Perioperative management of the severely obese patient: a selective pathophysiological review.
Obesity is widespread, yet it is often understood primarily as a disorder of body structure. This article provides anesthesiologists with a synopsis of recent research into the complex pathophysiology of obesity. It emphasizes the importance of this information for the perioperative planning and management of this patient group and for reviewing some of the major perioperative challenges. Obesity is a multisystem chronic pro-inflammatory disorder associated with increased morbidity and mortality. Adipocytes are far more than storage vessels for lipids. They secrete a large number of physiologically active substances called adipokines that lead to inflammation, vascular and cardiac remodelling, airway inflammation, and altered microvascular flow patterns. They contribute to linked abnormalities, such as insulin resistance and the metabolic syndrome, and they attract and activate inflammatory cells such as macrophages. These changes can lead ultimately to organ dysfunction, especially cardiovascular and pulmonary issues. In the respiratory system, anesthesiologists should be familiar not just with screening tools for obstructive sleep apnea but also with obesity hypoventilation syndrome, which is less well appreciated and carries a significant outcome disadvantage. Perioperative management is challenging. It is centred around cardiorespiratory and metabolic optimization, minimizing adverse effects of both pain and systemic opioids, effective use of regional anesthesia, and an emphasis on mobilization and nutrition - given the prevalence of micronutrient deficiencies in the severely obese. There is a risk of incorrect drug dosing in obesity, which requires an understanding of the appropriate dosing weights for perioperative medications. The literature clearly highlights the complexity of severe obesity as a multisystem disease, and anesthesiologists caring for these patients perioperatively must have a sound understanding of the changes in order to offer the highest quality care to these patients.


The junior doctor changeover effect: does it exist in general surgery?
Junior doctor changeover has been perceived as a period of increased risk to patients. However, there is a paucity of contemporary evidence of this 'changeover effect'. The aim of this study was to evaluate the presence of an adverse patient effect during periods of junior doctor changeover. Data were requested on all patients aged 18 years or older admitted acutely under General Surgery in the North of England between 2005 and 2016. This included patient characteristics, diagnoses, comorbidities, procedure codes, mortality and length of stay. Patients were included in the study if they were admitted during the 'changeover week'; defined as the first day of the changeover followed by the six subsequent days. For junior trainees (FY1-CT2), this is the first Wednesday of August, December and April each year. For higher surgical trainees (ST3-ST8), it is the first Wednesday in October. Another week, four weeks prior, was chosen as a historical comparator. In total, 61,714 patients were included in this study. Patient characteristics did not vary between the cohorts. There was no difference in 30-day mortality between changeover and non-changeover groups (2.5% vs 2.6%, p = 0.280) or length of stay (5.3 vs 5.2, p = 0.613). Changeover week was not a predictor of increased mortality (OR 1.06, p = 0.302) following multivariable adjustment. Further analysis of the first junior and higher specialty trainee periods, August and October, respectively, showed no significant difference for measured outcomes. This retrospective cohort study provides contemporary evidence that the 'changeover effect' does not exist in acute general surgical admissions in the UK.


Separation of digesta fractions complicates estimation of ileal digestibility using marker methods with Cr2O3 and cobalt-ethylenediamine tetraacetic acid in broiler chickens.
Marker methodologies to measure ileal and total tract digestibilities of diets varying in content and degradability of dietary fiber in broiler chickens were evaluated. Chromium sesquioxide (Cr2O3) and cobalt-ethylenediamine tetraacetic acid (Co-EDTA) were used as markers of solid and soluble fractions, respectively, and compared with digestibility values obtained with the total collection method. Groups of broilers (n = 17, 11 broilers/group) were assigned to a low-fiber diet or 1 of 2 high-fiber diets, the latter 2 containing 35% rapeseed meal (RSM). Pectolytic enzymes were added to one RSM diet to improve degradability of the fiber fraction. Excreta were quantitatively collected for 96 h, and contents from ileum and ceca were collected at slaughter at 29, 30, or 31 d of age. Chromium recovery in excreta ranged between 86 and 95%, whereas cobalt recovery was considerably lower (66 to 70%). Chromium:cobalt ratio was higher in ileal digesta than in feed. Hardly any chromium was found in the ceca, indicating that separation of the marker and specific digesta fractions occurs. Estimates of apparent total tract digestibility (ATTD) were lower when calculated using the marker method compared with the total collection method, particularly in high-fiber diets. Using Cr2O3 as a marker, differences were relatively small and effects due to enzyme addition were generally similar. Using Co-EDTA as a marker, ATTD of all components were lower compared with values obtained using the collection method (3 to 45 percentage units, P < 0.001), likely related to the low Co recovery. When estimating apparent ileal digestibility (AID), separation of marker and digesta resulted in unrealistically high estimates for the digestibility of nonglucose polysaccharides (54 to 66%), exceeding ATTD values by 16 to 42 percentage units. Moreover, the effect of pectolytic enzyme addition on the AID of nonglucose polysaccharides was in the opposite direction when compared with total collection. The data illustrate that fractionation of digesta, particularly in high-fiber diets, complicates accurate AID measurements in broilers, regardless of the choice of markers used.


Effect of neurodynamic mobilization on fluid dispersion in median nerve at the level of the carpal tunnel: A cadaveric study.
To evaluate the effect of neurodynamics mobilization (NDM) on an artificially induced edema in the median nerve at the level of the carpal tunnel in unembalmed cadavers and to assess whether NDM tensioning techniques (TT) and NDM sliding techniques (SLT) induce similar effects on intraneural fluid dispersion. Fourteen upper extremities of seven unembalmed cadavers were used in this study. A biomimetic solution was injected directly under the epineurium of the median nerve at the level of the proximal transverse carpal ligament. The initial dye spread was allowed to stabilize and measured with a digital caliper. Tensioning and sliding techniques were applied following a randomized crossover design to each upper extremity and were performed for a total of 5 min each. Post-intervention dye spread measurements were taken after each technique. After the first mobilization, the mean longitudinal dye spread (7.5 ± 6.6 mm) was significantly greater (p = 0.024) compared to the stabilized dye spread. There was a significant longitudinal diffusion effect with both, TT (p = 0.018) and SLT (p = 0.016), with no statistically significant difference between techniques (p = 0.976). The order in which techniques were administered did not influence the diffusion. Five minute of passive NDM in the form of tensioning or sliding technique induced significant fluid dispersion in the median nerve at the carpal tunnel of unembalmed human cadavers. This study provides support for clinical mechanism of NDM in reducing intraneural edema.


Human UDP-glucuronosyltransferase expression in insect cells: ratio of active to inactive recombinant proteins and the effects of a C-terminal his-tag on glucuronidation kinetics.
Many laboratories use recombinant UDP-glucuronosyltransferases (UGTs), expressed in baculovirus-infected insect cells, for drug glucuronidation studies. We have infected Sf9 insect cells with increasing amounts of recombinant baculovirus, encoding either UGT1A9 or UGT2B7, and measured both glucuronidation activity and immunodetectable UGT in the resulting cell homogenates. The correlation between glucuronidation rates and degree of infection followed different trends, depending on whether activity was the actual activity measured or was corrected for UGT expression level. Above a certain low level of infection, further increases in infection ratios led to a large decline in normalized activity, presumably due to the presence of full-length but inactive enzyme in the sample. Because immunodetection does not distinguish between active and inactive UGT, comparison of normalized activity between different batches of a recombinant UGT, mutants of a given UGT, or different UGTs is prone to large inaccuracies. Such inaccuracies could be reduced by lowering the degree of infection of the insect cells, in combination with careful monitoring of UGT expression. However, the latter requires suitable antibodies for comparing UGT expression levels among preparations, antibodies that are not always available. Poly-His (His-tag)-containing peptides, fused to the UGT C terminus, allow sensitive immunodetection of expressed enzymes with monoclonal antibodies. We have now carefully examined the effects of two such fusion peptides on enzyme kinetics. A minor increase in the K(m) values has been detected in the His-tagged UGTs, but no changes in parameters such as the kinetic model and the effects of albumin addition.


Collaborative Method Performance Study of the Measurement of Nicotine, Its Metabolites, and Total Nicotine Equivalents in Human Urine.
Background: Biomarkers of tobacco exposure have a central role in studies of tobacco use and nicotine intake. The most significant exposure markers are nicotine itself and its metabolites in urine. Therefore, it is important to evaluate the performance of laboratories conducting these biomarker measurements.Methods: This report presents the results from a method performance study involving 11 laboratories from 6 countries that are currently active in this area. Each laboratory assayed blind replicates of seven human urine pools at various concentrations on three separate days. The samples included five pools blended from smoker and nonsmoker urine sources, and two additional blank urine samples fortified with pure nicotine, cotinine, and hydroxycotinine standards. All laboratories used their own methods, and all were based on some form of liquid chromatography/tandem mass spectrometry.Results: Overall, good agreement was found among the laboratories in this study. Intralaboratory precision was good, and in the fortified pools, the mean bias observed was < + 3.5% for nicotine, approximately 1.2% for hydroxycotinine, and less than 1% for cotinine (1 outlier excluded in each case). Both indirect and direct methods for analyzing the glucuronides gave comparable results.Conclusions: This evaluation indicates that the experienced laboratories participating in this study can produce reliable and comparable human urinary nicotine metabolic profiles in samples from people with significant recent exposure to nicotine.Impact: This work supports the reliability and agreement of an international group of established laboratories measuring nicotine and its metabolites in urine in support of nicotine exposure studies. Cancer Epidemiol Biomarkers Prev; 27(9); 1083-90. ©2018 AACR.


Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing.
The plasma total and low-density lipoprotein-cholesterol (LDL-C) levels that are used as diagnostic criteria for familial hypercholesterolaemia (FH) probands in the general population are too stringent for use in relatives, given the higher prior probability of a first-degree relative being FH (50% vs. 1/500). Our objective was therefore to develop more appropriate LDL-C cutoffs to identify "affected" first-degree relatives found by cascade testing, to test their accuracy and utility in case identification, and to compare them with the published "Make early diagnosis to prevent disease" (MEDPED) cutoffs from the US. Using a large, anonymised sample of genetically tested first-degree relatives of Netherlands FH probands (mutation carriers/non-carriers, n=825/2,469), age- and gender-specific LDL-C diagnostic cutoffs for first-degree relatives were constructed. These were used to test similar data from Denmark (n=160/161) and Norway (n=374/742). Gender-specific LDL-C diagnostic cutoffs were established for six different age groups, which achieved an overall accuracy (measured as Youden's index) of 0.53 in the Netherlands data, and performed significantly better amongst younger (<25 years) compared to older first-degree relatives (0.68 vs. 0.42 Youden's index, p<0.001). Compared with the Netherlands data, age- and gender-adjusted mean LDL-C levels were significantly higher (approximately 0.5 mmol/L) in the Denmark and Norway subjects for both mutation carriers and non-carriers. After adjusting for this difference, the LDL-C cut-offs showed a similar accuracy in identifying mutation carriers from Denmark (81%, range 78%-86%) and Norway (84%, range 82%-86%). Although the MEDPED cutoffs performed significantly worse than these for the Netherlands data (p<0.001), they performed equally well in overall accuracy for the Norwegian and Danish data, although the LDL-C cutoffs had a significantly higher sensitivity but lower specificity for all three countries. The cutoffs developed here are designed to give the greatest overall accuracy when testing relatives of FH patients in the absence of a genetic diagnosis. They have a more balanced specificity and sensitivity than the MEDPED cutoffs that are designed to achieve higher specificity, which is more appropriate for cascade testing purposes. The data suggest that country-specific LDL-C cutoffs may lead to greater accuracy for identifying FH patients, but should be used with caution and only when a genetic diagnosis (DNA) is not available.


[Passive cable properties of relay cells in dorsal lateral geniculate nucleus of the rabbit].
We measured the passive membrane properties of 24 relay cells in slice preparation of the lateral geniculate nucleus of the rabbit. The resting membrane potential was -62.7 +/- 4.1 mV (mean +/- SD) with an input resistance of 30.4 +/- 11.2 M omega. According to Rall's linear cable model, the electrotonic length (L) of the dendrite was 0.79 +/- 0.13. The voltage attenuation factor (H) was 1.33 +/- 0.11. All these indicated that the relay cells were electrically compact. DC voltage on the distal dendrite could spread to the soma attenuated only by 25%.


Modeling menopause: The utility of rodents in translational behavioral endocrinology research.
The human menopause transition and aging are each associated with an increase in a variety of health risk factors including, but not limited to, cardiovascular disease, osteoporosis, cancer, diabetes, stroke, sexual dysfunction, affective disorders, sleep disturbances, and cognitive decline. It is challenging to systematically evaluate the biological underpinnings associated with the menopause transition in the human population. For this reason, rodent models have been invaluable tools for studying the impact of gonadal hormone fluctuations and eventual decline on a variety of body systems. While it is essential to keep in mind that some of the mechanisms associated with aging and the transition into a reproductively senescent state can differ when translating from one species to another, animal models provide researchers with opportunities to gain a fundamental understanding of the key elements underlying reproduction and aging processes, paving the way to explore novel pathways for intervention associated with known health risks. Here, we discuss the utility of several rodent models used in the laboratory for translational menopause research, examining the benefits and drawbacks in helping us to better understand aging and the menopause transition in women. The rodent models discussed are ovary-intact, ovariectomy, and 4-vinylcylohexene diepoxide for the menopause transition. We then describe how these models may be implemented in the laboratory, particularly in the context of cognition. Ultimately, we aim to use these animal models to elucidate novel perspectives and interventions for maintaining a high quality of life in women, and to potentially prevent or postpone the onset of negative health consequences associated with these significant life changes during aging.


Efficacy and safety of a GABAergic drug (Gamalate® B6): effects on behavior and cognition in young adults with borderline-to-mild intellectual developmental disabilities and ADHD.
We evaluated Gamalate® B6 (GB6) in patients with borderline intellectual functioning (BIF) or mild intellectual development disability (IDD). This was a prospective phase IV observational pilot study in 30 patients who underwent neuropsychological evaluation during treatment with GB6 for 12 weeks. In comparison with baseline, the responses were positive, with a significant improvement in hyperactivity (51.7%), irritability (35.5%), and logorrhea (50%), and no sedative effect. The Clinical Global Impressions - Severity (CGI-S) score was much improved or very much improved in 73% of cases. Reaction time was better with fewer errors, thus indicating an improvement in attentional processes. A statistically significant result was obtained for the number of movements used to solve the problem and for the total number of correctly solved problems. In this pilot study, GB6 was effective and well tolerated in cases of ADHD and challenging behavior in young adults with borderline-to-mild BIF/IDD. However, given the small number of patients involved and the uncontrolled nature of the study, these results should be viewed cautiously.


A window on the normal development of sensitivity to global form in Glass patterns.
We studied the development of sensitivity to global form in 6-year-olds, 9-year-olds, and adults (n = 24 in each group) using Glass patterns with varying ratios of paired signal dots to noise dots. The developmental pattern was similar whether the global structure within the Glass patterns was concentric or parallel. Thresholds were equally immature for both types of pattern at 6 years of age (about twice the adult value) but were adult-like at 9 years of age. Together, the results indicate that the cortical structures involved in the processing of global form achieve functional maturity between 6 and 9 years of age. During middle childhood, the mechanisms mediating sensitivity to concentric structure develop at the same rate as those mediating sensitivity to parallel structure.


Kinetics feasibility study of alcohol sulfate esterification reactions in tropospheric aerosols.
Sulfate esters have recently been identified in the secondary organic aerosol (SOA) formed in the photooxidation of biogenic hydrocarbons both in laboratory and under ambient atmospheric conditions. In the present study, the kinetics feasibility of direct reactions between alcohols and sulfuric acid to form sulfate esters in aerosol particles is explored. Nuclear magnetic resonance methods were used to monitor the bulk reaction kinetics of sulfate esterification reactions for a number of simple alcohols. The experiments were carried out at various sulfuric acid concentrations and a range of temperatures in order to estimate the rate constants of such reactions in aerosols under the previously studied laboratory conditions and under ambient atmospheric conditions. The measured rate constants did not depend greatly on the identity of the reactant alcohol, but increased strongly as a function of the sulfuric acid concentration, as predicted by excess acidity theory. Because of the strong temperature dependence of the rate constants for the direct reaction of alcohols with sulfuric acid, it appears that these reactions are kinetically infeasible for low temperature upper tropospheric sulfuric aerosols. For lower tropospheric SOA, it appears that the aerosol acidity is rarely high enough such that these reactions are likely to be responsible for the presence of sulfate esters in SOA.


The EcoRI restriction endonuclease with bacteriophage lambda DNA. Kinetic studies.
The kinetics of the reactions of the EcoRI restriction endonuclease at individual recognition sites on the DNA from bacteriophage lambda were found to differ markedly from site to site. Under certain conditions of pH and ionic strength, the rates for the cleavage of the DNA were the same at each recognition site. But under altered experimental conditions, different reaction rates were observed at each recognition site. These results are consistent with a mechanism in which the kinetic stability of the complex between the enzyme and the recognition site on the DNA differs among the sites, due to the effect of interactions between the enzyme and DNA sequences surrounding each recognition site upon the transition state of the reaction. Reactions at individual sites on a DNA molecule containing more than one recognition site were found to be independent of each other, thus excluding the possibility of a processive mechanism for the EcoRI enzyme. The consequences of these observations are discussed with regard to both DNA-protein interactions and to the application of restriction enzymes in the study of the structure of DNA molecules.


Experience with the second-generation Wallis interspinous dynamic stabilization device implanted in degenerative lumbar disease: a case series of 50 patients.
This study aimed to evaluate the short- to medium-term outcomes of the second-generation Wallis interspinous dynamic stabilization device for treatment of lumbar degenerative disease. Fifty patients with lumbar degenerative disease treated from August 2007 to September 2009 were included in this retrospective study. The Japanese Orthopedic Association (JOA) score and the Oswestry Disability Index (ODI) were used for therapeutic efficacy evaluation. Odom's criteria were used to evaluate postoperative outcome with regard to symptoms. Anteroposterior X-rays were obtained after surgery. All patients were followed up for 2 years. Based on Odom's criteria, 22, 24 and 4 patients had excellent, good, and fair results respectively. The JOA score at 3, 12, and 24 months after surgery was significantly higher than before surgery (all p < 0.001), and the ODI score at 3, 12, and 24 months after surgery was significantly lower than before surgery (all p < 0.001). The posterior intervertebral disc height and the neural foramina height at 12 and 24 months after surgery was significantly higher than before surgery (both p < 0.001). Implantation of the second-generation Wallis interspinous dynamic stabilization device produced satisfactory clinical outcome at short- and medium-term follow-up in patients with lumbar degenerative disease.


Blink: Characteristics, Controls, and Relation to Dry Eyes.
Blink is a complex phenomenon that is profoundly affected by diverse endogenous and exogenous stimuli. It has been studied in the context of cognition, emotional, and psychological states, as an indicator of fatigue and sleepiness, particularly in the automobile and transportation industry, in visual tasking, and finally, as it relates to tear film stability and ocular surface health. The fact that it is highly variable and has input from so many sources makes it very difficult to study. In the present review, the behavior of blink in many of these systems is discussed, ultimately returning in each instance to a discussion of how these factors affect blink in the context of dry eyes. Blink is important to ocular surface health and to an individual's optimal functioning and quality of life. Disturbances in blink, as cause or effect, result in a breakdown of tear film stability, optical clarity, and visual function.


Should there be greater use of preprint servers for publishing reports of biomedical science?
Vitek Tracz and Rebecca Lawrence declare the current journal publishing system to be broken beyond repair. They propose that it should be replaced by immediate publication followed by transparent peer review as the starting place for more open and efficient reporting of science. While supporting this general objective, we suggest that research is needed both to understand why biomedical scientists have been slow to take up preprint options, as well as to assess the relative merits of this and other alternatives to journal publishing.


Design, characterization, and in vitro evaluation of antifungal polymeric films.
The objective of the present paper was the development and the full characterization of antifungal films. Econazole nitrate (ECN) was loaded in a polymeric matrix formed by chitosan (CH) and carbopol 971NF (CB). Polyethylene glycol 400 and sorbitol were used as plasticizing agents. The mechanical properties of films were poorer when the drug was loaded, probably because crystals of ENC produces network outages and therefore reduces the polymeric interactions between the polymers. Polymers-ECN and CH-CB interactions were analyzed by Fourier-transform infrared spectroscopy (FTIR), thermal gravimetry analysis, and differential thermal analysis (DTA-TGA). ECN did not show structure alterations when loaded into the films. In scanning electron microphotographs and atomic force microscopy analysis, films prepared with CB showed an evident wrinkle pattern probably due to the strong interactions between the polymers, which were observed by FTIR and DTA-TGA. The in vitro activity of the formulations against Candida krusei and Candida parapsilosis was twice as greater as the commercial cream, probably as a result of the antifungal combination of the drug with the CH activity. All these results suggest that these polymeric films containing ECN are potential candidates in view of alternatives dosages forms for the treatment of the yeast assayed.


von Recklinghausen's disease with involvement of right parapharyngeal space: report of a case.
A 42-year-old patient of von Recklinghausen's disease suffered from odynophagia, trismus and prominent gag reflex for seven months. Physical examination revealed a firm, nonpulsatile submucosal mass in the right oropharynx. CT scan showed a huge, well-defined mass in the right parapharyngeal space and intracranial involvement was excluded. Pathological examination of the tumor after surgical excision demonstrated a neurofibroma about 7.5 x 4 x 3 cm in size, which was consistent with skin neurofibroma. After surgery the patient was free from the initial complaints and has remained well to the present. von Recklinghausen's disease, also known as neurofibromatosis type I, is characterized by numerous skin neurofibromas, cafe-au-lait spots, etc. It has quite diverse complications occurring in the head and neck region. Parapharyngeal space neurofibroma is one of the rare complications of neurofibromatosis type I, occurring in less than 5% of all parapharyngeal space neoplasia.


The role of computerized tomography in the preoperative assessment of chronic suppurative otitis media.
Twenty patients awaiting mastoid surgery for chronic suppurative otitis media underwent preoperative high resolution computerized tomography (CT) of the temporal bones. The CT scans were compared with the intraoperative findings. CT was helpful in determining the anatomy of the middle ear and mastoid, and accurately predicted the extent of the disease process in the sinus tympani and facial recess. However, it was unable to distinguish between cholesteatoma, mucosal disease and fluid, and it contributed little to the surgical management of the patients. This suggests that routine preoperative CT scanning of patients before uncomplicated virgin mastoid surgery is of questionable value.


[Coordination of public health education as a specialty with educational institutions for other related professions].
The authors believe that public health is a specific discipline with its own characteristics and precise objectives which, although it makes use of other subjects, must be distinguished and differentiated from others for teaching and practical purposes. Starting from this conceptual framework, they point out that public health teaching should encourage skills and impart knowledge on planning, organization and coordination of the services in order to provide the community with the greatest degree of health possible. They point out that public health should be taught in coordination with other teaching institutions and with the health services institutions. This will make for better use of available resources and additionally, will coordinate efforts in joint action. They further propose that the teaching cannot be limited to inherent aspects of statistics, administration, epidemiology, etc., but must also cover humanistic factors of motivation to undertake such a large task as providing health for all. It is therefore essential to select health workers properly, and to choose public health teachers well: they must have a positive, optimistic and determined attitude, if they are to be able to transmit the proper knowledge, attitudes and skills.


The relationship between clinical audit and ethics.
The aim of this paper is to start a debate about ethical issues associated with the practice of clinical audit. This is an area that has not received much consideration. The role of clinical audit is to raise general clinical standards. The ethical issues of clinical audit may have far-reaching consequences for clinicians, patients, health care providers and purchasers. Guidance is required to provide consistency in approach so that those involved in clinical audit, at whatever level, can be confident that they are following good practice. Clinicians and managers often think of good practice as being a technical matter. The main point of this paper is to bring out important ethical dimensions to good practice.


Transcript and protein expression decoupling reveals RNA binding proteins and miRNAs as potential modulators of human aging.
In studies of development and aging, the expression of many genes has been shown to undergo drastic changes at mRNA and protein levels. The connection between mRNA and protein expression level changes, as well as the role of posttranscriptional regulation in controlling expression level changes in postnatal development and aging, remains largely unexplored. Here, we survey mRNA and protein expression changes in the prefrontal cortex of humans and rhesus macaques over developmental and aging intervals of both species' lifespans. We find substantial decoupling of mRNA and protein expression levels in aging, but not in development. Genes showing increased mRNA/protein disparity in primate brain aging form expression patterns conserved between humans and macaques and are enriched in specific functions involving mammalian target of rapamycin (mTOR) signaling, mitochondrial function and neurodegeneration. Mechanistically, aging-dependent mRNA/protein expression decoupling could be linked to a specific set of RNA binding proteins and, to a lesser extent, to specific microRNAs. Increased decoupling of mRNA and protein expression profiles observed in human and macaque brain aging results in specific co-expression profiles composed of genes with shared functions and shared regulatory signals linked to specific posttranscriptional regulators. Genes targeted and predicted to be targeted by the aging-dependent posttranscriptional regulation are associated with biological processes known to play important roles in aging and lifespan extension. These results indicate the potential importance of posttranscriptional regulation in modulating aging-dependent changes in humans and other species.


Leveraging multiple data types to estimate the size of the Zika epidemic in the Americas.
Several hundred thousand Zika cases have been reported across the Americas since 2015. Incidence of infection was likely much higher, however, due to a high frequency of asymptomatic infection and other challenges that surveillance systems faced. Using a hierarchical Bayesian model with empirically-informed priors, we leveraged multiple types of Zika case data from 15 countries to estimate subnational reporting probabilities and infection attack rates (IARs). Zika IAR estimates ranged from 0.084 (95% CrI: 0.067-0.096) in Peru to 0.361 (95% CrI: 0.214-0.514) in Ecuador, with significant subnational variability in every country. Totaling infection estimates across these and 33 other countries and territories, our results suggest that 132.3 million (95% CrI: 111.3-170.2 million) people in the Americas had been infected by the end of 2018. These estimates represent the most extensive attempt to determine the size of the Zika epidemic in the Americas, offering a baseline for assessing the risk of future Zika epidemics in this region.


Microtubule stress modifies intra-nuclear location of Msh2 in mouse embryonic fibroblasts.
The maintenance of genomic stability in mitotic and meiotic cycles through mismatch repair (MMR) demands the coordination of MMR functions with multiple processes including cell cycle traverse, linked changes in microtubule dynamics, protein translocation at chromatin sites and checkpoint activation. We have studied changes in the intracellular location of the MMR protein Msh2 in response to mitosis, microtubule disruption by colcemid and DNA damage induction by cis-platin in mouse embryonic fibroblasts (MEFs). Image analysis indicated that MEFs have a normally high nuclear retention of Msh2 during interphase with a precipitous dispersal of protein from chromatin sites into the cytoplasm at mitosis. Dispersal was also observed in cisplatin- and colcemid-treated interphase MEFs without any change in the overall Msh2 levels throughout the cell cycle. There was no evidence of co-localization of the punctate cytoplasmic Msh2 foci with any microtubule structures and knockout of Msh2 altered neither the extent of microtubule disruption nor the functional activation of the spindle assembly checkpoint by colcemid. Critically, extra-nuclear relocation of protein did not alter the ability to mount an Msh2-dependent G2 checkpoint delay in response to cisplatin-induced DNA damage. Depletion of the nuclear pool of Msh2 protein in cells undergoing dispersal was found to involve a rapid relocation of protein from AT-rich chromatin sites as defined by coassociation studies exploiting a newly-characterized base-pair preference of the fluorescent DNA binding probe DRAQ5. The study reveals the unexpected mobility of MMR protein pools during the MEF cell cycle and in response to different stress-inducing agents. The results link for the first time microtubule-integrity with intra-nuclear Msh2 protein dynamics. The high nuclear retention of Msh2 in interphase MEFs is in contrast to human tumor cells while the observations on protein dispersal suggest that only low levels of nuclear-located Msh2 are needed for G2 checkpoint activation by DNA damage.


Distribution, lateral mobility and function of membrane proteins incorporated into giant unilamellar vesicles.
GUVs have been widely used for studies on lipid mobility, membrane dynamics and lipid domain (raft) formation, using single molecule techniques like fluorescence correlation spectroscopy. Reports on membrane protein dynamics in these types of model membranes are by far less advanced due to the difficulty of incorporating proteins into GUVs in a functional state. We have used sucrose to prevent four distinct membrane protein(s) (complexes) from inactivating during the dehydration step of the GUV-formation process. The amount of sucrose was optimized such that the proteins retained 100% biological activity, and many proteo-GUVs were obtained. Although GUVs could be formed by hydration of lipid mixtures composed of neutral and anionic lipids, an alternate current electric field was required for GUV formation from neutral lipids. Distribution, lateral mobility, and function of an ATP-binding cassette transport system, an ion-linked transporter, and a mechanosensitive channel in GUVs were determined by confocal imaging, fluorescence correlation spectroscopy, patch-clamp measurements, and biochemical techniques. In addition, we show that sucrose slows down the lateral mobility of fluorescent lipid analogs, possibly due to hydrogen-bonding with the lipid headgroups, leading to larger complexes with reduced mobility.


Effect of congestive heart failure on the intrinsic metabolic capacity of the liver in the dog.
The intrinsic metabolic capacity of the liver at end-stage heart failure in the pacing overdrive dog model of congestive heart failure was evaluated ex vivo. Congestive heart failure was induced in seven adult mongrel dogs (20-30 kg) by cardiac electrical pacing at a frequency of 240 stimuli/min until the development of overt heart failure; seven other dogs served as controls. The animals were then anesthetized and the right ventricular papillary muscles and samples from the left lateral hepatic lobes were collected. The degree of myocardial dysfunction as well as the total amount and the activities of cytochromes P-450 were evaluated. Tension, maximum rate of tension rise, and Vmax were significantly lower (40-60%) in the paced than in the control dogs, indicating a marked myocardial dysfunction. Moreover, significant decreases in total cytochrome P-450 (0.31 +/- 0.04 vs. 0.53 +/- 0.03 nmol/mg of microsomal protein, p less than 0.01) and in the intensity of four different electrophoretic protein bands (molecular masses of 46, 48, 50, and 59 kDa) occurred in the dogs with congestive heart failure. The decrease in total cytochrome P-450 was accompanied by a significant reduction in aminopyrine N-demethylase activity (1.74 +/- 0.25 vs. 2.91 +/- 0.40 nmol/min/mg of microsomal protein, p less than 0.05). Immunoblot analysis using antibodies to two different dog liver phenobarbital-inducible cytochromes P-450 demonstrated that PBD-1 (a P-450IIIA) was not affected by congestive heart failure, whereas PBD-2 (a P-450IIB) was markedly decreased.(ABSTRACT TRUNCATED AT 250 WORDS)


Computed tomography findings in cerebral hydatid disease.
To describe imaging findings of cerebral hydatid cysts on computed tomography of brain. We retrospectively reviewed CT scans of brain in 5 patients with pathologically confirmed hydatid cysts in cerebral hemispheres. The patients were scanned either on a spiral (single slice) CT or on multidetector-row CT before and after intravenous injection of iodinated contrast material. All the patients were children aged 8 to 13 years with 3 boys and 2 girls. Features of raised intracranial tension were present in all the cases at presentation. CT findings of a large intracerebral cystic lesion with significant mass effect and without any calcification or enhancement were common in all 5 cases. Perilesional edema was present in 1 case. Cerebral hydatid was seen as either a homogenous fluid attenuation unilocular cyst (3 cases) or a unilocular cyst with few peripheral daughter cysts (1 case) or cyst filled by multiple daughter cysts inside (1 case). All the cases were operated and cyst was removed completely after craniotomy. Accurate preoperative diagnosis of cerebral hydatid by CT followed by surgery with care to avoid cyst rupture can result in favorable outcome.


Sports-related factors predicting maintained participation and dropout in organized sports in emerging adulthood: A four-year follow-up study.
This study explored sports-related factors predicting organized sports participation in emerging adulthood. In the Finnish Health Promoting Sports Club (FHPSC) study, 354 sports club participants aged 15 at baseline reported their main sport, onset age, training volume, current competitive level, and future competitive orientation and participated in the follow-up study at age 19. There were differences in the proportions of maintainers and dropouts in a few sports: football (maintainers 58.6%), and among females, skating (maintainers 60.7%), and swimming (dropouts 80.0%). A binary logistic regression analysis showed that those who had started their main sport by school age (females OR 3.05/95% CI 1.34, 6.98; males OR 3.97/95% CI 1.48, 10.64) and had competed at national top level plus had aimed at success at the adult level competitions in future (females OR 3.42/95% CI 1.16, 10.09; males OR 3.58/95% CI 1.12, 11.41; among females, also had competed at national top level plus had aimed at success at junior level competitions [OR 3.42/95% CI 1.20, 9.78]) were more likely maintainers than dropouts. Early onset in the main sport and competitiveness were related to maintained sports participation while the opposites were related to dropouts in the current organized sports system.


Controlling the duality of the mechanism in liquid-phase oxidation of benzyl alcohol catalysed by supported Au-Pd nanoparticles.
In the solvent-free oxidation of benzyl alcohol to benzaldehyde using supported gold-palladium nanoparticles as catalysts, two pathways have been identified as the sources of the principal product, benzaldehyde. One is the direct catalytic oxidation of benzyl alcohol to benzaldehyde by O(2), whereas the second is the disproportionation of two molecules of benzyl alcohol to give equal amounts of benzaldehyde and toluene. Herein we report that by changing the metal oxide used to support the metal-nanoparticles catalyst from titania or niobium oxide to magnesium oxide or zinc oxide, it is possible to switch off the disproportionation reaction and thereby completely stop the toluene formation. It has been observed that the presence of O(2) increases the turnover number of this disproportionation reaction as compared to reactions in a helium atmosphere, implying that there are two catalytic pathways leading to toluene.


Divergent influences of leukotrienes C4, D4, and E4 on mesenteric and renal blood flow.
Influences of leukotrienes C4 (LTC4), D4 (LTD4), and E4 (LTE4) on mesenteric and renal blood flow were investigated in the anesthetized dog. Blood flow was measured with noncannulating electromagnetic flow probes, and all agonists were injected as a bolus close arterially. When injected into the superior mesenteric artery, LTC4 (0.1-3.0 ng), LTD4 (0.1-1.0 ng), and LTE4 (1-30 ng) produced dose-dependent decreases in blood flow in absence of a change in mean arterial pressure. When compared with intestinal vasoconstrictor responses caused by angiotension II, which was most active, and norepinephrine, which was least active, the leukotrienes were intermediate between these two well-known vasoactive hormones. LTD4 was more active than LTC4, and both were considerably more active than LTE4. In contrast to the intestine, injection of leukotrienes (1,000 ng) into the kidney resulted in little to no change in renal blood flow or mean arterial pressure, but mesenteric flow decreased 10-15 s later. Administration of indomethacin (5 mg/kg iv) did not alter mesenteric vasoconstrictor responses produced by LTD4. However, mesenteric vasoconstrictor responses to prostaglandin (PG)D2 were reduced after indomethacin, whereas renal vasodilation caused by PGD2 was unaffected. These results demonstrate that LTC4, LTD4, and LTE4 differentially affect blood flow in the intestine and kidney and suggest that if circulating levels of leukotrienes are increased, blood flow would be expected to be diverted away from the intestine. These data are thus compatible with the hypothesis that leukotrienes may participate in regulation of peripheral regional blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)


Amylin and beta amyloid proteins interact to form amorphous heterocomplexes with enhanced toxicity in neuronal cells.
Human pancreatic islet amyloid polypeptide (hIAPP) and beta amyloid (Aβ) can accumulate in Type 2 diabetes (T2D) and Alzheimer's disease (AD) brains and evidence suggests that interaction between the two amyloidogenic proteins can lead to the formation of heterocomplex aggregates. However, the structure and consequences of the formation of these complexes remains to be determined. The main objective of this study was to characterise the different types and morphology of Aβ-hIAPP heterocomplexes and determine if formation of such complexes exacerbate neurotoxicity. We demonstrate that hIAPP promotes Aβ oligomerization and formation of small oligomer and large aggregate heterocomplexes. Co-oligomerized Aβ42-hIAPP mixtures displayed distinct amorphous structures and a 3-fold increase in neuronal cell death as compared to Aβ and hIAPP alone. However, in contrast to hIAPP, non-amyloidogenic rat amylin (rIAPP) reduced oligomer Aβ-mediated neuronal cell death. rIAPP exhibited reductions in Aβ induced neuronal cell death that was independent of its ability to interact with Aβ and form heterocomplexes; suggesting mediation by other pathways. Our findings reveal distinct effects of IAPP peptides in modulating Aβ aggregation and toxicity and provide new insight into the potential pathogenic effects of Aβ-IAPP hetero-oligomerization and development of IAPP based therapies for AD and T2D.


Somatic mutations and T-cell clonality in patients with immunodeficiency.
Common variable immunodeficiency and other late-onset immunodeficiencies often co-manifest with autoimmunity and lymphoproliferation. The pathogenesis of most cases is elusive, as only a minor subset harbors known monogenic germline causes. The involvement of both B and T cells is however implicated. To study whether somatic mutations in CD4+ and CD8+ T cells associate with immunodeficiency, we recruited 17 patients and 21 healthy controls. Eight patients had late-onset common variable immunodeficiency and nine patients other immunodeficiency and/or severe autoimmunity. In total, autoimmunity occurred in 94% and lymphoproliferation in 65%. We performed deep sequencing of 2533 immune-associated genes from CD4+ and CD8+ cells. Deep T-cell receptor beta sequencing was used to characterize CD4+ and CD8+ T-cell receptor repertoires. The prevalence of somatic mutations was 65% in all immunodeficiency patients, 75% in common variable immunodeficiency and 48% in controls. Clonal hematopoiesis-associated variants in both CD4+ and CD8+ cells occurred in 24% of immunodeficiency patients. Results demonstrated mutations in known tumor suppressors, oncogenes, and genes that are critical for immune- and proliferative functions, such as STAT5B (two patients), C5AR1 (two patients), KRAS (one patient), and NOD2 (one patient). Additionally, as a marker of T-cell receptor repertoire perturbation, common variable immunodeficiency patients harbored increased frequencies of clones with identical complementarity determining region 3 sequences despite unique nucleotide sequences when compared to controls. In conclusion, somatic mutations in genes implicated for autoimmunity and lymphoproliferation are common in CD4+ and CD8+ cells of patients with immunodeficiency. They may contribute to immune dysregulation in a subset of immunodeficiency patients.


Alpha- and theta-range cortical synchronization and corticomuscular coherence during joystick manipulation in a virtual navigation task.
Previous studies have reported that multiple brain regions are activated during spatial navigation, but it remains unclear how this activation is converted to motor commands for navigation. This study was aimed to investigate synchronization across different brain regions and between cortical areas and muscles during spatial navigation. This synchronization has been suggested to be essential for integrating activity in the multiple brain areas to support higher cognitive functions and for conversion of cortical activity to motor commands. In the present study, the subjects were required to sequentially trace ten checkpoints in a virtual town by manipulating a joystick and to perform this three times while electroencephalograms and electromyograms from the right arm were monitored. Time spent on the task in the third trial was significantly lesser than that in the first trial indicating an improvement in task performance. This repeated learning was associated with an increase in alpha power at the electrodes over the contralateral sensorimotor region and in theta power at the electrodes over the bilateral premotor and frontotemporal regions. Alpha- and theta-range corticocortical coherences between these regions and other brain areas were also increased in the third trial compared to the first trial. Furthermore, alpha- and theta-range corticomuscular coherence was significantly increased in the second and third trials compared to the first trial. These results suggest that alpha- and theta-range synchronous activity across multiple systems is essential for the integrated brain activity required in spatial navigation and for the conversion of this activity to motor commands.


"This Is Not Gym": Enacting Student Voice Pedagogies to Promote Social and Emotional Learning and Meaningful Physical Education.
The purpose of this study was to explore learners' experiences enacting youth/student voice pedagogies (SVP) to promote Social and Emotional Learning (SEL) and meaningful physical education (MPE) in an alternative education setting. Drawing on social constructivist learning theory in understanding and implementing a MPE approach, and a systemic framework for SEL, two research questions guided the research process: (1) How did students interpret and enact these pedagogies? (2) What contribution did the enactment of these pedagogies have in promoting SEL and MPE? This study implemented a qualitative case study design framed by a participatory action research (PAR) approach spanning 12 weeks from February to May 2021. Participants in this study included 16 ninth grade alternative high school students (eight girls/eight boys) aged 14-15 who had just returned to face-to-face learning in January 2021 for the first time following COVID-19. A range of traditional and innovative participatory qualitative research methods including focus group interviews, students' personal biographies, timelines, digital and written reflections, photovoice, and class artifacts were utilized. The Miles, Huberman, and Saldana Framework for Qualitative Data Analysis was implemented involving both deductive and inductive combinations of comparative and thematic analysis. The following themes were constructed: Making responsible decisions; unearthing and sharing mixed emotions; picturing physical activity beyond the classroom; recognizing the role of relationships; considering challenge and competence; and, pursuing meaning. Findings demonstrate how enacting SVP can lead to the development of students' SEL and MPE experiences complimenting multiple learning domains. We call for further embedding of SVP capturing students' physical activity and movement experiences inside and outside of PE in teacher education and professional development that helps teachers and their students make sense of, shape, influence, and enact more MPE and physical activity learning experiences.


Atrial natriuretic factor stimulates Na/K/Cl cotransport in vascular smooth muscle cells.
Atrial natriuretic factor (ANF) is a collective term used to describe a group of peptides isolated from mammalian atria which have vasorelaxant activity as well as diuretic and natriuretic activity. Recently, ANF peptides have been shown to bind to specific receptors on vascular smooth muscle cells (VSMC) and to cause an elevation in cGMP levels. We have previously demonstrated that VSMC possess a prominent, cyclic-nucleotide-sensitive Na/K/Cl cotransport system. In the present study, the effects of the ANF peptide rat atriopeptin III (rAP III) were measured on Na/K/Cl cotransport of VSMC by using primary cultures derived from rat thoracic aorta. It was found that rAP III caused a marked elevation of Na/K/Cl cotransport. Maximal stimulation occurred at 100 nM, and the dose of rAP III required for half-maximal potassium influx (K1/2) was 9 nM. We also investigated the effect of rAP III on cGMP levels in VSMC. It was found that rAP III increased cGMP in a dose-dependent manner, with a K1/2 value of 10 nM. Finally, we measured the effect of the permeable cGMP analog 8-bromo-cGMP on Na/K/Cl cotransport. It was found that 8-bromo-cGMP stimulated cotransport to the same extent as did a saturating dose of rAP III (K1/2 = 0.2 microM). Saturating doses of rAP III and 8-Br-cGMP in combination did not stimulate cotransport in an additive manner, suggesting that rAP III probably does not elevate cGMP via inhibition of phosphodiesterase. These findings suggest that activation of Na/K/Cl cotransport via elevations in cGMP may be associated with ANF-mediated vasorelaxation and/or ANF-mediated diuresis and natriuresis.


Serum cortisol concentration in patients with major depression after treatment with fluoxetine.
Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevated cortisol levels is characteristic of the pathophysiology of major depressive disorder (MDD). The aim of this study was to determine whether increased plasma cortisol levels appear in patients with major depression and if effective antidepressant treatment by fluoxetine leads to regulation of cortisol level. This aim was realized by describing and validation of methods of determining fluoxetine and cortisol in serum and searching for correlation between their concentrations in patients with endogenous depression, the therapeutic effect as assessed in Hamilton Depression Rating Scale (HDRS), age and sex of patients. Plasma cortisol and fluoxetine levels were measured using high performance liquid chromatography (HPLC) methods with applying Shimadzu chromatograph with UV detection. Plasma cortisol and fluoxetine levels were measured at time zero (before therapy) and after 6h, 24h, 2, 4, 6 and 8 weeks of fluoxetine administration in patients with major depression qualified for therapeutic drug monitoring (TDM). The study included 21 patients (14 women, 7 men; mean age 29-75 years) and 24 healthy comparison subjects. The patients had a mean score on the 21-item HDRS. As the effect of fluoxetine administration the decrease of the level of cortisol was observed in patients who responded to the therapy (the reduction of points in HDRS scale in at least 50%). The validation parameters of HPLC method of fluoxetine and cortisol determination indicate the possibility of applying them for determination of both: the level of concentration of the drug in therapeutic drug monitoring and the level of cortisol in serum of patients with endogenous depression.


Learning Kernel Extended Dictionary for Face Recognition.
A sparse representation classifier (SRC) and a kernel discriminant analysis (KDA) are two successful methods for face recognition. An SRC is good at dealing with occlusion, while a KDA does well in suppressing intraclass variations. In this paper, we propose kernel extended dictionary (KED) for face recognition, which provides an efficient way for combining KDA and SRC. We first learn several kernel principal components of occlusion variations as an occlusion model, which can represent the possible occlusion variations efficiently. Then, the occlusion model is projected by KDA to get the KED, which can be computed via the same kernel trick as new testing samples. Finally, we use structured SRC for classification, which is fast as only a small number of atoms are appended to the basic dictionary, and the feature dimension is low. We also extend KED to multikernel space to fuse different types of features at kernel level. Experiments are done on several large-scale data sets, demonstrating that not only does KED get impressive results for nonoccluded samples, but it also handles the occlusion well without overfitting, even with a single gallery sample per subject.


Independent mutations in Ad2ts111 cause degradation of cellular DNA and defective viral DNA replication.
An adenovirus mutant, Ad2ts111, has previously been shown to be temperature sensitive for viral DNA replication in vivo and also to induce degradation of cellular DNA. Soluble nuclear extracts prepared from Ad2ts111-infected HeLa cells grown at either the permissive (32 degrees C) or the nonpermissive (39.5 degrees C) temperature are thermolabile for elongation but not for initiation of DNA replication in vitro. Adenovirus single-stranded-DNA-binding protein purified from wild-type-infected cells can complement these extracts at the restrictive temperature in vitro. The DNA-binding protein synthesized in Ad2ts111-infected cells is stable at the nonpermissive temperature and is phosphorylated, as is the wild-type protein. In contrast, the mutant DNA-binding protein synthesized in Ad5ts125-infected cells is unstable. Ad2ts111 and Ad5ts125 do not complement each other for virus growth in vivo. These results suggest that Ad2ts111 contains a mutation in the DNA-binding protein that affects viral DNA synthesis. Finally, we demonstrated that, unlike viral DNA synthesis, the induction of cellular DNA degradation in Ad2ts111-infected cells is not temperature sensitive and that this phenotype is a result of a mutation in early region 1 on the virus genome. Thus, the two phenotypes displayed in Ad2ts111-infected cells, namely, the temperature-sensitive replication of viral DNA and the degradation of cell DNA, are the result of two separate mutations.


No evidence of carbon limitation with tree age and height in Nothofagus pumilio under Mediterranean and temperate climate conditions.
Trees universally decrease their growth with age. Most explanations for this trend so far support the hypothesis that carbon (C) gain becomes limited with age; though very few studies have directly assessed the relative reductions of C gain and C demand with tree age. It has also been suggested that drought enhances the effect of C gain limitation in trees. Here tests were carried out to determine whether C gain limitation is causing the growth decay with tree age, and whether drought accentuates its effect. The balance between C gain and C demand across tree age and height ranges was estimated. For this, the concentration of non-structural carbohydrates (NSCs) in stems and roots of trees of different ages and heights was measured in the deciduous temperate species Nothofagus pumilio. An ontogenetic decrease in NSCs indicates support for C limitation. Furthermore, the importance of drought in altering the C balance with ontogeny was assessed by sampling the same species in Mediterranean and humid climate locations in the southern Andes of Chile. Wood density (WD) and stable carbon isotope ratios (δ(13)C) were also determined to examine drought constraints on C gain. At both locations, it was effectively found that tree growth ultimately decreased with tree age and height. It was found, however, that NSC concentrations did not decrease with tree age or height when WD was considered, suggesting that C limitation is not the ultimate mechanism causing the age/height-related declining tree growth. δ(13)C decreased with tree age/height at the Mediterranean site only; drought effect increased with tree age/height, but this pattern was not mirrored by the levels of NSCs. The results indicate that concentrations of C storage in N. pumilio trees do not decrease with tree age or height, and that reduced C assimilation due to summer drought does not alter this pattern.


An anthropometric study of young schoolchildren in an area of Cape Town.
A survey of the weights and heights of 896 Sub A (Grade I) schoolchildren was carried out in a working-class area of Cape Town where education is compulsory. Twenty-four per cent of all children were under the National Center for Health Statistics 5th percentile for weight and 20% were under that for height. The children under 7 1/2 years of age were felt to be truly representative of the community as a whole. For this group the proportions below the 5th percentile were 22% for weight and 18% for height. This relatively favourable picture is compared with earlier studies.


SOCR Analyses - an Instructional Java Web-based Statistical Analysis Toolkit.
The Statistical Online Computational Resource (SOCR) designs web-based tools for educational use in a variety of undergraduate courses (Dinov 2006). Several studies have demonstrated that these resources significantly improve students' motivation and learning experiences (Dinov et al. 2008). SOCR Analyses is a new component that concentrates on data modeling and analysis using parametric and non-parametric techniques supported with graphical model diagnostics. Currently implemented analyses include commonly used models in undergraduate statistics courses like linear models (Simple Linear Regression, Multiple Linear Regression, One-Way and Two-Way ANOVA). In addition, we implemented tests for sample comparisons, such as t-test in the parametric category; and Wilcoxon rank sum test, Kruskal-Wallis test, Friedman's test, in the non-parametric category. SOCR Analyses also include several hypothesis test models, such as Contingency tables, Friedman's test and Fisher's exact test.The code itself is open source (http://socr.googlecode.com/), hoping to contribute to the efforts of the statistical computing community. The code includes functionality for each specific analysis model and it has general utilities that can be applied in various statistical computing tasks. For example, concrete methods with API (Application Programming Interface) have been implemented in statistical summary, least square solutions of general linear models, rank calculations, etc. HTML interfaces, tutorials, source code, activities, and data are freely available via the web (www.SOCR.ucla.edu). Code examples for developers and demos for educators are provided on the SOCR Wiki website.In this article, the pedagogical utilization of the SOCR Analyses is discussed, as well as the underlying design framework. As the SOCR project is on-going and more functions and tools are being added to it, these resources are constantly improved. The reader is strongly encouraged to check the SOCR site for most updated information and newly added models.


Critical Reflections on Visualization Authoring Systems.
An emerging generation of visualization authoring systems support expressive information visualization without textual programming. As they vary in their visualization models, system architectures, and user interfaces, it is challenging to directly compare these systems using traditional evaluative methods. Recognizing the value of contextualizing our decisions in the broader design space, we present critical reflections on three systems we developed -Lyra, Data Illustrator, and Charticulator. This paper surfaces knowledge that would have been daunting within the constituent papers of these three systems. We compare and contrast their (previously unmentioned) limitations and trade-offs between expressivity and learnability. We also reflect on common assumptions that we made during the development of our systems, thereby informing future research directions in visualization authoring systems.


Clinical electrophysiology and visual outcome in optic nerve hypoplasia.
In optic nerve hypoplasia (ONH), the extent of functional loss of retinal ganglion cells cannot be determined by ophthalmoscopic examination. The prognostic value of visual electrodiagnostic tests in infants and toddlers with ONH was assessed by comparison with visual outcome. 85 participants with ONH had electroretinogram (ERG) and visual-evoked potential (VEP) testing to flash and to pattern-reversal checks and ocular fundus photography prior to 36 months of age. These initial measures were compared with visual acuity outcomes at 5 years of age in the better-seeing eye. Visual outcomes ranged from normal to no light perception. Electrodiagnostic tests with prognostic value were: the amplitude of the flash VEP (Spearman's rank correlations, p<0.001), the threshold category of stimulus (flash or check size) that elicited a VEP (p<0.001) and the amplitude of the N95 component of the pattern ERG (PERG) to 4-degree checks (p<0.02). Optic nerve size and co-existing pallor were also significant correlates. Stepwise regression analysis composed a best prediction model from VEP threshold category, optic nerve size and optic disc pallor (R(2)=58%; p<0.001). Optic disc diameter, observation of disc pallor, VEP and PERG testing in infancy are useful for establishing the visual prognosis at 5 years of age in children with ONH. This is consistent with the notion that these parameters are related to the anatomic and functional preservation of retinal ganglion cells.


A new biopesticide from a local Bacillus thuringiensis var. tenebrionis (Xd3) against alder leaf beetle (Coleoptera: Chrysomelidae).
Use of chemical pesticides in agriculture harms humans, non-target organisms and environments, and causes increase resistance against chemicals. In order to develop an effective bio-pesticide against coleopterans, particularly against Agelastica alni (Coleoptera: Chrysomelidae) which is one of the serious pests of alder leaf and hazelnut, we tested the insecticidal effect of 21 Bacillus isolates against the larvae and adults of the pest. Bacillus thuringiensis var. tenebrionis-Xd3 (Btt-Xd3) showed the highest insecticidal effect based on screening tests. For toxin protein production and high sporulation of Xd3, the most suitable medium, pH and temperature conditions were determined as nutrient broth medium enriched with salts, pH 7 and 30 °C, respectively. Sporulated Btt-Xd3 in nutrient broth medium enriched with salts transferred to fermentation medium containing soybean flour, glucose and salts. After fermentation, the mixture was dried in a spray dryer, and spore count of the powder product was determined as 1.6 × 1010 c.f.u. g-1. Moisture content, suspensibility and wettability of the formulation were determined as 8.3, 86% and 21 s, respectively. Lethal concentrations (LC50) of formulated Btt-Xd3 were determined as 0.15 × 105 c.f.u. ml-1 for larvae at laboratory conditions. LC50 values were also determined as 0.45 × 106 c.f.u. ml-1 at the field condition on larval stage. Our results showed that a new bio-pesticide developed from B. thuringiensis tenebrionis (Xd3) (Btt-Xd3) may be valuable as a biological control agent for coleopteran pests.


Adaptive pseudo dilation for gestalt edge grouping and contour detection.
We consider the problem of detecting object contours in natural images. In many cases, local luminance changes turn out to be stronger in textured areas than on object contours. Therefore, local edge features, which only look at a small neighborhood of each pixel, cannot be reliable indicators of the presence of a contour, and some global analysis is needed. We introduce a new morphological operator, called adaptive pseudo-dilation (APD), which uses context dependent structuring elements in order to identify long curvilinear structure in the edge map. We show that grouping edge pixels as the connected components of the output of APD results in a good agreement with the gestalt law of good continuation. The novelty of this operator is that dilation is limited to the Voronoi cell of each edge pixel. An efficient implementation of APD is presented. The grouping algorithm is then embedded in a multithreshold contour detector. At each threshold level, small groups of edges are removed, and contours are completed by means of a generalized reconstruction from markers. The use of different thresholds makes the algorithm much less sensitive to the values of the input parameters. Both qualitative and quantitative comparison with existing approaches prove the superiority of the proposed contour detector in terms of larger amount of suppressed texture and more effective detection of low-contrast contours.


Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma.
Pancreatic intraductal neoplasia (PanIN) is thought to be the precursor to infiltrating pancreatic ductal adenocarcinoma. We have previously shown that the preproenkephalin (ppENK) and p16 genes are aberrantly methylated in pancreatic adenocarcinoma. In this study we define the methylation status of the ppENK and p16 genes in various grades of PanINs. One hundred seventy-four samples (28 nonneoplastic pancreatic epithelia, 7 reactive epithelia, 29 PanIN-1A, 48 PanIN-1B, 27 PanIN-2, 14 PanIN-3, 15 invasive ductal adenocarcinomas, and 6 miscellaneous pancreatic neoplasms) were microdissected from 29 formalin-fixed paraffin-embedded surgically resected pancreata, and were analyzed by methylation-specific polymerase chain reaction. Fourteen of 15 (93.3%) invasive pancreatic ductal adenocarcinomas showed methylation of the ppENK gene and 4 of 15 (26.7%) showed methylation of the p16 gene. Nonneoplastic pancreatic epithelia did not harbor methylation of either gene. The prevalence of methylation of the ppENK gene increased significantly with increasing PanIN grade. A similar nonsignificant trend was noted for p16 methylation. Aberrant methylation of the ppENK gene was found in 7.7% of PanIN-1A, 7.3% of PanIN-1B, 22.7% of PanIN-2, and 46.2% of PanIN-3. Aberrant methylation of the p16 gene was found in 12% of PanIN-1A, 2.6% of PanIN-1B, 4.5% of PanIN-2, and 21.4% of PanIN-3. All but one of the PanINs from the 14 pancreata without pancreatic carcinoma was unmethylated with respect to either the p16 or ppENK gene. Our results suggest that methylation-related inactivation of the ppENK and p16 genes is an intermediate or late event during pancreatic carcinogenesis. Because aberrant methylation of ppENK or p16 was more often detected in similar grade PanINs from patients with pancreatic carcinoma than in those with other pancreatic diseases, it may be a useful indicator of the potential malignancy of epithelial cells of the pancreas.


Circulating Sphingolipids and Glucose Homeostasis: An Update.
Sphingolipids are a family of lipid molecules produced through different pathways in mammals. Sphingolipids are structural components of membranes, but in response to obesity, they are implicated in the regulation of various cellular processes, including inflammation, apoptosis, cell proliferation, autophagy, and insulin resistance which favors dysregulation of glucose metabolism. Of all sphingolipids, two species, ceramides and sphingosine-1-phosphate (S1P), are also found abundantly secreted into the bloodstream and associated with lipoproteins or extracellular vesicles. Plasma concentrations of these sphingolipids can be altered upon metabolic disorders and could serve as predictive biomarkers of these diseases. Recent important advances suggest that circulating sphingolipids not only serve as biomarkers but could also serve as mediators in the dysregulation of glucose homeostasis. In this review, advances of molecular mechanisms involved in the regulation of ceramides and S1P association to lipoproteins or extracellular vesicles and how they could alter glucose metabolism are discussed.


Magnetic nanoparticles coated with different shells for biorecognition: high specific binding capacity.
Modifying the surfaces of magnetic nanoparticles (MNPs) by the covalent attachment of biomolecules will enable their application as media for magnetically-assisted bioseparations. In this paper, we reported both the activity and specific binding capacity of ferritin antibodies on core-shell MNPs. The antibodies were covalently attached on silica-, silver- and polydopamine-coated MNPs by different methods. Anti-ferritin was bound onto the silica- or silver-coated MNPs by conventional methods using 3-aminopropyltriethoxysilane (APTES) or 11-mercaptoundecanoic acid (MUA), which was followed by activation of carboxyl groups by EDC/NHS. However with anti-ferritin immobilized onto the Fe3O4 nanoparticles modified with polydopamine, an in situ coating formed through the adhesive proteins. In addition, a great deal of anti-ferritin biomolecules covalently attached onto the MNPs. According to our results, the amounts of bound anti-ferritin onto the silica-, silver- and PDA-coated MNPs were 70, 75 and 95 μg anti-ferritin per mg MNP, respectively. In the experiments, polydopamine (PDA)-coated MNPs showed faster adsorption, more significant selectivity and a larger binding capacity than the others. Also, the equilibrium dissociation constants of the antigen-antibody complexes were determined on the anti-ferritin-immobilized MNPs. Silica-, PDA- and silver-coated MNPs had Kd values of 5.45 × 10(-7), 2.12 × 10(-7) and 3.91 × 10(-8) mol L(-1), respectively. Based on these results, the affinity of the anti-ferritin for ferritin on the PDA-coated MNPs was approximately 10-fold higher than that on the silica- and silver-coated MNPs. In addition, among the anti-ferritin-immobilized silica-, silver- and PDA-coated MNPs, the PDA-coated MNPs showed the highest antigen selectivity values. As a result, anti-ferritin-immobilized PDA-coated MNPs represented a higher activity and stronger affinity for the specific antigen than the others.


Isolation of the Drosophila melanogaster dunce chromosomal region and recombinational mapping of dunce sequences with restriction site polymorphisms as genetic markers.
Using the method of chromosomal walking, we have isolated a contiguous region of the Drosophila melanogaster X chromosome which corresponds to salivary gland chromosome bands 3C12 to 3D4. This five-band region contains approximately 100 kilobases of DNA, including those sequences comprising dunce, a gene which functions in memory and cyclic nucleotide metabolism. Genome blots of DNA from flies carrying several different chromosomal aberrations with breakpoints in the region have been probed with the isolated clones to map the breakpoints on the cloned DNA and to delimit dunce sequences. This has localized dunce to a 50-kilobase region. In addition, we have searched this 50-kilobase region for restriction site polymorphisms between X chromosomes from different Drosophila strains by genome blotting experiments, and we have followed the segregation of detected polymorphisms and dunce alleles after meiotic recombination. The data map one dunce mutation between two polymorphisms located 10 to 12 kilobases apart.


Cost-Effectiveness of Urolithiasis Management in Pregnancy.
Urolithiasis complicating pregnancy presents a challenge for urology and obstetric teams. The management options of ureteral stenting, percutaneous nephrostomy and ureteroscopy vary significantly with regard to efficacy, complications, impact on quality of life and costs. This analytic model compares these factors to determine an optimal strategy per gestational age at presentation. A decision analytic model was built that compared stenting, percutaneous nephrostomy and ureteroscopy. Outcomes included treatment failure, need for re-treatment and complications stratified by severity. Probabilities and utilities were derived from the literature and costs were derived from institutional charge data. The time horizon was 1 year with disutilities limited to gestation length or recovery time for treatment or complication. Multivariate sensitivity analyses and Monte Carlo analysis were performed to evaluate model robustness. In a simulated cohort of 1,000 pregnant women with urolithiasis ureteroscopy would yield 960 quality adjusted life years, compared to 870 with stenting and 880 with percutaneous nephrostomy. Treatment via stenting or percutaneous nephrostomy would fail more than twice as often as ureteroscopy and more than half of patients would require subsequent definitive management. In this cohort ureteroscopy would save $38.8 million compared to stenting and $17.6 million compared to percutaneous nephrostomy. Given its lower costs and improved outcomes, ureteroscopy was the dominant strategy across all gestational ages and remained dominant in all sensitivity analyses and Monte Carlo simulations. Regardless of gestational age, ureteroscopy was a cost-effective strategy to manage urolithiasis compared to stenting or percutaneous nephrostomy. This result was robust against substantial changes in model parameters.


[Interaction of a cAMP-deficient Yersinia pseudotuberculosis mutant with a macrophage culture in vitro].
The behavior of a virulent Y. pseudotuberculosis strain and its c-AMP-deficient mutant possessing lower virulence in their in vitro interaction with the culture of peritoneal macrophages of white mice, as well as a change in the level of c-AMP in macrophages in the process of the phagocytosis of the initial and mutant strains were studied. The c-AMP-deficient mutant was shown to retain its ability to infect macrophages and to multiply in them, while loosing its cytotoxic effect. Macrophages obtained from mice previously immunized with the mutant acquired the capacity of resisting the cytotoxic action of the initial virulent strain. The mutant proved to be unable to elevate the level of c-AMP in macrophages in the process of phagocytosis, while the initial strain caused a considerable increase in the level of c-AMP in macrophages.


Synthesis, Activity and Structure-Activity Relationship of Noroviral Protease Inhibitors.
The protease of norovirus, an important human pathogen, is essential for the viral replication and, therefore, represents a potential drug target. A series of tripeptide-based inhibitors of the protease were designed, synthesized and tested, among which several potent inhibitors were identified with Ki values as low as 75 nM. The structure-activity relationships of these inhibitors are discussed.


Changes in onion root development induced by the inhibition of peptidyl-prolyl hydroxylase and influence of the ascorbate system on cell division and elongation
Post-translational hydroxylation of peptide-bound proline residues, catalyzed by peptidyl-prolyl-4 hydroxylase (EC 18.104.22.168) using ascorbate as co-substrate, is a key event in the maturation of a number of cell wall-associated hydroxyproline-rich glycoproteins (HRGPs), including extensins and arabinogalactan-proteins, which are involved in the processes of wall stiffening, signalling and cell proliferation. Allium cepa L. roots treated with 3, 4-DL-dehydroproline (DP), a specific inhibitor of peptidyl-prolyl hydroxylase, showed a 56% decrease in the hydroxyproline content of HRGP. Administration of DP strongly affected the organization of specialized zones of root development, with a marked reduction of the post-mitotic isodiametric growth zone, early extension of cells leaving the meristematic zone and a huge increase in cell size. Electron-microscopy analysis showed dramatic alterations both to the organization of newly formed cell walls and to the adhesion of the plasma membranes to the cell walls. Moreover, DP administration inhibited cell cycle progression. Root tips grown in the presence of DP also showed an increase both in ascorbate content (+53%) and ascorbate-specific peroxidase activity in the cytosol (+72%), and a decrease in extracellular "secretory" peroxidase activity (-73%). The possible interaction between HRGPs and the ascorbate system in the regulation of both cell division and extension is discussed.


Metal-catalysed reactions enabled by guanidine-type ligands.
Guanidines, which exist widely in nature, have been frequently utilised as strong Brønsted bases in organic chemistry. As ligands, guanidines can have different coordination modes with the metal center. However, the exploitation of these guanidine complexes as catalysts has been much less successful. The anionic counterpart of guanidine, which is known as guanidinate, is also able to function as a ligand. The catalytic activities of metal-guanidinate complexes are of great interest to chemists. The potential of catalytic guanidine or guanidinate metal complexes to catalyse unique chemical transformations is immensely promising. This field is currently being pursued with great interest by synthetic organic chemists. In this review, the representative reactions enabled by guanidine and guanidinate metal complexes are highlighted.


Dispersal, migration, and offspring retention in saturated habitats.
We examine the evolutionary stability of year-round residency in territorial populations, where breeding sites are a limiting resource. The model links individual life histories to the population-wide competition for territories and includes spatial variation in habitat quality as well as a potential parent-offspring conflict over territory ownership. The general form of the model makes it applicable to the evolution of dispersal, migration, partial migration, and delayed dispersal (offspring retention). We show that migration can be evolutionarily stable only if year-round residency in a given area would produce a sink population, where mortality exceeds reproduction. If this applies to a fraction of the breeding habitat only, partial migration is expected to evolve. In the context of delayed dispersal, habitat saturation has been argued to form an ecological constraint on independent breeding, which favors offspring retention and cooperative breeding. We show that habitat saturation must be considered as a dynamic outcome of birth, death, and dispersal rates in the population, rather than an externally determined constraint. Although delayed dispersal often associates with intense competition for territories, life-history traits have direct effects on stable dispersal strategies, which can often override the effect of habitat saturation. As an example, high survival of floaters selects against delayed dispersal, even though it increases the number of competitors for each breeding vacancy (the "habitat saturation factor"). High survival of territory owners, by contrast, generally favors natal philopatry. We also conclude that spatial variation in habitat quality only rarely selects for delayed dispersal. Within a population, however, offspring retention is more likely in high-quality territories.


Chemotherapy of leprosy.
The WHO MDT regimens have proved highly successful in preventing relapse of leprosy cases. It has indirectly lad to marked reduction in prevalence of disabilities. For PB leprosy, rifampicin 600 mg monthly and 100 mg dapsone daily for a total of 6 months therapy is required. For MB leprosy clofazimine 300 mg once monthly, supervised and 50 mg daily self administered is added. For single skin lesion the current WHO recommendation is 600 mg rifampicin + 400 mg ofloxacin + 100 mg minocycline given as a single dose for adults. Dose adjustment for children and clinical information have been discussed in a nutshell. A number of trials are going on, some are yet to be completed which do offer the prospect of perhaps simplifying therapy and improving with shorter duration.


Heparin modulates the cellular uptake of nanomedicines.
Liposomal formulations are used to improve the safety and cellular absorption of conventional drugs by limiting their interaction with phagocytes. The uptake behaviour of these nanocarriers is affected by the blood composition, and accordingly the presence of an anticoagulant in the blood could have a critical impact on the efficiency of nanomedicines. For the negatively charged liposomes, such as AmBisome®, no significant change in the uptake could be observed when co-incubated with heparin and primary phagocytes. Yet, we observed that a peak of the uptake extent of cationic liposomes was reached at a clinically relevant concentration of heparin for phagocytes and cancer cells. Hence, we recommend avoiding treatment of a heparinized patient with cationic nanomedicines because unexpectedly high uptake can occur in phagocytes.


Multiplex PCR targeting tpi (triose phosphate isomerase), tcdA (Toxin A), and tcdB (Toxin B) genes for toxigenic culture of Clostridium difficile.
A multiplex PCR toxigenic culture approach was designed for simultaneous identification and toxigenic type characterization of Clostridium difficile isolates. Three pairs of primers were designed for the amplification of (i) a species-specific internal fragment of the tpi (triose phosphate isomerase) gene, (ii) an internal fragment of the tcdB (toxin B) gene, and (iii) an internal fragment of the tcdA (toxin A) gene allowing distinction between toxin A-positive, toxin B-positive (A+B+) strains and toxin A-negative, toxin B-positive (A-B+) variant strains. The reliability of the multiplex PCR was established by using a panel of 72 C. difficile strains including A+B+, A-B-, and A-B+ toxigenic types and 11 other Clostridium species type strains. The multiplex PCR assay was then included in a toxigenic culture approach for the detection, identification, and toxigenic type characterization of C. difficile in 1,343 consecutive human and animal stool samples. Overall, 111 (15.4%) of 721 human samples were positive for C. difficile; 67 (60.4%) of these samples contained A+B+ toxigenic isolates, and none of them contained A-B+ variant strains. Fifty (8%) of 622 animal samples contained C. difficile strains, which were toxigenic in 27 (54%) cases, including 1 A-B+ variant isolate. Eighty of the 721 human stool samples (37 positive and 43 negative for C. difficile culture) were comparatively tested by Premier Toxins A&B (Meridian Bioscience) and Triage C. difficile Panel (Biosite) immunoassays, the results of which were found concordant with toxigenic culture for 82.5 and 92.5% of the samples, respectively. The multiplex PCR toxigenic culture scheme described here allows combined diagnosis and toxigenic type characterization for human and animal C. difficile intestinal infections.


siRNA nanotherapeutics: a Trojan horse approach against HIV.
The concept of RNA interference (RNAi) is gaining popularity for the better management of various diseases, including HIV. Currently, the successful biomedical utilization of siRNA therapeutics is hampered, both in vivo and in vitro, mainly by the inherent inability of naked siRNA to cross the cell membrane. RNAi can potentially improve the weakness of current highly active antiretroviral therapy (HAART) by diminishing the chances of the appearance of antiHIV-resistant strains. Here, we discuss the nanocarrier-mediated delivery of siRNA delivery as well as highlighted the scope of siRNA-mediated gene-silencing technology for improved HIV treatment.


Antipsychotics in the maintenance phase for psychotic depression.
This study aimed to associate antidepressants with versus without antipsychotics with readmission and suicide in patients with psychotic unipolar depression. Swedish national registers were used to identify inpatients with psychotic unipolar depression, treated 2007-2016. The participants collected antidepressants with or without antipsychotics from a pharmacy within 14 days after discharge and were followed up for 2 years. The primary outcome was hospital readmission due to any psychiatric disorder, suicide attempt, or completed suicide. Cox regression was used to analyze the data, which were adjusted for sex, age, prior admissions, comorbidity, electroconvulsive therapy, and other pharmacological treatments. We identified 4391 patients, of which 2972 were in the antidepressant + antipsychotic combination therapy group, and 1419 were in the antidepressant monotherapy group. After 2 years, 42.3% and 36.6% of patients were readmitted or committed suicide in the combination therapy and monotherapy group, respectively. Monotherapy was significantly associated with a lower risk of reaching the outcome in the main analysis (hazard ratio = 0.86; 95% confidence interval: 0.77-0.95). The results went in the same direction in all sensitivity analyses. Our findings do not indicate any advantage of adding antipsychotics as adjunctive to antidepressants as maintenance treatment. Considering the wide use, known side effects, and the current lack of evidence supporting the benefit, further studies on the effect of antipsychotics in the maintenance phase of psychotic unipolar depression are urgently warranted.


Panic-related outcomes in patients with a personal physician.
Although having a regular source of care is associated with positive health behaviors, its effect in specific disorders is not known. This study assessed differences in outcomes of patients with panic attacks, including symptoms, health care utilization, and treatment for panic symptoms based on the presence and specialty of a self-defined personal physician. In this community-based study, 97 subjects with Diagnostic and Statistical Manual, Third Edition, Revised (DSM-IIIR) panic attacks were interviewed concerning total and recent health care utilization for panic symptoms, total and current treatment for panic symptoms, and panic-related outcomes such as quality of life, psychiatric symptoms, work disability, substance abuse, and perceived control. Although the absence of a personal family physician was not related to outcomes, the specialty of the personal physician was associated with significant differences in recent health care utilization and treatment for panic and in panic-related outcomes. Having a mental health provider was associated with more utilization and treatment but worse outcomes. However, such differences could generally be explained by differences in preexisting psychiatric disorders and the severity of panic symptoms. Compared with having a mental health provider, having a family physician was associated with fewer recent ambulatory visits, particularly to mental health settings, and less-frequent current use of prescription, over-the-counter, or illicit drugs for panic. Yet, when corrected for panic severity and prior mental disorders, there was no difference in these outcomes.


[A falsely reassuring cervical smear in adenocarcinoma of the external os].
3 women with only mild changes in cervical smears were later found to be suffering from cervical adenocarcinoma. The first patient was 53 years old. Her smears repeatedly showed Pap 3 with moderately atypical glandular cells. After 3 colposcopic examinations with biopsies and 2 loop electrosurgical excision procedures of the cervix which showed no histological signs of malignancy, diagnostic conization revealed an adenocarcinoma of the endocervix. She underwent a radical hysterectomy and chemoradiation because of positive pelvic nodes. The second patient was 30 years old and had persistent vaginal discharge and an enlarged cervix, but no cytological abnormalities. Colposcopy was unsatisfactory and the tissue obtained by loop electrosurgical excision was normal. Adenocarcinoma was diagnosed after conization. She was treated with radical hysterectomy and radiotherapy but died after one year. The third patient, aged 26, had a long history of slightly abnormal Pap smears and vulvar condylomata, and was referred with vaginal discharge. A severe abnormal smear with glandular atypia was followed by colposcopical biopsies and conization, which revealed an endocervical adenocarcinoma. She underwent radical hysterectomy. Adenocarcinoma is a rare type of cervical cancer: III cases out of 584 patients with cervical cancer in 2003 in the Netherlands. This neoplasm is more difficult to detect than cervical squamous cell carcinoma. Cervical cytology is not an effective tool for screening and diagnosis. Due to the localization, multifocality and diversity in its presentation, the assessment of cytology has a high false-negative percentage. Screening may be enhanced by combining cytology with testing for high-risk HPV types, notably type 18. If cervical cytology shows persistent atypical glandular cells with no conclusive histological result, then due to the endocervical localisation of the lesions adenocarcinoma can only be excluded by conization.


Near infra-red polymeric nanoparticle based optical imaging in Cancer diagnosis.
Cancer disease is a foremost health concern and top basis of death in comparison with many diseases including cardiovascular disorders. During initial diagnosis (usually late diagnosis), a majority of cancer patients suffer from metastatic and advanced cancer stages which resulted in limited therapeutic modalities based interventions and effectiveness. Though considerable advancement has been made in combating the disease, continuous and intense efforts are ongoing for early diagnosis and development of therapies. Generally applied treatment options for cancer are surgery, chemotherapy and radiotherapy, which are restricted by failure to early diagnose, insufficient on-targeted drug delivery, systemic toxicity, and lack of real-time monitoring of therapeutic responses in cancer. Noninvasive imaging or minimally invasive imaging methodology is valuable in clinical diagnostic settings. Specifically, noninvasive optical imaging integrated with polymeric nanomaterial have been extensively investigated in the field of cancer diagnostics and therapy. Currently, optical imaging methods go together with polymer-based fluorescent nanoparticles in accomplishing the molecular level detection of tumor boundaries. NIR probe tagged polymeric nanoparticles have potential to provide an advantage in the early cancer detection, therapeutic monitoring and image guided surgery procedures. This article review the recent progress in state-of-the-art NIRF polymeric nanoparticles used for optical imaging particularly on cancer diagnosis.


[Two pneumococcal vaccines: the 7-valent conjugate vaccine (Prevenar) for children up to the age of 5 years and the 23-valent polysaccharide vaccine (Pneumo 23) for the elderly and specific groups at risk].
Despite the availability of antibiotics and the care offered by intensive-care units, invasive pneumococcal disease still causes serious illness with high morbidity and mortality. Currently, two vaccines are available in the Netherlands that offer protection against invasive pneumococcal disease: a 7-valent conjugated vaccine and a 23-valent polysaccharide vaccine. Case reports and pharmaceutical use as registered by the Foundation for Pharmaceutical Statistics (SFK) show that general practitioners and pharmacists are not always aware of the appropriate use of both vaccines. For vaccination against pneumococci in children aged 0-5 years, general practitioners should prescribe only the conjugated vaccine. The non-conjugated polysaccharide vaccine is intended especially for the elderly and specific groups at risk. Pharmacists should verify that the pneumococcal vaccines they hand out on prescription are recommended for the age-group of the individuals to whom the vaccine will be administered.


Subversion of Programed Cell Death by Poxviruses.
Poxviruses have been long regarded as potent inhibitors of apoptotic cell death. More recently, they have been shown to inhibit necroptotic cell death through two distinct strategies. These strategies involve either blocking virus sensing by the host pattern recognition receptor, ZBP1 (also called DAI) or by influencing receptor interacting protein kinase (RIPK)3 signal transduction by inhibition of activation of the executioner of necroptosis, mixed lineage kinase-like protein (MLKL). Vaccinia virus E3 specifically blocks ZBP1 → RIPK3 → MLKL necroptosis, leaving virus-infected cells susceptible to the TNF death-receptor signaling (e.g., TNFR1 → FADD → RIPK1 → RIPK3 → MLKL), and, potentially, TLR3 → TRIF → RIPK3 → MLKL necroptosis. While E3 restriction of necroptosis appears to be common to many poxviruses that infect vertebrate hosts, another modulatory strategy not observed in vaccinia or variola virus manifests through subversion of MLKL activation. Recently described viral mimics of MLKL in other chordopoxviruses inhibit all three modes of necroptotic cell death. As with inhibition of apoptosis, the evolution of potentially redundant viral mechanisms to inhibit programmed necroptotic cell death emphasizes the importance of this pathway in the arms race between pathogens and their hosts.


The preconditioning phenomenon: A tool for the scientist or a clinical reality?
The possibility that an innate mechanism of myocardial protection might be inducible in the human heart has generated considerable excitement and enthusiastic research. The potential to enhance myocardial resistance to ischemic injury in patients suffering the consequences of coronary artery disease has led to studies with more direct clinical relevance. However, in common with many other areas of clinical interest based on advances in basic scientific understanding, early enthusiasm may be disproportionate to ultimate therapeutic significance. There can be little doubt that our understanding of the mechanisms underlying the pathogenesis of ischemia-reperfusion injury has been enhanced significantly by the plethora of research stimulated by interest in endogenous myocardial protection. Direct extrapolation of observations in the laboratory to the cardiology clinic or operating theater is tempting but should be avoided. The results of recent clinical experiments that suggest that preconditioning can protect against ischemia, although encouraging, should be interpreted cautiously, with particular attention to the limitations of the end points available. A reasoned evaluation of recent research should prevent unrealistic expectations and allow improved design of future trials so that this potent adaptive phenomenon can be exploited to its maximum potential.


The Leadership and Organizational Context Required to Support Patient Partnerships.
Healthcare providers and managers typically design programs based on what they believe patients need and want. Yet patients have knowledge and insight into how the system can be changed to better meet their needs, improve outcomes and reduce costs. We describe challenges in creating a culture of patient partnerships and the leadership actions and organizational context required now and in the future to support engagement-capable environments at the organizational and policy levels in Canada. Case examples illustrate the need for leaders to set clear expectations, develop the infrastructure to support patient partnerships and provide education to staff, physicians and patient partners.