States, 72,000 pediatric patients develop septic shock, at a cost of $4.8 billion. Adherence to practice guidelines can significantly reduce mortality; however, few methods to compare performance across a spectrum of emergency departments (EDs) have been described. We employed standardized, in situ simulations to measure and compare adherence to pediatric sepsis guidelines across a spectrum of EDs. We hypothesized that pediatric EDs (PEDs) would have greater adherence to the guidelines than general EDs (GEDs). We also explored factors associated with improved performance. This multi-center observational study examined in situ teams caring for a simulated infant in septic shock. The primary outcome was overall adherence to the pediatric sepsis guideline as measured by six subcomponent metrics. Characteristics of teams were compared using multivariable logistic regression to describe factors associated with improved performance. We enrolled 47 interprofessional teams from 24 EDs. Overall, 21/47 teams adhered to all six sepsis metrics (45%). PEDs adhered to all six metrics more than GEDs (93% vs. 22%; difference 71%, 95% confidence interval [CI] 43-84). Adherent teams had significantly higher Emergency Medical Services for Children readiness scores, MD composition of physicians to total team members, teamwork scores, provider perceptions of pediatric preparedness, and provider perceptions of sepsis preparedness. In a multivariable regression model, only greater composite team experience had greater adjusted odds of achieving an adherent sepsis score (adjusted odds ratio 1.38, 95% CI 1.01-1.88). Using standardized in situ scenarios, we revealed high variability in adherence to the pediatric sepsis guideline across a spectrum of EDs. PEDs demonstrated greater adherence to the guideline than GEDs; however, in adjusted analysis, only composite team experience level of the providers was associated with improved guideline adherence.


Characterization of invasive Neisseria meningitidis isolates recovered from children in Turkey during a period of increased serogroup B disease, 2013-2017.
Diverse Neisseria meningitidis strains belonging to various serogroups and clonal complexes cause epidemic and endemic life-threatening disease worldwide. This study aimed to investigate the genetic diversity of recent invasive meningococci in Turkey with respect to multilocus sequence type (MLST) and also meningococcal serogroup B (MenB) vaccine antigens to enable assessment of potential MenB strain coverage using the genetic Meningococcal Antigen Typing System (gMATS). Fifty-four isolates, representing 37.5% of all pediatric (ages 0-18 years) invasive meningococcal disease cases in Turkey from January 2013 to December 2017, underwent genome sequence analysis. Thirty-six (66.7%) isolates were MenB, 10 (18.5%) were serogroup W (MenW), 4 (7.4%) were serogroup A (MenA), 3 (5.6%) were serogroup Y (MenY) and 1 (1.8%) was serogroup X (MenX). The MenB isolates were diverse with cc35 (19.4%), cc41/44 (19.4%) and cc32 (13.8%) as the most prevalent clonal complexes. The MenW isolates (n = 10) comprised cc11 (n = 5), ST-2754 (cc-unassigned; n = 4) and cc22 (n = 1). gMATS was indicative of high 4CMenB coverage (72.2-79.1%) of Turkish invasive MenB strains from pediatric patients. Strain coverage of several clonal complexes differed from that seen elsewhere in Europe highlighting the importance of performing local assessments and also the use of phenotypic methods, i.e. MATS, where possible. All of the isolates possessed in-frame fhbp alleles and so were potentially covered by MenB-fHbp. Continued surveillance is essential to guide recommendations for current and future vaccines as well as understanding changes in epidemiology.


Inappropriate use of antibiotics and Clostridium difficile infection.
We assessed appropriateness of preceding and concurrent antibiotics in 126 consecutive patients with hospital-associated Clostridium difficile infection. In 93 (73.8%) episodes, at least 1 preceding course of antibiotics was inappropriate. We provided feedback on concurrent antibiotics on the day of diagnosis during the final 8 months: 17 of 74 (23.0%) patients were on inappropriate antibiotics. Our recommendations were well received. Reviewing C difficile-infected patients allowed for identification of opportunities to improve antibiotic utilization and potentially improved patient outcomes.


Enhanced erythro-phagocytosis in polycythemic mice overexpressing erythropoietin.
Adaptive mechanisms to hematocrit levels of 0.9 in our erythropoietin-overexpressing mice (tg6) include increased plasma nitric oxide levels and erythrocyte flexibility. Doubled reticulocyte counts in tg6 suggest an increased erythrocyte turnover. Here we show that compared with wild-type (wt) animals, erythrocyte lifespan in tg6 is 70% lower in tg6 mice. Transgenic mice have a younger erythrocyte population as indicated by higher intercellular water and potassium content, higher flexibility, decreased density, increased surface to volume ratio, and decreased osmotic fragility. Interestingly, despite being younger, the tg6 erythrocyte population also harbors characteristics of accelerated aging such as an increased band 4.1a to 4.1b ratio, signs of oxidative stress, or decreased surface CD47 and sialic acids. In tg6, in vivo tracking of PKH26-labeled erythrocytes revealed dramatically increased erythrocyte incorporation by their liver macrophages. In vitro experiments showed that tg6 macrophages are more active than wt macrophages and that tg6 erythrocytes are more attractive for macrophages than wt ones. In conclusion, in tg6 mice erythrocyte aging is accelerated, which results, together with an increased number and activity of their macrophages, in enhanced erythrocyte clearance. Our data points toward a new mechanism down-regulating red cell mass in excessive erythrocytosis in mice.


Autism and Piaget's theory: are the two compatible?
Autism is interpreted in Piagetian terms with particular reference to the question of whether the atypical cognitive development represents an exception to the similar sequence hypothesis. Findings from relevant research applying Piaget's theory to mental retardation, psychosis, and autism are reviewed. The apparent exceptions to the hypothesis presented in autistic individuals are explained by Piaget's two-factor theory of figurative versus operative functions. Many autistic individuals show an arrest in operative functions at the sensorimotor level while continuing to progress in figurative functions. The early arrest interferes with subsequent development of higher-level conceptual, symbolic, and social skills. Questions for research are offered.


A eukaryotic-acquired gene by a biotrophic phytopathogen allows prolonged survival on the host by counteracting the shut-down of plant photosynthesis.
Xanthomonas citri pv. citri, the bacteria responsible for citrus canker posses a biological active plant natriuretic peptide (PNP)-like protein, not present in any other bacteria. PNPs are a class of extracellular, systemically mobile peptides that elicit a number of plant responses important in homeostasis and growth. Previously, we showed that a Xanthomonas citri pv. citri mutant lacking the PNP-like protein XacPNP produced more necrotic lesions in citrus leaves than wild type infections and suggested a role for XacPNP in the regulation of host homeostasis. Here we have analyzed the proteome modifications observed in citrus leaves infected with the wild type and XacPNP deletion mutant bacteria. While both of them cause down-regulation of enzymes related to photosynthesis as well as chloroplastic ribosomal proteins, proteins related to defense responses are up-regulated. However, leaves infiltrated with the XacPNP deletion mutant show a more pronounced decrease in photosynthetic proteins while no reduction in defense related proteins as compared to the wild-type pathogen. This suggests that XacPNP serves the pathogen to maintain host photosynthetic efficiency during pathogenesis. The results from the proteomics analyses are consistent with our chlorophyll fluorescence data and transcript analyses of defense genes that show a more marked reduction in photosynthesis in the mutant but no difference in the induction of genes diagnostic for biotic-stress responses. We therefore conclude that XacPNP counteracts the shut-down of host photosynthesis during infection and in that way maintains the tissue in better conditions, suggesting that the pathogen has adapted a host gene to modify its natural host and render it a better reservoir for prolonged bacterial survival and thus for further colonization.


Recent climate observations compared to projections.
We present recent observed climate trends for carbon dioxide concentration, global mean air temperature, and global sea level, and we compare these trends to previous model projections as summarized in the 2001 assessment report of the Intergovernmental Panel on Climate Change (IPCC). The IPCC scenarios and projections start in the year 1990, which is also the base year of the Kyoto protocol, in which almost all industrialized nations accepted a binding commitment to reduce their greenhouse gas emissions. The data available for the period since 1990 raise concerns that the climate system, in particular sea level, may be responding more quickly to climate change than our current generation of models indicates.


The Promise of Whole Genome Pathogen Sequencing for the Molecular Epidemiology of Emerging Aquaculture Pathogens.
Aquaculture is the fastest growing food-producing sector, and the sustainability of this industry is critical both for global food security and economic welfare. The management of infectious disease represents a key challenge. Here, we discuss the opportunities afforded by whole genome sequencing of bacterial and viral pathogens of aquaculture to mitigate disease emergence and spread. We outline, by way of comparison, how sequencing technology is transforming the molecular epidemiology of pathogens of public health importance, emphasizing the importance of community-oriented databases and analysis tools.


On the use of computer-assistance to facilitate systematic mapping.
The volume of published academic research is growing rapidly and this new era of "big literature" poses new challenges to evidence synthesis, pushing traditional, manual methods of evidence synthesis to their limits. New technology developments, including machine learning, are likely to provide solutions to the problem of information overload and allow scaling of systematic maps to large and even vast literatures. In this paper, we outline how systematic maps lend themselves well to automation and computer-assistance. We believe that it is a major priority to consolidate efforts to develop and validate efficient, rigorous and robust applications of these novel technologies, ensuring the challenges of big literature do not prevent the future production of systematic maps.


Elucidating the role of matrix stiffness in 3D cell migration and remodeling.
Reductionist in vitro model systems which mimic specific extracellular matrix functions in a highly controlled manner, termed artificial extracellular matrices (aECM), have increasingly been used to elucidate the role of cell-ECM interactions in regulating cell fate. To better understand the interplay of biophysical and biochemical effectors in controlling three-dimensional cell migration, a poly(ethylene glycol)-based aECM platform was used in this study to explore the influence of matrix cross-linking density, represented here by stiffness, on cell migration in vitro and in vivo. In vitro, the migration behavior of single preosteoblastic cells within hydrogels of varying stiffness and susceptibilities to degradation by matrix metalloproteases was assessed by time-lapse microscopy. Migration behavior was seen to be strongly dependent on matrix stiffness, with two regimes identified: a nonproteolytic migration mode dominating at relatively low matrix stiffness and proteolytic migration at higher stiffness. Subsequent in vivo experiments revealed a similar stiffness dependence of matrix remodeling, albeit less sensitive to the matrix metalloprotease sensitivity. Therefore, our aECM model system is well suited to unveil the role of biophysical and biochemical determinants of physiologically relevant cell migration phenomena.


[Splenectomy in epithelial ovarian cancer: analysis of 32 cases].
To investigate the clinicopathologic features, the complications of splenectomy and the survival of epithelial ovarian cancer patients with splenic metastasis. A retrospective study was performed of 32 patients with epithelial ovarian cancer who underwent splenectomy for tumor cytoreduction at Zhejiang Cancer Hospital between Jan 1998 and Jun 2006. Of 32 patients, 23 patients (72%) were serous adenocarcinoma and 9 were non-serous adenocarcinoma. According to pathological grade, none was of G1, 11 were of G2, 21 were of G3. Postoperatively, 20 patients were left with no residual tumor, 7 were with < or = 2 cm and 5 were with > 2 cm residual tumor. Postoperative complications developed in 8 patients (25%), including subphrenic abscess, wound infection, gastric perforation, gastrorrhagia, phlebothrombosis, and bowel obstruction. The median follow up was 38 months, estimated 2-year and 5-year overall survival were 70% and 36%. Univariate analysis revealed that histological grade, residual tumor and courses of chemotherapy were influencing factors of the survival (P < 0.05), but multivariate analysis indicated that only residual tumor and courses of chemotherapy independently influenced survival (P < 0.05). In epithelial ovarian cancer patients with splenic metastasis, low grade serous adenocarcinoma is most common. Splenectomy as part of cytoreductive surgery is associated with modest morbidity and mortality. Residual tumor and courses of chemotherapy are independent factors associated with the prognosis of the patients.


Murine Borrelia arthritis is highly dependent on ASC and caspase-1, but independent of NLRP3.
The protein platform called the NOD-like-receptor -family member (NLRP)-3 inflammasome needs to be activated to process intracellular caspase-1. Active caspase-1 is able to cleave pro-Interleukin (IL)-1β, resulting in bioactive IL-1β. IL-1β is a potent proinflammatory cytokine, and thought to play a key role in the pathogenesis of Lyme arthritis, a common manifestation of Borrelia burgdorferi infection. The precise pathways through which B. burgdorferi recognition leads to inflammasome activation and processing of IL-1β in Lyme arthritis has not been elucidated. In the present study, we investigated the contribution of several pattern recognition receptors and inflammasome components in a novel murine model of Lyme arthritis. Lyme arthritis was elicited by live B. burgdorferi, injected intra-articularly in knee joints of mice. To identify the relevant pathway components, the model was applied to wild-type, NLRP3-/-, ASC-/-, caspase-1-/-, NOD1-/-, NOD2-/-, and RICK-/- mice. As a control, TLR2-/-, Myd88-/- and IL-1R-/- mice were used. Peritoneal macrophages and bone marrow-derived macrophages were used for in vitro cytokine production and inflammasome activation studies. Joint inflammation was analyzed in synovial specimens and whole knee joints. Mann-Whitney U tests were used to detect statistical differences. We demonstrate that ASC/caspase-1-driven IL-1β is crucial for induction of B. burgdorferi-induced murine Lyme arthritis. In addition, we show that B. burgdorferi-induced murine Lyme arthritis is less dependent on NOD1/NOD2/RICK pathways while the TLR2-MyD88 pathway is crucial. Murine Lyme arthritis is strongly dependent on IL-1 production, and B. burgdorferi induces inflammasome-mediated caspase-1 activation. Next to that, murine Lyme arthritis is ASC- and caspase-1-dependent, but NLRP3, NOD1, NOD2, and RICK independent. Also, caspase-1 activation by B. burgdorferi is dependent on TLR2 and MyD88. Based on present results indicating that IL-1 is one of the major mediators in Lyme arthritis, there is a rationale to propose that neutralizing IL-1 activity may also have beneficial effects in chronic Lyme arthritis.


Vascular challenges in renal transplantation.
The increasing demand for transplantable organs, especially kidneys, has led to expanded criteria for renal transplant donors. As a result of the expanded criteria, more organs with vascular anomalies and/or pathologies are available for transplant. This retrospective study evaluated the impact of vascular repair on the outcome in kidney transplantation in a single center over a 15-year period. Between January 1997 and May 2012, 1134 deceased donor renal transplantations were performed in the Department for Vascular and Endovascular Surgery of the University of Düsseldorf, Germany. A vascular reconstruction of some type was necessary to repair renal vessels or to prepare the recipient site for transplantation in 374 of 1134 (33.0%) renal transplantations. The iliac artery in 12.3% (139/1134) of cases and the renal artery in 10.1% (115/1134) of cases showed severe atherosclerosis and a thrombo-endarterectomy was required. Organ loss occurred in 13 cases (1.1%) due to vascular failure. The 5-year graft survival for kidneys with reconstructed renal arteries was 84.3% in deceased donor renal transplantations (86.1% without arterial reconstruction). The demand for renal transplants has led to more marginal-quality organs and older donors and/or recipients waiting for a second or third transplantation. Thus, the expertise of a vascular surgeon is extremely helpful in a transplantation center because it allows for marginal organ transplantation with acceptable 5-year graft survival rates.


Impaired orientation discrimination and localisation following parietal damage: On the interplay between dorsal and ventral processes in visual perception.
We report the case of a patient with left parietal damage (MH) who is selectively impaired at both detecting and localising targets defined in terms of their orientation. Performance was relatively good in other tasks where the target was defined either by a single feature (colour) or an orientation conjunction. The results are consistent with the idea that the dorsal stream supports some aspects of basic visual perception (i.e., the discrimination and localisation of orientation-defined targets). The effect of a parietal deficit may be to stress processing via the intact ventral stream, which groups information for object recognition, making differences in orientation less salient. Consistent with this, MH performed better when localising targets at a larger display size, where elements were less likely to group into a familiar shape and where local texture-based processes can come into play. In addition, MH's ability to localise a target was more impaired than his ability to detect a target, supporting the argument that orientation discrimination precedes (or operates independently of) feature localisation.


Real-life outcome of anti-tumor necrosis factor α in the ambulatory treatment of ulcerative colitis.
To evaluate the outcome of anti-tumor necrosis factor alpha (anti-TNFα) therapy in outpatients with ulcerative colitis at a tertiary referral center. All patients with a confirmed diagnosis of ulcerative colitis undergoing therapy with infliximab and/or adalimumab at the outpatient clinic for inflammatory bowel diseases at the University Hospital Heidelberg between January 2011 and February 2014 were retrospectively enrolled. Patients with a follow-up period of less than 6 mo from start of anti-TNFα therapy were excluded. Medical records of all eligible individuals were carefully reviewed. Steroid-free clinical remission of a duration of at least 3 mo, colectomy rate, duration of anti-TNFα therapy, need for anti-TNFα dose escalation, and the occurrence of adverse events were evaluated as the main outcome parameters. Seventy-two patients were included (35 treated with infliximab, 17 with adalimumab, 20 with both consecutively). Median follow-up was 27 mo (range: 6-87 mo). Steroid-free clinical remission was achieved by 22.2% of the patients (median duration: 21 mo until end of follow-up; range: 3-66 mo). Patients attaining steroid-free clinical remission displayed lower hemoglobin and albumin blood levels at the start of treatment than those who did not achieve remission. The overall colectomy rate was 20.8%. Nearly 50% of the patients underwent anti-TNFα dose escalation during the follow-up period. For both the infliximab and the adalimumab treated patients, non-response to anti-TNFα therapy was the major reason for treatment discontinuation. 18.2% of the infliximab-treated patients and 13.5% of the adalimumab-treated patients had to discontinue their therapy due to adverse events. Real-life remission rates of ulcerative colitis under anti-TNFα are overall low, but some patients have a clear long-term benefit.


What Are We Looking for in Computer-Based Learning Interventions in Medical Education? A Systematic Review.
Computer-based learning (CBL) has been widely used in medical education, and reports regarding its usage and effectiveness have ranged broadly. Most work has been done on the effectiveness of CBL approaches versus traditional methods, and little has been done on the comparative effects of CBL versus CBL methodologies. These findings urged other authors to recommend such studies in hopes of improving knowledge about which CBL methods work best in which settings. In this systematic review, we aimed to characterize recent studies of the development of software platforms and interventions in medical education, search for common points among studies, and assess whether recommendations for CBL research are being taken into consideration. We conducted a systematic review of the literature published from 2003 through 2013. We included studies written in English, specifically in medical education, regarding either the development of instructional software or interventions using instructional software, during training or practice, that reported learner attitudes, satisfaction, knowledge, skills, or software usage. We conducted 2 latent class analyses to group articles according to platform features and intervention characteristics. In addition, we analyzed references and citations for abstracted articles. We analyzed 251 articles. The number of publications rose over time, and they encompassed most medical disciplines, learning settings, and training levels, totaling 25 different platforms specifically for medical education. We uncovered 4 latent classes for educational software, characteristically making use of multimedia (115/251, 45.8%), text (64/251, 25.5%), Web conferencing (54/251, 21.5%), and instructional design principles (18/251, 7.2%). We found 3 classes for intervention outcomes: knowledge and attitudes (175/212, 82.6%), knowledge, attitudes, and skills (11.8%), and online activity (12/212, 5.7%). About a quarter of the articles (58/227, 25.6%) did not hold references or citations in common with other articles. The number of common references and citations increased in articles reporting instructional design principles (P=.03), articles measuring online activities (P=.01), and articles citing a review by Cook and colleagues on CBL (P=.04). There was an association between number of citations and studies comparing CBL versus CBL, independent of publication date (P=.02). Studies in this field vary highly, and a high number of software systems are being developed. It seems that past recommendations regarding CBL interventions are being taken into consideration. A move into a more student-centered model, a focus on implementing reusable software platforms for specific learning contexts, and the analysis of online activity to track and predict outcomes are relevant areas for future research in this field.


Probiotic administration improves sperm quality in asthenozoospermic human donors.
The objective of this study is to analyse the effect of the ingestion of two selected antioxidant probiotics strains (Lactobacillus rhamnosus CECT8361 and Bifidobacterium longum CECT7347) on sperm quality parameters in asthenozoospermic males after three and six weeks of administration. Nine asthenozoospermic men without any medical treatment under similar diet conditions participated in the study. The quality of individual sperm samples was evaluated before (previous to ingestion), during (after 3 and 6 weeks of ingestion) and after probiotic administration (3 and 6 weeks after finishing the treatment). Sperm motility was evaluated by computer-assisted sperm analysis system, DNA fragmentation by sperm chromatin structure assay, cell viability by flow cytometry and measurement of intracellular H2O2 (reactive oxygen species; ROS) by flow cytometry using dichloro-dihydrofluorescein diacetate. Sperm motility was drastically improved after the treatment (approximately 6 fold change), DNA fragmentation was statistically reduced after probiotic administration from (approximately 1.2 fold change) and intracellular H2O2 level was decreased (approximately 3.5 fold change). Cell viability was not affected by the treatment. The significant improvement in sperm motility and the decrease in DNA fragmentation reported in this study provide preliminary evidence that probiotics could be administrated to improve motility and decrease DNA fragmentation and ROS levels in asthenozoospermic human males.


Statutory health insurance in Germany: a health system shaped by 135 years of solidarity, self-governance, and competition.
Bismarck's Health Insurance Act of 1883 established the first social health insurance system in the world. The German statutory health insurance system was built on the defining principles of solidarity and self-governance, and these principles have remained at the core of its continuous development for 135 years. A gradual expansion of population and benefits coverage has led to what is, in 2017, universal health coverage with a generous benefits package. Self-governance was initially applied mainly to the payers (the sickness funds) but was extended in 1913 to cover relations between sickness funds and doctors, which in turn led to the right for insured individuals to freely choose their health-care providers. In 1993, the freedom to choose one's sickness fund was formally introduced, and reforms that encourage competition and a strengthened market orientation have gradually gained importance in the past 25 years; these reforms were designed and implemented to protect the principles of solidarity and self-governance. In 2004, self-governance was strengthened through the establishment of the Federal Joint Committee, a major payer-provider structure given the task of defining uniform rules for access to and distribution of health care, benefits coverage, coordination of care across sectors, quality, and efficiency. Under the oversight of the Federal Joint Committee, payer and provider associations have ensured good access to high-quality health care without substantial shortages or waiting times. Self-governance has, however, led to an oversupply of pharmaceutical products, an excess in the number of inpatient cases and hospital stays, and problems with delivering continuity of care across sectoral boundaries. The German health insurance system is not as cost-effective as in some of Germany's neighbouring countries, which, given present expenditure levels, indicates a need to improve efficiency and value for patients.


Intracranial hypertension after resection of cerebral arteriovenous malformations. Predisposing factors and management strategy.
Surgical excision of cerebral arteriovenous malformations (AVMs) may be complicated by postoperative breakthrough edema and hemorrhage and by intracranial hypertension. Embolization, staged resection, and meticulous surgical technique have decreased but not completely eliminated this complication. In this study we prospectively assess the prevalence of intracranial hypertension after excision of cerebral AVMs, examine factors predisposing to this complication, and document the outcome of aggressive monitoring and treatment of elevated intracranial pressure (ICP). During a 4-year period at a single institution, 32 consecutive patients with cerebral AVMs underwent surgical excision after staged embolization. All patients underwent postoperative monitoring of ICP and a uniform management protocol of intracranial hypertension. Intractable intracranial hypertension was encountered after resection of 9 of 32 cerebral AVMs, including 3 of 20 (15%) AVMs 6 cm or less in maximum diameter and 6 of 12 (50%) AVMs greater than 6 cm in maximum diameter. This complication occurred in 5 of 10 (50%) lesions located in distal or border-zone locations, in 4 of 9 (44%) AVMs arising directly off proximal cerebral arteries, and in none of 13 AVMs in other locations. Preoperative single-photon emission-computed tomography perfusion scans were performed in 17 patients and demonstrated parenchymal hypoperfusion beyond the AVM nidus in 5 of 10 AVMs 6 cm or less in maximum diameter, none of which manifested postoperative intractable ICP. Hypoperfusion was observed on single-photon emission-computed tomography in 7 of 7 AVMs greater than 6 cm that were studied by this modality, and intractable ICP was observed postoperatively in 5 of these cases despite preoperative staged embolization in every case. Patients with symptomatic intractable ICP were treated with intravenous short-acting barbiturates under a strict critical care protocol. There was no instance of uncontrollable intracranial hypertension or break-through edema while on barbiturate therapy. There was no permanent morbidity related to this treatment and no mortality or new disability morbidity in this series. We conclude that intractable intracranial hypertension remains a common complication after resection of a subgroup of cerebral AVMs despite preoperative embolization, modern neuroanesthesia and critical care management, and microsurgical technique. A proactive management protocol aimed at ICP control is safe and effective in the management of this complication.


Central role of Th2/Tc2 lymphocytes in pattern II multiple sclerosis lesions.
Multiple sclerosis (MS) is a disease of the central nervous system with marked heterogeneity in several aspects including pathological processes. Based on infiltrating immune cells, deposition of humoral factors and loss of oligodendrocytes and/or myelin proteins, four lesion patterns have been described. Pattern II is characterized by antibody and complement deposition in addition to T-cell infiltration. MS is considered a T-cell-mediated disease, but until now the study of pathogenic T cells has encountered major challenges, most importantly the limited access of brain-infiltrating T cells. Our objective was to identify, isolate, and characterize brain-infiltrating clonally expanded T cells in pattern II MS lesions. We used next-generation sequencing to identify clonally expanded T cells in demyelinating pattern II brain autopsy lesions, subsequently isolated these as T-cell clones from autologous cerebrospinal fluid and functionally characterized them. We identified clonally expanded CD8(+) but also CD4(+) T cells in demyelinating pattern II lesions and for the first time were able to isolate these as live T-cell clones. The functional characterization shows that T cells releasing Th2 cytokines and able to provide B cell help dominate the T-cell infiltrate in pattern II brain lesions. Our data provide the first functional evidence for a putative role of Th2/Tc2 cells in pattern II MS supporting the existence of this pathogenic phenotype and questioning the protective role that is generally ascribed to Th2 cells. Our observations are important to consider for future treatments of pattern II MS patients.


Evaluation of detection and response times of fire sensors using an atmospheric monitoring system.
Atmospheric monitoring systems (AMS) are required when using air from conveyor belt entries to ventilate working sections in U.S. underground coal mines. AMS technology has the potential to increase fire safety mine-wide, but research is needed to determine the detection and response times for fires of a variety of combustible materials. To evaluate the potential of an AMS for fire detection in other areas of a coal mine, a series of full-scale fire experiments were conducted to determine detection and response times from fires of different combustible materials that are found in U.S. underground coal mines, including high- and low-volatility coals, conveyor belts, brattice materials, different types of wood, diesel fuel, and a foam sealant. These experiments were conducted in the Safety Research Coal Mine (SRCM) of the U.S. National Institute for Occupational Safety and Health (NIOSH) located in Pittsburgh, PA, using a commercially available AMS that is typical of current technology. The results showed that through proper selection of sensors and their locations, a mine-wide AMS can provide sufficient early fire warning times and improve the health and safety of miners.


Adherence to antiretroviral treatment by adults in a rural area of Botswana.
As antiretroviral therapy (ART) is becoming increasingly available to people in developing countries, ART adherence challenges assume ever greater significance. Often underlying treatment failure is the fact that suboptimal adherence to ART is the strongest predictor of failure to achieve viral suppression below the level of detection. The study's main objective was to identify factors affecting ART adherence levels, as well as the impact on immunologic and virologic responses in adult patients in one rural district in Botswana. A cross-sectional quantitative survey, was used. Structured interviews were conducted with 300 ART patients between November 2011 and February 2012. Data were analysed, then presented in charts, graphs and frequency tables. The prevalence of non-adherence to ART was 14.0%. Motivators of good adherence included disclosure of HIV-positive status to more than one person, frequent adherence counselling, self-efficacy for adherence to ART, positive interactions between patients and healthcare providers; and using adherence partners. Barriers to adherence were forgetfulness, transportation costs to and from the clinic, time away from work and side-effects. There was a strong positive correlation between adherence, CD4 counts and viral load. Adherence was closely tied to immunologic and virologic improvements. Respondents with poor adherence were likely to have unsuppressed viral loads (OR 12.98, 95% CI 4.9-34). Adherence to ART is closely tied to virologic, immunologic, and clinical outcomes. Increases in adherence levels resulted in significant improvements in these outcomes. Near perfect adherence, however, is required to maximise the likelihood of long-term clinical success, which could pose challenges to many ART patients, especially in resource-limited rural settings.


A comparison between the early and mid-term results of surgical as opposed to percutaneous closure of defects in the oval fossa in children aged less than 6 years.
To compare surgical as opposed to percutaneous interventional closure of isolated atrial septal defects in the oval fossa in terms of hospital stay, efficacy, and complications, and to study the respective role of the two techniques in current practice. Between January 1998 and April 2004, 126 out of 1210 patients treated at our institution for closure of an isolated defect in the oval fossa were aged less than 6 years. The mean age of these 126 patients at procedure was 4.2 plus or minus 1 year. The ratio of females to males was 74 to 52. Of the patients, 62% were treated successfully using a percutaneous approach. The groups treated surgically or percutaneously did not differ for age, gender, or indications for treatment. No deaths occurred. The rates of total and major complications were higher in the group undergoing surgical closure, at 34% versus 9%, p less than 0.0001, and 10.5% versus 1%, p equal to 0.01, respectively. Embolisation of the device requiring subsequent surgery occurred in 1% of patients. The stay in hospital was shorter in those closed percutaneously, at 3.2 plus or minus 0.9 days versus 6.8 plus or minus 2.8 days, p equal to 0.0001. During a mean follow-up of 3.4 plus or minus 1.9 years, no major complications occurred in either group, and symptoms improved significantly in both groups. Additional sequels occurred in 2 patients who had major complications subsequent to surgical closure. Even in young children, it is both feasible and safe to close defects in the oval fossa percutaneously. Compared to surgical closure, the transcatheter approach allows a shorter stay in hospital, and has a lower rate of complications. Early and mid-term follow-up has confirmed the safety and efficacy of both techniques.


Does drug education work?
Recent research indicates that certain drug education programmes do stop or delay the onset of drug use under optimum conditions. Social inoculation programmes have generally enjoyed the greaterst degree of success, but the behaviour changes have been confined to a small number of students; have not been uniform across all drugs and have diminished over time. Research on the cost effectiveness of drug education progammes indicates that they compare favourably with the cost effectiveness of most law enforcement approaches, but are not as cost effective as treatment. While there are some methodological qualifications, the drug education literature does indicate that soundly conceptualized and rigorously implemented programmes can influence drug using behaviour and that comprehensive provision of such programmes is likely to produce a net social cost saving to society. This does not mean that proven drug education programs will necessarily be implemented. The most powerful factor in the implementation process is selection of programmes on the basis of ideal outcomes, rather than on the evidence of what can realistically be achieved. Ultimately, this is self-defeating, because programme failures will again discredit the whole drug education approach. Drug education programmes must be selected because they have demonstrated the ability to have a beneficial impact on youth drug use and youth drug problems.


Neuromuscular and physiological variables evolve independently when running immediately after cycling.
During the early period of running after cycling, EMG patterns of the leg are modified in only some highly trained triathletes. The majority of studies have analysed muscle EMG patterns at arbitrary, predetermined time points. The purpose of this study was to examine changes to EMG patterns of the lower limb at physiologically determined times during the cycle-run transition period to better investigate neuromuscular adaptations. Six highly trained triathletes completed a 10 m in isolated run (IR), 30 min of rest, then a 20 min cycling procedure, before a 10 min transition run (C-R). Surface EMG activity of eight lower limb muscles was recorded, normalised and quantified at four time points. Oxygen uptake and heart rate values were also collected. Across all muscles, mean (± SD) EMG patterns, demonstrated significant levels of reproducibility for each participant at all four time points (α < 0.05; r = 0.52-0.97). Mean EMG patterns during C-R correlated highly with the IR patterns (α < 0.05). These results show that EMG patterns during subsequent running are not significantly affected by prior cycling. However, variability of muscle recruitment activity does appear to increase during C-R transition when compared to IR.


Excited-state dynamics of structurally characterized [ReI(CO)3(phen)(HisX)]+ (X = 83, 109) Pseudomonas aeruginosa azurins in aqueous solution.
The triplet metal-to-ligand charge transfer ((3)MLCT) dynamics of two structurally characterized Re(I)(CO)(3)(phen)(HisX)-modified (phen = 1,10-phenanthroline; X = 83, 109) Pseudomonas aeruginosa azurins have been investigated by picosecond time-resolved infrared (TRIR) spectroscopy in aqueous (D(2)O) solution. The (3)MLCT relaxation dynamics exhibited by the two Re(I)-azurins are very different from those of the sensitizer [Re(I)(CO)(3)(phen)(im)](+) (im = imidazole). Whereas the Re(I)(CO)(3) intramolecular vibrational relaxation in Re(I)(CO)(3)(phen)(HisX)Az (4 ps) is similar to that of [Re(I)(CO)(3)(phen)(im)](+) (2 ps), the medium relaxation is much slower ( approximately 250 vs 9.5 ps); the 250-ps relaxation is attributable to reorientation of D(2)O molecules as well as structural reorganization of the rhenium chromophore and nearby polar amino acids in each of the modified proteins.


A review of the available clinical therapies for vulvodynia management and new data implicating proinflammatory mediators in pain elicitation.
Localised provoked vulvodynia (LPV) is a common, chronic, and disabling condition: patients experience profound pain and a diminished quality of life. The aetiologic origins of vulvodynia are poorly understood, yet recent evidence suggests a link to site-specific inflammatory responses. Fibroblasts isolated from the vestibule of LPV patients are sensitive to proinflammatory stimuli and copiously produce pain-associated proinflammatory mediators (IL-6 and PGE2 ). Although LPV is a multifactorial disorder, understanding vulvar inflammation and targeting the inflammatory response should lead to treatment advances, especially for patients exhibiting signs of inflammation. NFκB (already targeted clinically) or other inflammatory components may be suitable therapeutic targets. Vulvodynia is a poorly understood, prevalent, and serious women's health issue requiring better understanding to improve therapy.


Serious Adverse Events Reported with Dietary Supplement Use in the United States: A 2.5 Year Experience.
Dietary supplement marketers assure the safety of their products by complying with current good manufacturing practices and a host of federal regulations, including those enforced by the Food and Drug Administration (FDA). Post-market surveillance is a key part of identifying safety problems associated with dietary supplement products. FDA requires dietary supplement marketers to provide a domestic address or phone number on product labels for consumers, family members, or health care professionals to report adverse events (AEs) associated with product use and to report all serious adverse events (SAEs) to the agency within 15 business days of receipt. We aimed to evaluate the characteristics of AEs reported with dietary supplement use, including dietary supplement type and Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) that occur with reported SAEs. A total of 41,121 unique adverse event cases reported to two large, U.S.-based dietary supplement marketers in a 2.5-year period (March 1, 2014-August 31, 2016) were assessed for seriousness using established criteria. Each SAE was assigned one or more MedDRA preferred terms and system organ classes (SOC). The types of supplements most responsible for SAEs were assessed. Of the 41,121 AE cases reported, 203 (0.48%) were SAEs. SAEs tended to occur with products marketed for weight loss (69.0%) and glycemic control (19.2%). SAEs occurred most commonly in the cardiovascular, gastrointestinal, and nervous system disorder SOCs. The percentage of SAEs reported to dietary supplement marketers is low, predominantly among consumers of two types of supplements. Further study is needed among a larger cohort of supplement users to determine causal associations between types of supplement products and serious adverse events.


Therapeutic potential of medicinal marijuana: an educational primer for health care professionals.
With the proposed Canadian July 2018 legalization of marijuana through the Cannabis Act, a thorough critical analysis of the current trials on the efficacy of medicinal marijuana (MM) as a treatment option is necessary. This review is particularly important for primary care physicians whose patients may be interested in using MM as an alternative therapy. In response to increased interest in MM, Health Canada released a document in 2013 for general practitioners (GPs) as an educational tool on the efficacy of MM in treating some chronic and acute conditions. Although additional studies have filled in some of the gaps since the release of the Health Canada document, conflicting and inconclusive results continue to pose a challenge for physicians. This review aims to supplement the Health Canada document by providing physicians with a critical yet concise update on the recent advancements made regarding the efficacy of MM as a potential therapeutic option. An update to the literature of 2013 is important given the upcoming changes in legislation on the use of marijuana. Also, we briefly highlight the current recommendations provided by Canadian medical colleges on the parameters that need to be considered prior to authorizing MM use, routes of administration as well as a general overview of the endocannabinoid system as it pertains to cannabis. Lastly, we outline the appropriate medical conditions for which the authorization of MM may present as a practical alternative option in improving patient outcomes as well as individual considerations of which GPs should be mindful. The purpose of this paper is to offer physicians an educational tool that provides a necessary, evidence-based analysis of the therapeutic potential of MM and to ensure physicians are making decisions on the therapeutic use of MM in good faith.


CWDM based HDMI interconnect incorporating passively aligned POF linked optical subassembly modules.
A four-channel transmitter OSA (TOSA) and a receiver optical sub-assembly (ROSA) module were presented. They take advantage of a coarse WDM (CWDM) scheme, employing two types of VCSELs at 780 and 850 nm, where no wavelength filters are involved in the TOSA. The ROSA and TOSA were constructed through a fully passive alignment process using components produced by virtue of a cost effective plastic injection molding technique. In order to build a high quality optical HDMI interconnect, four channel optical links between these modules ware established via two graded-index plastic optical fibers (GI-POFs). The HDMI interconnect was thoroughly evaluated in terms of the alignment tolerance, the light beam propagation, and the data transmission capability. For the ROSA, the measured tolerance, as affected by the photodiode alignment, was ~45 μm and over 200 μm for the transverse and longitudinal directions, respectively. For the TOSA, the tolerance, which is mostly dependent upon the VCSEL alignment, was ~20 μm and more than 200 μm for the transverse and longitudinal directions, respectively. The beam profiles for the TOSA and ROSA were monitored to confirm their feasibility from the optical coupling perspective. A digital signal at 2.5 Gb/s was efficiently transmitted through the HDMI interconnect with a bit error ratio of below 10-16. A 1080p HDMI signal from a Blu-ray player was delivered through the interconnect to an LCD monitor and successfully displayed a high quality video.


Effect of an integrated child nutrition intervention on the complementary food intake of young children in rural north Viet Nam.
Forty-two percent of Vietnamese children are stunted by two years of age. Since 1990, Save the Children Federation/US (SC) has implemented integrated nutrition programs targeting young children. We evaluated the effect of SC's nutrition program on the complementary food intake of young rural Vietnamese children. Using a longitudinal, prospective, randomized design, we followed 238 children (119 each from intervention and comparison communes) age 5 to 25 months old for six months with a re-survey at 12 months. We gathered 24-hour recall data at baseline and at months 2, 4, 6, and 12. Dietary energy intake was calculated using the 1972 Vietnamese food composition table. Key outcomes were daily frequency of consuming intervention-promoted food and non-breastmilk liquids and food, daily quantity of non-breastmilk liquids and food consumed, daily energy intake, and proportion of children meeting daily median energy requirements. Young rural children exposed to SC's program consumed intervention-promoted, and any, foods more frequently, ate a greater quantity of any food, consumed more energy, and were more likely to meet their daily energy requirements than comparison children. Some effects were only observed during the intensive intervention period; others persisted into or were evident only at the 12-month follow-up, approximately four months after program completion. Based on the mothers' reports, the intervention did not apparently compromise breastfeeding prevalence or frequency. The intervention improved children's food and energy intake and protected them from declining as rapidly as comparison children in meeting their energy requirements.


Oral contraceptive use for the primary prevention of ovarian cancer.
To estimate the overall balance of harms and benefits from the potential use of oral contraceptives (OCs) for the primary prevention of ovarian cancer We searched PubMed®, Embase®, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for English-language studies published from January 1990 to June 2012 that evaluated the potential benefits (reduction in ovarian, colorectal, and endometrial cancers) and harms (increase in breast and cervical cancer, and vascular complications) of OC use. Two investigators screened each abstract and full-text article for inclusion; the investigators abstracted data, and they performed quality ratings, applicability ratings, and evidence grading. Random-effects models were used to compute summary estimates of effects. A simulation model was used to estimate the effects of OC use on the overall balance of benefits and harms. We reviewed 55 studies relevant to ovarian cancer outcomes, 66 relevant to other cancers, and 50 relevant to vascular events. Ovarian cancer incidence was significantly reduced in OC users (OR [odds ratio], 0.73; 95% CI [confidence interval], 0.66 to 0.81), with greater reductions seen with longer duration of use. Breast cancer incidence was slightly but significantly increased in OC users (OR, 1.08; 95% CI, 1.00 to 1.17), with a significant reduction in risk as time since last use increased. The risk of cervical cancer was significantly increased in women with persistent human papillomavirus infection who used OCs, but heterogeneity prevented a formal meta-analysis. Incidences of both colorectal cancer (OR, 0.86; 95% CI, 0.79 to 0.95) and endometrial cancer (OR, 0.57; 95% CI, 0.43 to 0.76) were significantly reduced by OC use. The risk of vascular events was increased in current OC users compared with nonusers, although the increase in myocardial infarction was not statistically significant. The overall strength of evidence for ovarian cancer prevention was moderate to low, primarily because of the lack of randomized trials and inconsistent reporting of important characteristics of use, such as duration. The simulation model predicted that the combined increase in risk of breast and cervical cancers and vascular events was likely to be equivalent to or greater than the decreased risk in ovarian cancer, although the harm/benefit ratio was much more favorable when protection against endometrial and colorectal cancers was added, resulting in net gains in life expectancy of approximately 1 month. There is insufficient evidence to recommend for or against the use of OCs solely for the primary prevention of ovarian cancer. Although the net effects of the current patterns of OC use likely result in increased life expectancy when other noncontraceptive benefits are included, the harm/benefit ratio for ovarian cancer prevention alone is uncertain, particularly when the potential quality-of-life impact of breast cancer and vascular events are considered.