Accuracy of hemodialysis urea kinetic modeling. Comparison of different models.
To test the accuracy of urea kinetic modeling (UKM), the classic fixed-volume model UKMf, two variable-volume models (UKMvb and UKMvd), direct dialysis quantification (DDQ) and a partial dialysate collection method (PDC) were evaluated in 15 stable, high-hematocrit patients. Urea generation rate (G) was also determined from a 1-week collection of total dialysate and urine (OWC). The results, except distribution volumes, were highly correlated. However, Kt/V, the normalized whole-body urea clearance, was about 8% higher with UKMvb and UKMvd. Two of three simple equations for Kt/V rendered grossly deviating, but highly correlating, results. The normalized protein catabolic rate was 8% higher with UKMvd. With OWC as reference, UKMvb and UKMvd overestimated G by 19 and 15%, respectively. All results of PDC closely followed those of DDQ. This method may be an alternative for exact quantification. Before using a new UKM method it should be compared to an established reference method.


Time of day of taking immunosuppressive agents after renal transplantation: a possible influence on graft survival.
Large-amplitude circadian rhythms in immune responses and the known variations in the effects of glucocorticoids with the time of day of administration suggest that immunosuppressive regimens may need to take this variable into account. In two similar groups of patients with renal transplants functioning satisfactorily after three months subsequent graft failure developed in 66% of those taking all immunosuppressives in the evening, compared with only 22% of those taking immunosuppressives twice daily (p < 0.05). A survey of other transplant units showed that one unit with outstanding results--graft survival at three years 82%--had a unique policy of morning-only administration of immunosuppressives. Doctors need to consider more carefully the time of drug administration when prescribing, as it may be possible to obtain better results with less toxicity.


Identification of distinct metabolic pools of aggrecan and their relationship to type VI collagen in the chondrons of mature bovine articular cartilage explants.
The metabolism and distribution of newly synthesized aggrecan present in the extracellular matrix of intact explant cultures of mature articular cartilage was investigated with respect to type VI collagen-stained chondrons. Using biochemical, autoradiographical and novel confocal immunohistochemical techniques it was shown that aggrecan exists as a number of distinct pools that are located within the extracellular matrix of the tissue. The first was identified as a pool of high specific radioactivity, much of which appeared in the medium one day after incubation with radiolabeled sulfate. Of the radiolabeled aggrecan remaining within the extracellular matrix, three pools were differentiated on the basis of time and location within the extracellular matrix. One pool was resident within the pericellular microenvironment associated with the chondron, one migrated into the territorial matrix adjacent to the chondron and one was sequestered long term in the interterritorial matrix. Analysis of the kinetics of loss of radiolabeled aggrecan macromolecules present in the region of matrix defined by the chondron suggests that this pool rapidly turns over and is a precursor to the pools of aggrecan present in the territorial and interterritorial matrix. There were marked differences in the distribution of newly synthesized aggrecan present in these regions of the extracellular matrix in explant cultures maintained with or without fetal calf serum. In the absence of serum, more of the newly synthesized aggrecan moved into the territorial and interterritorial matrix indicating that the presence of serum in the culture medium influenced the tissue distribution of aggrecan. This work indicates that the pericellular microenvironment of the chondron plays an important role in the retention and maturation of aggrecan prior to the sequestration of aggrecan complexes into the functional load bearing matrices of adult articular cartilage.


Functional MRI in neonates using neonatal head coil and MR compatible incubator.
Structural and functional magnetic resonance imaging of the newborn brain is a complex and challenging task. Term and preterm neonates require a controlled microenvironment and close monitoring during the MRI study to maintain respiratory and cardiovascular functions, body temperature, and fluid and electrolyte homeostasis. In addition, to minimize motion artifacts, most neonates also need to be sedated, which carries the risk of respiratory depression compromising the neonate's ability to maintain appropriate ventilation and oxygenation during the procedure. Finally, because of their small head size, the use of the standard MR head coils results in suboptimal picture quality in the neonate. Thus, these limitations affect our ability to obtain both high quality structural and functional MRI studies. To overcome these difficulties, we have utilized an MR compatible incubator with a built-in radiofrequency head coil optimized for the neonatal brain volume. In this study we demonstrate that functional MRI and high-resolution structural MRI of the newborn brain can be achieved with this novel design. The use of this equipment offers potential for studying the development of the preterm and term neonatal brain and obtaining state-of-the-art, high-resolution structural and functional imaging in this most vulnerable patient population.


Finishing touches for beautiful smiles: orthodontist and general dentist coordinate efforts to achieve optimum esthetics. Part II.
It is not uncommon for teeth to still not be attractive, even though they are straight following treatment. Several examples have been given of what can be done to improve the attractiveness of teeth when this occurs. It is the responsibility of the dental team involved in the management of a persons total dental care to advise patients of what dental services are available to them. People should have the opportunity to evaluate what dental services are needed to accomplish a pleasing result that is satisfying to them and to the dental team involved.


Two functional epitopes of pigment epithelial-derived factor block angiogenesis and induce differentiation in prostate cancer.
Pigment epithelial-derived factor (PEDF), an angiogenesis inhibitor with neurotrophic properties, balances angiogenesis in the eye and blocks tumor progression. Its neurotrophic function and the ability to block vascular leakage is replicated by the PEDF 44-mer peptide (residues 58-101). We analyzed PEDFs' three-dimensional structure and identified a potential receptor-binding surface. Seeking PEDF-based antiangiogenic agents we generated and tested peptides representing the middle and lower regions of this surface. We identified previously unknown antiangiogenic epitopes consisting of the 34-mer (residues 24-57) and a shorter proximal peptide (TGA, residues 16-26) with the critical stretch L19VEEED24 and a fragment within the 44-mer (ERT, residues 78-94), which retained neurotrophic activity. The 34-mer and TGA, but not the 44-mer reproduced PEDF angioinhibitory signals hinged on c-jun-NH2-kinase-dependent nuclear factor of activated T cell deactivation and caused apoptosis. Conversely, the ERT, but not the 34-mer/TGA induced neuronal differentiation. For the 44-mer/ERT, we showed a novel ability to cause neuroendocrine differentiation in prostate cancer cells. PEDF and the peptides bound endothelial and PC-3 prostate cancer cells. Bound peptides were displaced by PEDF, but not by each other, suggesting multiple receptors. PEDF and its active fragments blocked tumor formation when conditionally expressed by PC-3 cells. The 34- and 44-mer used distinct mechanisms: the 34-mer acted on endothelial cells, blocked angiogenesis, and induced apoptosis whereas 44-mer prompted neuroendocrine differentiation in cancer cells. Our results map active regions for the two PEDF functions, signaling via distinct receptors, identify candidate peptides, and provide their mechanism of action for future development of PEDF-based tumor therapies.


Risk assessment of coumarin using the bench mark dose (BMD) approach: children in Norway which regularly eat oatmeal porridge with cinnamon may exceed the TDI for coumarin with several folds.
Coumarin is a naturally occurring flavouring substance in cinnamon and many other plants. It is known that coumarin can cause liver toxicity in several species, and it is considered a non-genotoxic carcinogen in rodents. By using the bench mark dose approach we re-assessed coumarin toxicity and established a new TDI for coumarin of 0.07 mg/kg bw/day. Oral intake of coumarin is related to consumption of cinnamon-containing foods and food supplements. Cinnamon is a widely used spice in Norway, and can be used as topping on oatmeal porridge. Based on analyses of coumarin in Norwegian foods, intake calculations for children and adults were conducted, and a risk assessment of coumarin in the Norwegian population was performed. Intake estimates of coumarin show that small children eating oatmeal porridge several times a week sprinkled with cinnamon could have a coumarin intake of 1.63 mg/kg bw/day and may exceeding the TDI with several folds. Adults drinking cinnamon-based tea and consuming cinnamon supplements also can exceed TDI. The coumarin intake could exceed the TDI by 7- to 20-fold in some intake scenarios. Such large daily exceedances of TDI, even for a limited time period of 1-2 weeks, cause concern of adverse health effects.


Full characterization of the Cu-, Zn-, and Cd-binding properties of CnMT1 and CnMT2, two metallothioneins of the pathogenic fungus Cryptococcus neoformans acting as virulence factors.
We report here the full characterization of the metal binding abilities of CnMT1 and CnMT2, two Cryptococcus neoformans proteins recently identified as metallothioneins (MTs), which have been shown to play a crucial role in the virulence and pathogenicity of this human-infecting fungus. In this work, we first performed a thorough in silico study of the CnMT1 and CnMT2 genes, cDNAs and corresponding encoded products. Subsequently, the Zn(II)-, Cd(II)- and Cu(I) binding abilities of both proteins were fully determined through the analysis of the metal-to-protein stoichiometries and the structural features (determined by ESI-MS, CD, ICP-AES and UV-vis spectroscopies) of the corresponding recombinant Zn-, Cd- and Cu-MT preparations synthesized in metal-enriched media. Finally, the analysis of the Zn/Cd and Zn/Cu replacement processes of the respective Zn-MT complexes when allowed to react with Cd(II) or Cu(I) aqueous solutions was performed. Comprehensive consideration of all gathered results allows us to consider both isoforms as genuine copper-thioneins, and led to the identification of unprecedented Cu5-core clusters in MTs. CnMT1 and CnMT2 polypeptides appear to be evolutionarily related to the small fungal MTs, probably by ancient tandem-duplication events responding to a highly selective pressure to chelate copper, and far from the properties of Zn- and Cd-thioneins. Finally, we propose a modular structure of the Cu-CnMT1 and Cu-CnMT2 complexes on the basis of Cu5 clusters, concordantly with the modular structure of the sequence of CnMT1 and CnMT2, constituted by three and five Cys-rich units, respectively.


Competition within Introns: Splicing Wins over Polyadenylation via a General Mechanism.
Most eukaryotic messenger RNAs are capped, spliced, and polyadenylated via co-transcriptional processes that are coupled to each other and to the transcription machinery. Coordination of these processes ensures correct RNA maturation and provides for the diversity of the transcribed isoforms. Thus, RNA processing is a chain of events in which the completion of one event is coupled to the initiation of the next one. In this context, the relationship between splicing and polyadenylation is an important aspect of gene regulation. We have found that cryptic polyadenylation signals are widely distributed over the intron sequences of Drosophila melanogaster. As shown by analyzing the distribution of genes arranged in a nested pattern, where one gene is fully located within an intron of another gene, overlapping of putative polyadenylation signals is a fairly common event affecting about 17% of all genes. Here we show that polyadenylation signals are silenced within introns: the poly(A) signal is utilized in the exonic but not in the intronic regions of the transcript. The transcription does not end within the introns, either in a transient reporter system or in the genomic context, while deletion of the 5'-splice site restores their functionality. According to a full Drosophila transcriptome analysis, utilization of intronic polyadenylation signals occurs very rarely and such events are likely to be inducible. These results confirm that the transcription apparatus ignores premature polyadenylation signals for as long as they are intronic.


Med12 is essential for early mouse development and for canonical Wnt and Wnt/PCP signaling.
The Mediator complex is commonly seen as a molecular bridge that connects DNA-bound transcription factors to the RNA polymerase II (Pol II) machinery. It is a large complex of 30 subunits that is present in all eukaryotes. The Med12 subunit has been implicated not only in the regulation of Pol II activity, but also in the binding of transcription factors to the bulk of the Mediator complex. We targeted Med12 in mouse embryonic stem cells to investigate the in vivo function of this subunit. We report here the developmental defects of Med12 hypomorphic mutants that have a drastic reduction in Med12 protein levels. These mutants fail to develop beyond embryonic day 10 and have severe defects in neural tube closure, axis elongation, somitogenesis and heart formation. We show that in Med12 hypomorphic embryos, the Wnt/planar cell polarity pathway is disrupted and that canonical Wnt/beta-catenin signaling is impaired. In agreement with this, embryos that are incapable of Med12 expression failed to establish the anterior visceral endoderm or activate brachyury expression, and did not complete gastrulation.


New Insights into Cardiovascular Diseases Treatment Based on Molecular Targets.
Cardiovascular diseases (CVDs) which consist of ischemic heart disease, stroke, heart failure, peripheral arterial disease, and several other cardiac and vascular conditions are one of the most common causes of death worldwide and often co-occur with diabetes mellitus and lipid disorders which worsens the prognosis and becomes a therapeutic challenge. Due to the increasing number of patients with CVDs, we need to search for new risk factors and pathophysiological changes to create new strategies for preventing, diagnosing, and treating not only CVDs but also comorbidities like diabetes mellitus and lipid disorders. As increasing amount of patients suffering from CVDs, there are many therapies which focus on new molecular targets like proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3, ATP-citrate lyase, or new technologies such as siRNA in treatment of dyslipidemia or sodium-glucose co-transporter-2 and glucagon-like peptide-1 in treatment of diabetes mellitus. Both SGLT-2 inhibitors and GLP-1 receptor agonists are used in the treatment of diabetes, however, they proved to have a beneficial effect in CVDs as well. Moreover, a significant amount of evidence has shown that exosomes seem to be associated with myocardial ischaemia and that exosome levels correlate with the severity of myocardial injury. In our work, we would like to focus on the above mechanisms. The knowledge of them allows for the appearance of new strategies of treatment among patients with CVDs.


Asthma and pregnancy: repercussions for neonates.
To describe socioeconomic and behavioral aspects of pregnant women with asthma and to analyze the effects of maternal asthma on certain perinatal parameters in a birth cohort. An observational crosssectional analytical study using data regarding the mothers of a birth cohort at maternity hospitals in the greater metropolitan area of Aracaju, Brazil, between the 8th of March and the 15th of July of 2005. In the pregnant women, asthma was self-reported, based on previous medical diagnosis. Epidemiological, obstetric and perinatal variables were studied. Of the 4,757 mothers included in the study, 299 (6.3%) had asthma. The mothers with asthma had lower family incomes and more frequently made use of the public health care system (for prenatal care and delivery) than did those without asthma. Although only 9.4% of the mothers with asthma smoked and only 27.6% consumed alcoholic beverages, these proportions were higher than were those observed for the control group. Asthma was not found to be associated with obstetric problems or with problems involving the neonates. Nor did we find asthma to be associated with cesarean delivery, prematurity or small-for-gestational-age neonates. Low socioeconomic level seems to be a risk factor for asthma.


Mechanisms of the comedolytic and anti-inflammatory properties of topical retinoids.
Retinoids comprise a family of compounds with structures and mechanisms of action that resemble those of vitamin A (retinol), an essential nutrient which plays a role in cell growth and differentiation. The retinoids, which interact with nuclear receptors and affect gene transcription, have enormous therapeutic potential, particularly if they are receptor- and function-selective. Tretinoin was the first topical retinoid employed for the treatment of acne. In recent years, other topical retinoids for the treatment of acne have been designed from a disease-specific approach, with enhanced receptor and function selectivity, which translates to improved therapeutic effects and more favorable tolerability. The properties that differentiate the topical retinoids tretinoin, adapalene, and tazarotene have permitted clinicians to tailor acne treatment regimens for maximum therapeutic outcomes. Tretinoin (all-trans-retinoic acid), considered a first-generation retinoid, acts by altering the milieu of the microcomedo and influences desquamation of abnormal epithelium. Two receptor-selective synthetic retinoids, adapalene and tazarotene, may be classified as third-generation retinoids. Adapalene, a derivative of naphthoic acid, has comedolytic, antiproliferative, and anti-inflammatory properties. Tazarotene is a prodrug metabolized to tazarotenic acid that modulates cellular differentiation, desquamation, and inflammation.


Potential Lipid-Lowering Mechanisms of Biochanin A.
Extensive studies have demonstrated that biochanin A (BCA) has a significant hypolipidemic effect. However, its mechanism of action is not clear. In this context, the effect of BCA on a high-fat diet (HFD)-induced hyperlipidemia in mice was determined. The results showed that treatment with a medium dose of biochanin A (BM) significantly decreased low-density lipoprotein cholesterol (LDL-C) 85% (from 1.196 ± 0.183 to 0.181 ± 0.0778 mM) and total cholesterol (TC) 39% (from 5.983 ± 0.128 to 3.649 ± 0.374 mM) levels, increased lipoprotein lipase (LPL) 96% (from 1.421 ± 0.0982 to 2.784 ± 0.177 U/mg protein) and hepatic triglyceride lipase (HTGL) 78% (from 1.614 ± 0.0848 to 2.870 ± 0.0977 U/mg protein) activities, significantly improved fecal lipid levels, and lowered the epididymal fat index in hyperlipidemic mice compared with the HFD control mice (p < 0.05). In vitro, the high antioxidant capacity of BCA was determined by the FRAP assay, ABTS•+ scavenging method, and an ROS assay. In RAW 264.7 macrophages, a dose of 10 μM BCA significantly increased the cholesterol efflux by 18.7% compared with the control cells. Moreover, molecular docking of BCA on cholesterol ester transfer protein (CETP) (Asn24 and Thr27 at the N-terminal; Ala274 and Phe270 at the C-terminal) gave new insights into the role of BCA in preventing cholesterol ester transport.


Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
The discovery of the autoimmune regulator (AIRE) protein and the delineation of its critical contributions in the establishment of central immune tolerance has significantly expanded our understanding of the immunological mechanisms that protect from the development of autoimmune disease. The parallel identification and characterization of patient cohorts with the monogenic disorder autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is typically caused by biallelic AIRE mutations, has underscored the critical contribution of AIRE in fungal immune surveillance at mucosal surfaces and in prevention of multiorgan autoimmunity in humans. In this review, we synthesize the current clinical, genetic, molecular and immunological knowledge derived from basic studies in Aire-deficient animals and from APECED patient cohorts. We also outline major advances and research endeavors that show promise for informing improved diagnostic and therapeutic approaches for patients with APECED.


The Distribution of Apolipoprotein E Gene Polymorphism and Apolipoprotein E Levels among Coronary Artery Patients Compared to Controls.
Coronary artery disease (CAD) is a multifactorial disease that is caused by various genetics and environmental factors. Genetically, predisposition is an important component for CAD. The candidate apolipoprotein E (apoE) gene is the most studied one. ApoE is composed of e2, e3, e4 alleles and E2/2, E2/3, E2/4, E3/3, E3/4, E4/4 genotypes. In this study, the relationship between CAD and apoE polymorphism and apoE level has been studied in Tokat region. The study population is composed of 100 CAD patients diagnosed by coronary angiography and 100 control patients of whom fifty have normal coronary angiography and fifty did not have any CAD symptoms. The serum lipid and apoE levels and apoE genotypes of all participants have been measured, and the relationship between these parameters has been evaluated. Apolipoprotein E, total cholesterol, HDL cholesterol and LDL cholesterol levels were statistically low at CAD patients than control patients (p=0.0004, p=0.0005, p=0.0107, p=0.0052 respectively). There was not any significant difference between triglyceride levels (p=0.0848). Waist circumferences were significantly high at CAD patients (p=0.0012). Allele frequencies were as e2 (7.25%), e3 (83.5%), e4 (9.25%) and genotype distributions were as E2/2 (0.5%), E2/3 (13%), E2/4 (0.5%), E3/3 (68.5%), E3/4 (16.5%), E4/4 (1%). The distribution of alleles and genotypes were not significantly different (p>0.05). ApoE levels were higher at e2 allele carriers than e3 and e4 allele carriers (p<0.05). However, there was no significant difference between e3 and e4 allele carriers. In conclusion, the distribution of apoE genotype and allele at our region is similar to the general of Turkey. The low apoE levels in CAD patients may show the influence of apoE on CAD by local and systemic mechanisms.


The prevalence of underweight, overweight, obesity and associated risk factors among school-going adolescents in seven African countries.
The burden caused by the coexistence of obesity and underweight in Low and Middle Income Countries is a challenge to public health. While prevalence of underweight among youth has been well documented in these countries, overweight, obesity and their associated risk factors are not well understood unlike in high income countries. Cross-sectional data from the Global School-based Student Health Survey (GSHS) conducted in seven African countries were used for this study. The survey used a clustered design to obtain a representative sample (n = 23496) from randomly selected schools. 53.6% of the sample was male, and participants ranged in age from 11-17 years old. Body Mass Index (BMI) was calculated using age and sex adjusted self-reported heights and weights. Classification of weight status was based on the 2007 World Health Organization growth charts (BMI-for-age and sex). Multivariable Logistic Regression reporting Odds Ratios was used to assess potential risk factors on BMI, adjusting for age, sex, and country. Statistical analyses were performed with Stata with an alpha of 0.05 and reporting 95% confidence intervals. Unadjusted rates of being underweight varied from 12.6% (Egypt) to 31.9% (Djibouti), while being overweight ranged from 8.7% (Ghana) to 31.4% (Egypt). Obesity rates ranged from 0.6% (Benin) to 9.3% (Egypt). Females had a higher overweight prevalence for every age group in five of the countries, exceptions being Egypt and Malawi. Overall, being overweight was more prevalent among younger (≤12) adolescents and decreased with age. Males had a higher prevalence of being underweight than females for every country. There was a tendency for the prevalence of being underweight to increase starting in the early teens and decrease between ages 15 and 16. Most of the potential risk factors captured by the GSHS were not significantly associated with weight status. The prevalence of both overweight and underweight was relatively high, demonstrating the existence of the double burden of malnutrition among adolescents in developing countries. Several factors were not associated with weight status suggesting the need to explore other potential risk factors for overweight and underweight, including genetic factors and socioeconomic status.


A bibliometric analysis of PCSK9 inhibitors from 2007 to 2022.
Since the approval of the proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies for marketing in 2015, PCSK9 inhibitors have attracted significant interest in the field of cardiovascular endocrinology. A large number of clinical trials have confirmed the efficacy and safety of PCSK9 inhibitors in reducing cholesterol and the risk of cardiovascular events. No bibliometric analysis of PCSK9 inhibitors has been performed as of yet. This study aims to analyze the research trends and hotspots of PCSK9 inhibitors through bibliometric analysis. We searched the Web of Science Core Collection (WoSCC) database for PCSK9 inhibitor-related publications from 2007 to 2022. Data visualization analysis was performed using CiteSpace software. Microsoft Excel and Graphpad software were used for the drawing of some tables and figures. A total of 1072 pieces of literature were retrieved between 2007 and 2022. The number of publications concerning PCSK9 inhibitors is growing annually. The top five countries with the most articles published were the United States, England, Canada, Italy, and France. Harvard University, Amgen, Brigham & Women's Hospital, Harvard Medical School, and Imperial College London are the five institutions with the highest output. The Journal of Clinical Lipidology is the most popular journal in this field. The most frequently cited journal is the New England Journal of Medicine. As for authors, Sabatine MS and Giugliano RP from Brigham & Women's Hospital have the highest number of published articles. Amgen is the funding agency for most of the research. According to keyword analysis, "low density lipoprotein", "familial hypercholesterolemia", "PCSK9 inhibitor", "PCSK9", and "efficacy" are the five keywords with the highest frequency of co-occurrence. The past 15 years have witnessed a rapid and fruitful development of PCSK9 inhibitors. The research trend and focus for PCSK9 inhibitors are from the mechanism of reducing low-density lipoprotein cholesterol to related clinical trials. Developed countries such as the United States have contributed prominently in this area. Coronary artery and inflammation are currently at the forefront of research in the field and are in an explosion period.


Incidental findings on computed tomography scans for acute appendicitis: prevalence, costs, and outcome.
CT scan is increasingly being used to diagnose appendicitis due to its specificity and literature suggesting its cost-effectiveness. CT scans are associated with incidental findings. We sought to investigate the rates of incidental findings identified on CT scans, the follow-up of these findings, and the added cost associated with this follow-up. A retrospective review of patients who underwent appendectomies for acute appendicitis between 2003 and 2005 was completed at Elmhurst Hospital Center (Elmhurst, NY). Incidental findings were grouped into low and high significance, based on workup or follow-up needed. The diagnostic workup and cost of each incidental finding was ascertained. For patients who did not receive a workup due to lack of follow-up, an estimate of the minimum workup was calculated. Of 1142 patients with acute appendicitis, 876 (77%) had a CT scan. This rate increased over time (from 66% in 2003 to 85% in 2005, P < 0.01) and with age (70% in patients under 20 and 98% in patients over 50, P < 0.001). Incidental findings were common and increased with age (23% in the youngest group vs 78% in patients older than 50, P < 0.001). The cost associated with workup of these incidental findings increased with age as well. The increased use of CT scans is associated with a high rate of incidental findings. These findings are usually of low clinical significance but may require further workup and follow-up. Physicians need to be aware of the high rate of incidental findings, the need for further workup, and the associated costs.


Cutting edge: protein phosphatase 2A confers susceptibility to autoimmune disease through an IL-17-dependent mechanism.
The contribution of individual molecular aberrations to the pathogenesis of systemic lupus erythematosus (SLE), an autoimmune disease that affects multiple organs, is often difficult to evaluate because of the presence of abundant confounding factors. To assess the effect of increased expression of the phosphatase protein phosphatase 2A (PP2A) in T cells, as recorded in SLE patients, we generated a transgenic mouse that overexpresses the PP2Ac subunit in T cells. The transgenic mouse displays a heightened susceptibility to immune-mediated glomerulonephritis in the absence of other immune defects. CD4(+) T cells produce increased amounts of IL-17 while the number of neutrophils in the peripheral blood is increased. IL-17 neutralization abrogated the development of glomerulonephritis. We conclude that increased PP2Ac expression participates in SLE pathogenesis by promoting inflammation through unchecked IL-17 production and facilitating the development of end-organ damage.


A stochastic model for subcellular dosimetry in boron neutron capture therapy.
The therapeutic effectiveness of boron neutron capture therapy is highly dependent on the microscopic distribution of the administered boron compound. Two boron compounds with different uptake mechanisms in the tumour cells may thus cause effects of different degrees even if the macroscopic boron concentrations in the tumour tissue are the same. This difference is normally expressed quantitatively by the so-called relative local efficiency (RLE). In this work, a stochastic model for the subcellular dosimetry has been developed. This model can be used to calculate the probability for an energy deposition above a certain threshold level in the cell nucleus due to a single neutron capture reaction. If a threshold cell-kill function is assumed, and if the dose is low enough that multiple energy depositions are rare, the model can also be applied to calculations of the survival probability for a cell population. Subcellular boron distributions in rats carrying RG 2 rat gliomas were measured by subcellular fractionation after administration of two different boron compounds: a sulphydryl boron hydride (BSH) and a boronated porphyrin (BOPP). Based on these data, the RLE factors were then calculated for these compounds using the stochastic model.


Future habitat suitability for coral reef ecosystems under global warming and ocean acidification.
Rising atmospheric CO2 concentrations are placing spatially divergent stresses on the world's tropical coral reefs through increasing ocean surface temperatures and ocean acidification. We show how these two stressors combine to alter the global habitat suitability for shallow coral reef ecosystems, using statistical Bioclimatic Envelope Models rather than basing projections on any a priori assumptions of physiological tolerances or fixed thresholds. We apply two different modeling approaches (Maximum Entropy and Boosted Regression Trees) with two levels of complexity (one a simplified and reduced environmental variable version of the other). Our models project a marked temperature-driven decline in habitat suitability for many of the most significant and bio-diverse tropical coral regions, particularly in the central Indo-Pacific. This is accompanied by a temperature-driven poleward range expansion of favorable conditions accelerating up to 40-70 km per decade by 2070. We find that ocean acidification is less influential for determining future habitat suitability than warming, and its deleterious effects are centered evenly in both hemispheres between 5° and 20° latitude. Contrary to expectations, the combined impact of ocean surface temperature rise and acidification leads to little, if any, degradation in future habitat suitability across much of the Atlantic and areas currently considered 'marginal' for tropical corals, such as the eastern Equatorial Pacific. These results are consistent with fossil evidence of range expansions during past warm periods. In addition, the simplified models are particularly sensitive to short-term temperature variations and their projections correlate well with reported locations of bleaching events. Our approach offers new insights into the relative impact of two global environmental pressures associated with rising atmospheric CO2 on potential future habitats, but greater understanding of past and current controls on coral reef ecosystems is essential to their conservation and management under a changing climate.


Closing the pneumococcal conjugate vaccine (PCV) introduction gap: an archetype analysis of last-mile countries.
Pneumonia remains the leading infectious cause of global childhood deaths, despite the availability of pneumococcal conjugate vaccine (PCV) products and widespread evidence of their safety and efficacy. To map the landscape of countries that are yet to fully include PCV in their National Immunization Programs, we conducted an archetype analysis of country indicators related to barriers and facilitators for PCV decision-making. We created a country matrix focused on three key domains - health characteristics, immunisation factors, and policy framework, and identified ten related indicators. We scored countries based on indicator performance and subsequently ranked and grouped them into three archetypes of low-, moderate-, and high-barrier countries with regard to PCV introduction. Our results indicated 39 countries (33 low- and middle-income countries [LMICs] and 6 high-income countries) that are yet to introduce PCV. Among LMICs, 15 countries were classified as 'low-barrier,' indicating factors favourable for PCV introduction such as high immunisation coverage of common childhood vaccines, supportive governments, and substantial disease burden and eligibility for Gavi support. Countries classified in the 'moderate-barrier' (12) and 'high-barrier' (6) archetypes demonstrated adequate capacity in immunisation systems but had competing national priorities and cost barriers that impeded policy decision-making on PCV introduction. The current health and policy indicator-based categorisation provides an actionable framework to design tailored PCV advocacy within these last-mile countries. Policy approaches emerging from this framework can lead to strengthened decision-making on vaccine introduction and sustained vaccine access that can enhance child survival worldwide.


Use of dantrolene plus multiple pulses to detect stress-susceptible porcine muscle.
Twitch characteristics of tibialis anterior muscles in situ were examined in stress-susceptible and normal swine. Three groups of pigs were studied: (1) purebred Pietrain stress-susceptible, (2) purebred Yorkshire normal, and (3) a crossbred (Pietrain-Yorkshire) litter containing both stress-susceptible and normal animals. Purebred and crossbred stress-susceptible pigs provided qualitatively similar results, as did purebred and crossbred normal pigs. Single stimuli produced greater than normal peak tensions and faster rates of tension development in stress-susceptible animals. Multiple stimuli (2-6 pulses at 5-ms intervals) increased peak tensions and rates of tension development, but did not augment differences between normal and stress-susceptible pigs. Intravenous administration of dantrolene reduced peak tensions and rates of tension development in all groups for single and multiple stimuli. However, the reduction was significantly less (P less than 0.01) for stress-susceptible pigs. Multiple stimuli (4-6 pulses) plus dantrolene amplified differences (P less than 0.01) in contractile properties between normal and stress-susceptible skeletal muscles, with stress-susceptible muscles obtaining larger peak tensions and faster rates of tension development. Normal and stress-susceptible pigs may, therefore, be distinguished by these procedures.


iRHOM2 takes control of rheumatoid arthritis.
The cytokine TNF-α is a major drug target for rheumatoid arthritis, an inflammatory joint disorder. An alternative approach is to target the protease TNF-α convertase (TACE), which releases TNF-α from cells. However, because TACE cleaves other proteins involved in development and cancer, a tissue-specific inhibition of TACE in immune cells appears mandatory. In this issue of the JCI, Issuree et al. report that iRHOM2 is a TACE activator in immune cells. Loss of iRHOM2 largely protects mice from inflammatory arthritis, making iRHOM2 a potential drug target for this condition.


Modulation of Countermovement Jump-Derived Markers of Neuromuscular Function With Concurrent vs. Single-Mode Resistance Training.
Pattison, KJ, Drinkwater, EJ, Bishop, DJ, Stepto, NK, and Fyfe, JJ. Modulation of countermovement jump-derived markers of neuromuscular function with concurrent vs. single-mode resistance training. J Strength Cond Res 34(6): 1497-1502, 2020-This study assessed changes in countermovement jump (CMJ)-derived markers of neuromuscular function with concurrent training vs. resistance training (RT) alone and determined associations between changes in CMJ parameters and other neuromuscular adaptations (e.g., maximal strength gain). Twenty-three recreationally active men performed 8 weeks of RT alone (RT group, n = 8) or combined with either high-intensity interval training cycling (HIIT + RT group, n = 8) or moderate-intensity continuous cycling (MICT + RT group, n = 7). Maximal strength and CMJ performance were assessed before (PRE), after 4 weeks of training (MID), and >72 hours (maximal strength) or >5-7 days (CMJ performance) after (POST) the training intervention. Improvements in CMJ relative peak force from both PRE to MID and PRE to POST were attenuated for both HIIT + RT (effect size [ES]: -0.44; ±90% confidence limit, ±0.51 and ES: -0.72; ±0.61, respectively) and MICT + RT (ES: -0.74; ±0.49 and ES: -1.25; ±0.63, respectively). Compared with RT alone, the change in the flight time to contraction time ratio (FT:CT) was attenuated from PRE to MID for MICT + RT (ES: -0.38; ±0.42) and from PRE to POST for both MICT + RT (ES: -0.60; ±0.55) and HIIT + RT (ES: -0.75; ±0.30). PRE to POST changes in both CMJ relative peak force and flight time:contraction time (F:C) ratio were also associated with relative 1 repetition maximum leg press strength gain (r = 0.26 and 0.19, respectively). These findings highlight the utility of CMJ testing for monitoring interference to improvements in neuromuscular function with concurrent training.


Isolation and characterization of the Xenopus laevis orthologs of the human papillary renal cell carcinoma-associated genes PRCC and MAD2L2 (MAD2B).
Recently we found that the human papillary renal cell carcinoma-associated protein PRCC interacts with the cell cycle control protein Mad2B, and translocates this protein to the nucleus where it exerts its mitotic checkpoint function. Here we have successfully isolated Xenopus laevis Mad2B and PRCC cDNAs. The full-length xMad2B cDNA encodes a 211 amino acid protein that is highly homologous to human Mad2B, thus pointing to an important function for this protein in higher eukaryotes. The full-length xPRCC cDNA encodes a 544 amino acid protein. Remarkably, this protein contains an amino-terminal region distinct from that in mouse and human, whereas the C-terminal region is highly conserved. Northern blot and RT-PCR analyses revealed a relatively low expression of both xMad2B and xPRCC in most tissues examined. However, an abundant expression was observed in testis and oocyte, indicating a role in meiotic division processes. Coimmunoprecipitation and immunofluorescence analyses revealed that, despite its distinct amino terminus, the xPRCC-protein is still capable of interacting with xMad2B and of shuttling this protein to the nucleus. Therefore, the well-established animal model Xenopus laevis can be used as a powerful system to study in detail the role of xPRCC and xMad2B in the intricate processes of cell cycle control.


Post 17th-century changes of European PAH emissions recorded in high-altitude Alpine snow and ice.
The occurrence of organic pollutants in European Alpine snow/ice has been reconstructed over the past three centuries using a new online extraction method for polycyclic aromatic hydrocarbons (PAH) followed by liquid chromatographic determination. The meltwater flow from a continuous ice core melting system was split into two aliquots, with one aliquot directed to an inductively coupled plasma quadrupole mass spectrometer for continuous trace elements determinations and the second introduced into a solid phase C18 (SPE) cartridge for semicontinuous PAH extraction. The depth resolution for PAH extractions ranged from 40 to 70 cm, and corresponds to 0.7-5 years per sample. The concentrations of 11 PAH were determined in dated snow/ice samples to reconstruct the atmospheric concentration of these compounds in Europe for the last 300 years. The PAH pattern is dominated by phenanthrene (Phe), fluoranthene (Fla), and pyrene (Pyr), which represent 60-80% of the total PAH mass. Before 1875 the sum of PAH concentration (SigmaPAH) was very low with total mean concentrations less than 2 ng/kg and 0.08 ng/kg for the heavier compounds (SigmaPAH*, more than four aromatic rings). During the first phase of the industrial revolution (1770-1830) the PAH deposition showed a weak increase which became much greater from the start of the second phase of the industrial revolution at the end of 19th Century. In the 1920s, economic recession in Europe decreased PAH emissions until the 1930s when they increased again and reached a maximum concentration of 32 ng/kg from 1945 to 1955. From 1955 to 1975 the PAH concentrations decreased significantly, reflecting improvements in emission controls especially from major point sources, while from 1975 to 2003 they rose to levels equivalent to those in 1910. The Fla/(Fla+Pyr) ratio is often used for source assignment and here indicates an increase in the relative contribution of gasoline and diesel combustion with respect to coal and wood burning from 1860 to the 1980s. This trend was reversed during the last two decades.


Association of CD247 with systemic lupus erythematosus in Asian populations.
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established. In this study, using a collection of 612 SLE patients and 2193 controls of Chinese ethnicity living in Hong Kong in a genome-wide study, single nucleotide polymorphisms (SNPs) in and around CD247 were identified as being associated with SLE. The two most significant SNPs in this locus were selected for further replication using TaqMan genotyping assay in 3339 Asian patients from Hong Kong, Mainland China, and Thailand, as well as 4737 ethnically and geographically matched controls. The association of CD247 with SLE in Asian populations was confirmed (rs704853: odds ratio [OR] = 0. 81, p = 2.47 × 10(-7); rs858543: OR = 1.10, p = 0.0048). Patient-only analysis suggested that rs704853 is also linked to oral ulcers, hematologic disorders and anti-double-stranded DNA (dsDNA) antibody production. A significant association between variants in CD247 and SLE was demonstrated in Asian populations. Understanding the involvement of CD247 in SLE may shed new light on disease mechanisms and development of new treatment paradigms.


The Austronesian Basic Vocabulary Database: from bioinformatics to lexomics.
Phylogenetic methods have revolutionised evolutionary biology and have recently been applied to studies of linguistic and cultural evolution. However, the basic comparative data on the languages of the world required for these analyses is often widely dispersed in hard to obtain sources. Here we outline how our Austronesian Basic Vocabulary Database (ABVD) helps remedy this situation by collating wordlists from over 500 languages into one web-accessible database. We describe the technology underlying the ABVD and discuss the benefits that an evolutionary bioinformatic approach can provide. These include facilitating computational comparative linguistic research, answering questions about human prehistory, enabling syntheses with genetic data, and safe-guarding fragile linguistic information.


Thrombolytic therapy for acute coronary obstruction: status in 1986.
The effect of thrombolysis in acute myocardial infarction on enzymatic infarct size, left ventricular function, and early mortality was studied in subsets of patients in a randomized trial at The Netherlands Interuniversity Cardiological Institute during a 5-year period. Early thrombolytic therapy with intracoronary streptokinase (152 patients) or with intracoronary streptokinase preceded by intravenous streptokinase (117 patients) was compared to conventional treatment (264 patients). All 533 patients were admitted to the coronary care unit within 4 hours after onset of symptoms indicative of acute myocardial infarction. There were 488 patients eligible for this detailed analysis, of whom 245 were allocated for thrombolytic therapy. Early angiography was performed in 212 of the 245 patients. Patency of the infarct-related artery was achieved in 181 patients (85%). Enzymatic infarct size measured from cumulative alpha HBDH release was smaller in patients allocated to thrombolytic therapy (median 760 U/l vs. 1179 U/l in controls, p = 0.0001). LVEF measured by radionuclide angiography before discharge was higher after thrombolytic therapy (median 50% vs. 43% in controls, p = 0.0001). The 12-month mortality was lower in patients allocated to thrombolytic therapy (8% vs. 16% in the control group, p < 0.01). In multivariate regression analysis, infarct size limitation, improvement of LVEF, and a 3-month mortality were predicted by ST, time from onset of symptoms to admission, and Killip class at admission. Thrombolysis was most useful in patients admitted within 2 hours after onset of symptoms and in patients with ST of 1.2 mV or more. On the other hand, no beneficial effects of streptokinase on enzymatic infarct size, left ventricular function, or mortality were observed in the subset of patients with ST less than 1.2 mV admitted 2 to 4 hours after onset of symptoms. In the long term, improved survival and enhanced quality of life are most evident after thrombolytic therapy in patients with larger anterior wall infarction, and less pronounced in patients with smaller inferior wall infarction.


Conformational changes in the Ca2+-regulatory region from soybean calcium-dependent protein kinase-alpha: fluorescence resonance energy transfer studies.
Calcium-dependent protein kinases are key proteins involved in plant and protozoal Ca2+ signaling. These unique molecules include a calcium regulatory calmodulin-like domain (CLD), which binds to another small regulatory domain named the junction domain (JD). Both CLD and JD are part of the same polypeptide as the protein kinase domain. The CLD consists of N- and C-terminal lobes, each having two helix-loop-helix Ca2+-binding motifs. In this study, fluorescence resonance energy transfer using a series of Trp and Cys site-directed mutants was undertaken to probe the relative motions of the two lobes of CLD between the apo- and Ca2+-saturated forms, as well as bound to a peptide encoding the JD sequence. Using an IAEDANS-modified Cys, a total of 15 Trp --> Cys distances were measured in these three states from the five donor-acceptor combinations F334W-Cys436, L371W-Cys436, L403W-Cys436, F334W-L403C, and L371W-L403C. Consistent with recently reported NMR diffusion measurements and with 1H,15N heteronuclear correlation NMR spectra, the distances derived from fluorescence resonance energy transfer measurements in apoCLD indicate partial unfolding and a subsequent contraction on binding Ca2+, which is maintained on addition of the JD peptide. Interpretation of the distances suggests that the Ca2+-saturated form is open with the two lobes sitting side-by-side although highly flexible. The transition to the JD-CLD state appears to be accompanied by a rotation of the N- and C-terminal domains with respect to each other inducing a slightly more closed overall complex. The observed differences between the behavior of CLD and the well studied related protein calmodulin are likely because of different physiological requirements for activation in vivo.


Necroptosis is active in children with inflammatory bowel disease and contributes to heighten intestinal inflammation.
A new caspase-independent mode of programmed cell death, termed necroptosis, has recently been identified. Altered expression of molecules involved in the necroptosis pathway has been shown to trigger intestinal inflammation. The initiation of necroptosis is principally mediated by the release of receptor interacting protein 3 (RIP3) from suppression by caspase-8. Furthermore, it has been suggested that the mixed lineage kinase domain-like (MLKL) factor is an interacting target of RIP3 in active necroptosis. This study aims at investigating the occurrence of necroptosis in children with inflammatory bowel disease (IBD) and its contribution to human intestinal inflammation. Biopsy samples were collected from the ileum and colon of 33 children with Crohn's disease, 30 with ulcerative colitis, and 20 healthy controls. Ten children with allergic colitis (AC) were used as non-IBD comparators. RIP3, caspase-8, and MLKL protein expression levels were evaluated by western blotting. The adenocarcinoma cell line HT29 was used for in vitro experiments. RIP3 and MLKL increased (P<0.01) in inflamed tissues of IBD and AC patients, whereas caspase-8 was reduced. No variations were observed in uninflamed tissues of patients. The relationship between RIP3 increase, active necroptosis, and intestinal inflammation was confirmed by in vitro analyses. We show for the first time that necroptosis is strongly associated with intestinal inflammation in children with IBD and contributes to strengthen the inflammatory process. We believe that RIP3 and MLKL could represent attractive targets for the management of human IBD.


Incidence of Surgical Site Infections in Second Intention Healing After Dermatologic Surgery.
There are few studies analyzing the surgical site infection (SSI) rate of second intention wounds after dermatologic surgery, and the results are inconclusive. Yet, the current dogma in dermatologic surgery is that wounds healed by second intention have lower infection rates. To determine the rate of SSI and associated pathogenic organisms of second intention wounds compared with sutured wounds after skin cancer extirpation. This was a retrospective cohort study of patients who had either Mohs micrographic surgery or wide local excision (WLE) for skin cancer extirpation between 2012 and 2016. Wounds were stratified by closure type, location, and associated organisms. Infection was diagnosed by a positive wound culture. The overall infection rate was 3.9%. The infection rate for sutured and second intention wounds was 3.2% and 6.8%, respectively. Second intention wounds were associated with a significantly higher risk of infection compared with sutured wounds (odds ratio = 2.22, 95% confidence interval 1.63-2.99). The lower extremity (LE) had the highest overall infection rate (10.5%). The face had the lowest overall infection rate (2.5%). Mohs micrographic surgery or WLE performed on the LE or lesions allowed to heal by second intention has an increased risk of SSI.


Chronic "brain death": meta-analysis and conceptual consequences.
One rationale for equating "brain death" (BD) with death is that it reduces the body to a mere collection of organs, as evidenced by purported imminence of asystole despite maximal therapy. To test this hypothesis, cases of prolonged survival were collected and examined for factors influencing survival capacity. Formal diagnosis of BD with survival of 1 week or longer. More than 12,200 sources yielded approximately 175 cases meeting selection criteria; 56 had sufficient information for meta-analysis. Diagnosis was judged reliable if standard criteria were described or physicians made formal declarations. Data were analyzed by means of Kaplan-Meier curves, with treatment withdrawals as "censored" data, compared by log-rank test. Survival probability over time decreased exponentially in two phases, with initial half-life of 2 to 3 months, followed at 1 year by slow decline to more than 14 years. Survival capacity correlated inversely with age. Independently, primary brain pathology was associated with longer survival than were multisystem etiologies. Initial hemodynamic instability tended to resolve gradually; some patients were successfully discharged on ventilators to nursing facilities or even to their homes. The tendency to asystole in BD can be transient and is attributable more to systemic factors than to absence of brain function per se. If BD is to be equated with death, it must be on some basis more plausible than loss of somatic integrative unity.


Stability and kinetics of G-quadruplex structures.
In this review, we give an overview of recent literature on the structure and stability of unimolecular G-rich quadruplex structures that are relevant to drug design and for in vivo function. The unifying theme in this review is energetics. The thermodynamic stability of quadruplexes has not been studied in the same detail as DNA and RNA duplexes, and there are important differences in the balance of forces between these classes of folded oligonucleotides. We provide an overview of the principles of stability and where available the experimental data that report on these principles. Significant gaps in the literature have been identified, that should be filled by a systematic study of well-defined quadruplexes not only to provide the basic understanding of stability both for design purposes, but also as it relates to in vivo occurrence of quadruplexes. Techniques that are commonly applied to the determination of the structure, stability and folding are discussed in terms of information content and limitations. Quadruplex structures fold and unfold comparatively slowly, and DNA unwinding events associated with transcription and replication may be operating far from equilibrium. The kinetics of formation and resolution of quadruplexes, and methodologies are discussed in the context of stability and their possible biological occurrence.


Education in medical billing benefits both neurology trainees and academic departments.
The objective of residency training is to produce physicians who can function independently within their chosen subspecialty and practice environment. Skills in the business of medicine, such as clinical billing, are widely applicable in academic and private practices but are not commonly addressed during formal medical education. Residency and fellowship training include limited exposure to medical billing, but our academic department's performance of these skills was inadequate: in 56% of trainee-generated outpatient notes, documentation was insufficient to sustain the chosen billing level. We developed a curriculum to improve the accuracy of documentation and coding and introduced practice changes to address our largest sources of error. In parallel, we developed tools that increased the speed and efficiency of documentation. Over 15 months, we progressively eliminated note devaluation, increased the mean level billed by trainees to nearly match that of attending physicians, and increased outpatient revenue by $34,313/trainee/year. Our experience suggests that inclusion of billing education topics into the formal medical curriculum benefits both academic medical centers and trainees.


The induction of interferon-alpha and interferon-beta mRNA in human natural interferon-producing blood leukocytes requires de novo protein synthesis.
The induction of interferon-alpha (IFN-alpha) and IFN-beta mRNA in natural IFN producing (NIP) cells in cultures of human peripheral blood mononuclear cells (PBMCs), stimulated by glutaraldehyde-fixed Herpes simplex virus type 1 (HSV)-infected WISH cells, was studied. The protein synthesis inhibitor cycloheximide (CHX) totally prevented the appearance of both IFN-alpha and IFN-beta mRNA, also in cultures supplemented with a conditioned medium (CM) assumed to contain soluble factors necessary for the IFN induction. However, when PBMCs were preincubated for 4 h in medium supplemented with fetal bovine serum (FBS) with or without addition of CM, the subsequent induction of IFN-alpha/beta mRNA became partially resistant to CHX. In serum-free medium containing interleukin-3 (IL-3) or granulocyte-macrophage colony-stimulating factor (GM-CSF), the early induction of IFN-alpha mRNA became resistant to CHX, and, in contrast to FBS and CM supplemented medium, this was observed also without a preincubation of the PBMCs. In contrast, IL-1, IL-2, IL-4, IL-6, tumor necrosis factor-alpha (TNF-alpha), IFN-alpha, or IFN-gamma had no such effects. Our results suggests that de novo synthesis of proteins normally is required for the induction of IFN-alpha/beta mRNA. Such proteins might be cytokines, possibly CSFs, which in turn also may require protein synthesis for their actions. In contrast, the actual triggering signal provided by the HSV-inducer is independent of protein synthesis.


Brain activity related to integrative processes in visual object recognition: bottom-up integration and the modulatory influence of stored knowledge.
We report evidence from a PET activation study that the inferior occipital gyri (likely to include area V2) and the posterior parts of the fusiform and inferior temporal gyri are involved in the integration of visual elements into perceptual wholes (single objects). Of these areas, the fusiform and inferior temporal gyri were more activated by tasks with recognizable stimuli than by tasks with unrecognizable stimuli. We propose that the posterior parts of the fusiform and inferior temporal gyri, compared with the inferior occipital gyri, are involved in higher level integration, due to the involvement of re-entrant activation from stored structural knowledge. Evidence in favor of this interpretation comes from the additional finding that activation of the anterior part of the left fusiform gyrus and a more anterior part of the right inferior temporal gyrus, areas previously associated with access to stored structural knowledge, was found with recognizable stimuli, but not with unrecognizable stimuli. This latter finding also indicates: (i) that subjects may not refrain from (automatically) identifying objects even if they only have to attend to the objects' global shape, and (ii) that perceptual and memorial processes can be dissociated on both functional and anatomical grounds. No evidence was obtained for the involvement of the parietal lobes in the integration of single objects.


Isolated colonic hemangioma in a child.
Hemangiomas of the large bowel are very rare and usually occur in the rectosigmoid. A large cavernous hemangioma of the colon was demonstrated in a 9-month-old child who presented with recurrent lower gastrointestinal tract bleeding. Barium examination demonstrated an annular lesion of the hepatic flexure. Computed tomography demonstrated the extent of the lesion, and contrast enhancement suggested the vascular nature of the tumour before a laparotomy was performed to remove the tumour.


Male Gender and High Trait Anxiety Are 2 Major Factors Associated With Severe Dental Fear and Avoidance.
The purpose of this article is to investigate the association between the background characteristics of patients with severe fear of dental treatment who frequently avoid dental care and the degree of difficulty in treating them. At the time of initial presentation at a dental phobia clinic, each of 321 subjects was asked to complete the State-Trait Anxiety Inventory, the Dental Anxiety Scale, and a health questionnaire related to phobic objects. Subjects who rejected oral examination with a dental mirror were categorized as being severely difficult to treat, whereas those who were able to undergo examination were categorized as being moderately difficult to treat. In the statistical analysis, assessment items that were correlated with difficulty to treat were designated as independent variables for a logistic regression analysis. In the logistic regression analysis, significant correlations were observed for gender (male > female with adjusted odds ratio, 4.121; 95% CI, 1.96-8.65) and level of trait anxiety (2.401; 1.01-5.73). Male gender and a high trait anxiety were identified as major factors associated with severe dental fear and avoidance.


Evaluating the Dissemination and Implementation Impact of a Rehabilitation Intervention: The Graded Repetitive Arm Supplementary Program (GRASP).
To evaluate the dissemination and implementation impacts of a rehabilitation intervention. Systematic evaluation of data sources including academic publishing metrics, publications, and surveys was used to describe the dissemination and implementation impact of the graded repetitive arm supplementary program (GRASP). Three categories in the Payback Framework were evaluated: knowledge production and dissemination, benefits to future research and research use, and real-world uptake and implementation. In the Knowledge production and dissemination category, seven publications, authored by the GRASP research team, were associated with the GRASP, and there were approximately 17,000 download counts of GRASP manuals from the website from 120 countries. In the Benefits to future research and research use category, 15 studies and 8 registered clinical trials, authored by researchers outside of the GRASP team, have used GRASP as an intervention. In the real-world uptake and implementation category, GRASP has informed recommendations in 2 clinical guidelines and 20 review papers, and had high implementation uptake (e.g., 35% [53/154] of UK therapists surveyed had used GRASP; 95% [649/681] who downloaded GRASP had used it). More than 75% of those who had used GRASP identified that GRASP provides more intensity in upper extremity rehabilitation, is evidence-based and easy to implement, and the equipment and manual are easy to obtain. The Payback Framework is useful to evaluate the dissemination and implementation impacts of a rehabilitation intervention. GRASP has been implemented extensively in clinical practice and community in a relatively short time since it has been developed.


Phytoplankton composition, growth and production in the Guadiana estuary (SW Iberia): unraveling changes induced after dam construction.
Water quality and quantity problems in the Guadiana estuary due to a recently built dam have been predicted, including an enhancement of cyanobacteria blooms. The main goal of this work was thus to describe the present phytoplankton dynamics in relation to its environmental drivers and to evaluate the effects of damming on phytoplankton in the Guadiana estuary. Sampling campaigns were conducted during 2007-2009 in 4 locations of the Guadiana estuary, covering the salinity gradient. Phytoplankton-related and physical-chemical variables were analyzed. Throughout our study, light availability was mainly controlled by suspended sediments and it was much lower than saturating intensities described for phytoplankton growth. Therefore, light was probably limiting to phytoplankton growth throughout the year, especially in the middle and upper estuarine zones. Nitrogen limitation of phytoplankton growth occurred occasionally throughout the study period, especially during spring and summer. Overall, light and nutrient availability were mainly controlled by river flow; anthropogenic sources of nutrients to the estuary were negligible. Phytoplankton showed a unimodal cycle with biomass maximum in late spring/early summer, and the typical seasonal succession of freshwater phytoplankton (diatoms, green algae, cyanobacteria) was observed. Diatoms were the main component of the phytoplankton community and their variability closely followed nitrate and river flow variability. The relative abundance of the main phytoplankton groups changed in relation to the period before dam construction, with a decrease on cyanobacteria contribution to total abundance. The environmental perturbation induced by dam construction has now stabilized and resulted in an overall decrease in nutrient concentrations, an increase in light availability and a decrease in cyanobacteria abundance.


Complex immune cell interplay in the gamma interferon response during Toxoplasma gondii infection.
Toxoplasma gondii is an obligate intracellular parasite of clinical importance, especially in immunocompromised patients. Investigations into the immune response to the parasite found that T cells are the primary effector cells regulating gamma interferon (IFN-γ)-mediated host resistance. However, recent studies have revealed a critical role for the innate immune system in mediating host defense independently of the T cell responses to the parasite. This body of knowledge is put into perspective by the unifying theme that immunity to the protozoan parasite requires a strong IFN-γ host response. In the following review, we discuss the role of IFN-γ-producing cells and the signals that regulate IFN-γ production during T. gondii infection.


Kinetic analysis of short-term effects of alpha-agonists on gluconeogenesis in isolated rat hepatocytes.
Isolated hepatocytes from fasted rats were perifused with glycerol as gluconeogenic substrate. Stimulation of gluconeogenesis with phenylephrine (10(-5) M) as alpha-adrenergic agonist consisted of two distinct phases. The first phase was a transient stimulation of gluconeogenesis and was accompanied by transient changes in cytosolic and mitochondrial redox state; this phase was abolished by the transaminase inhibitor aminooxyacetate. The second phase was a stable stimulation of less magnitude, without change in redox state and insensitive to addition of aminooxyacetate. It is concluded that the first phase is due to a transient enhancement of flux through the malate/aspartate shuttle and that the stable phase is probably due to a stimulation of mitochondrial glycerol-3-phosphate dehydrogenase and glycerol kinase.


The prognostic value of chest X-ray in patients with COVID-19 on admission and when starting CPAP.
The objective was to explore if chest X-ray severity, assessed using a validated scoring system, predicts patient outcome on admission and when starting continuous positive pressure ventilation (CPAP) for COVID-19. The study was a retrospective case-controlled study. There were 163 patients with COVID-19 deemed candidates for CPAP on admission, including 58 who subsequently required CPAP. On admission, we measured the proportion of patients meeting a composite 'negative' outcome of requiring CPAP, intubation or dying versus successful ward-based care. For those escalated to CPAP, 'negative' outcomes were intubation or death versus successful de-escalation of respiratory support. Our results were stratified into tertiles, those with 'moderate' or 'severe' X-rays on admission had significantly higher odds of negative outcome versus 'mild' (odds ratio (OR) 2.32; 95% confidence interval (CI) 1.121-4.803; p=0.023; and OR 3.600; 95% CI 1.681-7.708; p=0.001, respectively). This could not be demonstrated in those commencing CPAP (OR 0.976; 95% CI 0.754-1.264; p=0.856). We outline a scoring system to stratify X-rays by severity and directly link this to prognosis. However, we were unable to demonstrate this association in the patients commencing CPAP.


Regulation of beta-amyloid secretion by FE65, an amyloid protein precursor-binding protein.
The principal component of Alzheimer's amyloid plaques, Abeta, derives from proteolytic processing of the Alzheimer's amyloid protein precursor (APP). FE65 is a brain-enriched protein that binds to APP. Although several laboratories have characterized the APP-FE65 interaction in vitro, the possible relevance of this interaction to Alzheimer's disease has remained unclear. We demonstrate here that APP and FE65 co-localize in the endoplasmic reticulum/Golgi and possibly in endosomes. Moreover, FE65 increases translocation of APP to the cell surface, as well as both alphaAPPs and Abeta secretion. The dramatic (4-fold) FE65-dependent increase in Abeta secretion suggests that agents which inhibit the interaction of FE65 with APP might reduce Abeta secretion in the brain and therefore be useful for preventing or slowing amyloid plaque formation.


Multilevel ordinal factor analysis of the positive and negative syndrome scale (PANSS).
Clinical assessments of the presence and severity of psychopathology are often collected by health care professionals in mental health services or clinical researchers trained to use semi-structured interviews. Clustering by interviewer or rater needs to be considered when performing psychometric analyses such as factor analysis or item response modelling as non-independence of observations arises in these situations. We apply more suitable multilevel methods to analyse ordinally scored Positive and Negative Syndrome Scale (PANSS) items. Our aim is to highlight the differences in results that occur when the data are analysed using a hierarchically sensitive approach rather than using a traditional (aggregated) analysis. Our sample (n = 507) consisted of patients diagnosed with schizophrenia who participated in a multi-centre randomized control clinical trial, the DIALOG study. Analyses reported and compared include an exploratory factor analysis as well as several recently published multifactor models re-estimated within a confirmatory analysis framework. Our results show that the fit of the model and the parsimony of the exploratory factor analysis (EFA) models indicated by the number of factors necessary to explain the inter-correlation among PANSS items improved significantly when data clustering is taken into account through multilevel analysis. Our modeling results support the pentagonal PANSS model first proposed by White et al. (1997). Copyright © 2014 John Wiley & Sons, Ltd.


Parental Weight Status and Offspring Behavioral Problems and Psychiatric Symptoms.
To assess relations of prepregnancy maternal and paternal obesity with offspring behavioral problems and psychiatric symptoms at 7-8 years in the Upstate KIDS study, a prospective cohort study. Maternal body mass index (BMI) was calculated from prepregnancy height and weight provided in vital records or self-report at 4 months postpartum. Mothers reported paternal height and weight. At 7-8 years, mothers indicated if their children had been diagnosed with ADHD or anxiety (n = 1915). Additionally, children's behavior was measured with the Strengths and Difficulties Questionnaire at 7 years of age (n = 1386) and the Vanderbilt ADHD Diagnostic Parent Rating Scale at 8 years of age (n = 1484). Based on Strengths and Difficulties Questionnaire scores, we identified children with borderline behavioral problems. Adjusted risk ratios (aRR) and 95% CIs were estimated with robust multivariable Poisson regression. Compared with children of mothers with a BMI of <25, children whose mothers had BMI 25-30, 30-35, and ≥35 kg/m2 had higher risks of reported ADHD (aRR, 1.14, 95% CI, 0.78-1.69; aRR, 1.96, 95% CI, 1.29-2.98; and aRR, 1.82, 95% CI,1.21-2.74, respectively). Risks of hyperactivity problems identified by the Strengths and Difficulties Questionnaire and a positive screen for inattentive or hyperactive/impulsive behavior with the Vanderbilt ADHD Diagnostic Parent Rating Scale were also higher with increasing maternal prepregnancy BMI. Paternal BMI was not associated with child outcomes. Our findings suggest that maternal, rather than paternal, obesity is associated with maternal report of child ADHD diagnosis and inattentive or hyperactivity problems. Further research is needed to understand how maternal obesity might influence these behavioral changes during or after pregnancy.


Solution Structures of Bacillus anthracis Protective Antigen Proteins Using Small Angle Neutron Scattering and Protective Antigen 63 Ion Channel Formation Kinetics.
We are studying the structures of bacterial toxins that form ion channels and enable macromolecule transport across membranes. For example, the crystal structure of the Staphylococcus aureus α-hemolysin (α-HL) channel in its functional state was confirmed using neutron reflectometry (NR) with the protein reconstituted in membranes tethered to a solid support. This method, which provides sub-nanometer structural information, could also test putative structures of the Bacillus anthracis protective antigen 63 (PA63) channel, locate where B. anthracis lethal factor and edema factor toxins (LF and EF, respectively) bind to it, and determine how certain small molecules can inhibit the interaction of LF and EF with the channel. We report here the solution structures of channel-forming PA63 and its precursor PA83 (which does not form channels) obtained with small angle neutron scattering. At near neutral pH, PA83 is a monomer and PA63 a heptamer. The latter is compared to two cryo-electron microscopy structures. We also show that although the α-HL and PA63 channels have similar structural features, unlike α-HL, PA63 channel formation in lipid bilayer membranes ceases within minutes of protein addition, which currently precludes the use of NR for elucidating the interactions between PA63, LF, EF, and potential therapeutic agents.


Anti-hypertensive effect of manidipine: 24 hours monitoring evaluation and Doppler-echocardiographic remarks.
In order to evaluate the antihypertensive effects of manidipine, at the dosage of 10 or 20 mg once daily, we studied 36 patients (12 males and 24 females, mean age 54.3 years) with mild hypertension. After a wash-out period of 2 weeks and another 2 week run-in period with placebo, all the patients were assigned to a treatment with manidipine 10 mg/ day. After 2 weeks of treatment, the non-normalized (diastolic BP > 90 mmHg) and the non-responders (BP fall < 10 mmHg) received an increase in dosage to 20 mg/day. The drug effects were assessed by casual blood pressure (BP) measurement at baseline and after 4, 8, 12, 24, 36 and 52 weeks. At baseline and after 1 year of treatment a 24-h BP monitoring and a Doppler echocardiogram were performed. Routine laboratory tests were performed at baseline, after 6 months and after 1 year of treatment. At the end of the observation period, both casual systolic (p < 0.01) and diastolic (p < 0.001) BP were significantly reduced; 24-h BP monitoring showed a significant decrease in systolic (p < 0.05) and diastolic (p < 0.01) pressure, systolic and diastolic (p < 0.001) daytime and night-time measurements. The peak to through ratio was 67%. No difference was found in heart rate. Reduced interventricular septum thickness (p < 0.05), increased fractional shortening (p < 0.02), reduced end-systolic stress (p < 0.005) and systemic vascular resistances (p < 0.001), and lower values of atrial filling fraction (AFF) (p < 0.001) after 1 year of treatment have been shown at the Doppler-Echo evaluation. A multilinear regression analysis showed a relation between delta %AFF and delta %24-h systolic BP (R = 0.74; F = 7.5: p < 0.05) and with delta % daytime systolic BP (R = 0.77; F = 9.2; p < 0.02). No abnormal changes were observed in laboratory tests. Three non-responder patients and three patients with adverse effects (1 flushing and 2 ankle oedema) dropped out and were excluded from the final analysis. In conclusion, manidipine at an individualized dose of 10 or 20 mg. was effective and safe in the management of arterial hypertension. Hemodynamic evaluations after 1 year of treatment confirmed an improvement of systolic and diastolic function, with an evident reduction of afterload.


The interrelationship of neuroticism, sex, and stressful life events in the prediction of episodes of major depression.
Three potent risk factors for major depression are female sex, the personality trait of neuroticism, and adversity resulting from exposure to stressful life events. Little is known about how they interrelate in the etiology of depressive illness. In over 7,500 individual twins from a population-based sample, the authors used a Cox proportional hazard model to predict onsets of episodes of DSM-III-R major depression in the year before the latest interviews on the basis of previously assessed neuroticism, sex, and adversity during the past year; adversity was operationalized as the long-term contextual threat scored from 15 life event categories. In the best-fit Cox model for prediction of depressive onsets, neuroticism, female sex, and greater adversity all strongly increased risk for major depression. An interaction was seen between neuroticism and adversity such that individuals with high neuroticism were at greater overall risk for major depression and were more sensitive to the depressogenic effects of adversity. An interaction was also seen between adversity and sex, as the excess risk for major depression in women was confined to individuals with low stress exposure. Psychosocial adversity interacts both with neuroticism and with sex in the etiology of major depression. The impact of neuroticism on illness risk is greater at high than at low levels of adversity, while the effect of sex on probability of onset is the opposite--greater at low than at high levels of stress. Complete etiologic models for major depression should incorporate interactions between risk factor classes.


CD4+ T Cell-Specific Proteomic Pathways Identified in Progression of Hypertension Across Postmenopausal Transition.
Background Menopause is associated with an increase in the prevalence and severity of hypertension in women. Although premenopausal females are protected against T cell-dependent immune activation and development of angiotensin II (Ang II) hypertension, this protection is lost in postmenopausal females. Therefore, the current study hypothesized that specific CD4+ T cell pathways are regulated by sex hormones and Ang II to mediate progression from premenopausal protection to postmenopausal hypertension. Methods and Results Menopause was induced in C57BL/6 mice via repeated 4-vinylcyclohexene diepoxide injections, while premenopausal females received sesame oil vehicle. A subset of premenopausal mice and all menopausal mice were infused with Ang II for 14 days (Control, Ang II, Meno/Ang II). Proteomic and phosphoproteomic profiles of CD4+ T cells isolated from spleens were examined. Ang II markedly increased CD4+ T cell protein abundance and phosphorylation associated with DNA and histone methylation in both premenopausal and postmenopausal females. Compared with premenopausal T cells, Ang II infusion in menopausal mice increased T cell phosphorylation of MP2K2, an upstream regulator of ERK, and was associated with upregulated phosphorylation at ERK targeted sites. Additionally, Ang II infusion in menopausal mice decreased T cell phosphorylation of TLN1, a key regulator of IL-2Rα and FOXP3 expression. Conclusions These findings identify novel, distinct T cell pathways that influence T cell-mediated inflammation during postmenopausal hypertension.


[Clinical and pathological characteristics of estrogen receptor-positive breast cancer].
Estrogen receptor (ER) was measured in 275 samples from 170 patients with breast cancer by dextran-coated charcoal assay. The results showed that the ER positive rate was 51.2%. The ER status of female patients was not related to age or menopause. The positive rate was lowest in AB blood type. The distribution of positive patients in all types was similar to that reported by Japanese authors. The DNA levels of ER positive cancers were relatively lower than those of negative ones. Pathological examination of cancer tissue indicated that ER positive cancer is well differentiated. The 3 year disease-free rate and 4 year survival rate are both high in ER positive patients than that in the negative patients. Knowledge of ER status is helpful in planning the treatment of breast cancer.


Serum follistatin in patients with prostate cancer metastatic to the bone.
The clinical significance of circulating follistatin (FLST), an inhibitor of the multifunctional cytokine activin A (Act A), was investigated in patients with prostate cancer (PCa). The serum concentrations of this molecule were determined by an enzyme-linked immunosorbent assay (ELISA) in PCa patients with (M+) or without (M0) bone metastases, in patients with benign prostate hyperplasia (BPH) and in healthy subjects (HS). The effectiveness of FLST in detecting PCa patients with skeletal metastases was determined by the receiver operating characteristic (ROC) curve analysis. Serum FLST was significantly higher in PCa patients than in BPH patients (P = 0.001) or HS (P = 0.011). Conversely, in BPH patients, FLST levels resulted lower than in HS (P = 0.025). In cancer patients the serum concentrations of FLST significantly correlated with the presence of bone metastases (P = 0.0005) or increased PSA levels (P = 0.04). Interestingly, significant differences in the ratio between FLST and Act A serum concentrations (FLST/Act A) were observed between HS and BPH patients (P = 0.001) or PCa patients (P = 0.0005). Finally, ROC curve analysis, highlighted a sound diagnostic performance of FLST in detecting M+ patients (P = 0.0001). However, the diagnostic effectiveness of FLST did not result significantly superior to that of Act A or PSA. These findings suggest that FLST may be regarded as a potential, molecular target in the treatment of metastatic bone disease while its clinical role as soluble marker in the clinical management of PCa patients with bone metastases needs to be better defined.


Controlled subtotal evacuation of intracerebral haematomas by stereotactic technique.
A new instrument for stereotactic evacuation of intracerebral haematomas is presented, as well as preliminary clinical experiences. A combined screw-and-suction technique makes possible the evacuation of even densely coagulated clots. The principle for a limited removal of a hemorrhagic mass in the brain is discussed.


(PVA/Chitosan/Fucoidan)-Ampicillin: A Bioartificial Polymeric Material with Combined Properties in Cell Regeneration and Potential Antibacterial Features.
Chitosan, fucoidan, and polyvinyl alcohol are categorized as polymers with biomedical applications. Ampicillin, on the other hand, is considered as an important antibiotic that has shown effectivity in both gram-positive and gram-negative micro-organisms. The aforementioned polymers possess unique properties that are considered desirable for cell regeneration although they exhibit drawbacks that can affect their final application. Therefore, films of these biomaterials were prepared and they were characterized using FTIR, SEM, XRD, degree of swelling and solubility, and MTT assay. The statistical significance of the experiments was determined using a two-way analysis of variance (ANOVA) with p < 0.05. The characterization techniques demonstrated that the obtained material exhibits properties suitable for cell regeneration, and that a higher concentration of natural polymers promotes cells proliferation to a greater extent. The presence of PVA, on the other hand, is responsible for matrix stability and dictates the degree of swelling and solubility. The SEM images demonstrated that neither aggregations nor clusters were formed, which is favorable for the biological properties without detrimental to the morphological and physical features. Cell viability was comparatively similar in samples with and without antibiotic, and the physical and biological properties were not negatively affected. Indeed, the inherent bactericidal effect of chitosan was reinforced by the presence of ampicillin. The new material is an outstanding candidate for cell regeneration as a consequence of the synergic effect that each component provides to the blend.


[A case of lung adenocarcinoma presenting with chorea with bilateral basal ganglial lesions on MRI].
The patient, a 63-year-old man, experienced the subacute onset of chorea, for which his family doctor prescribed oral haloperidol. However, the involuntary movements gradually worsened, and the patient was referred and admitted. High-signal lesions were seen in the caudate nucleus, putamen and globus pallidus bilaterally on MRI T2-weighted and FLAIR images. Chest CT, FDG-PET and tissue biopsies also revealed that the patient had lung adenocarcinoma with multiple lymph node metastases. The patient was diagnosed as having paraneoplastic chorea associated with primary lung adenocarcinoma. Antineuronal antibodies, such as anti-CRMP-5 and anti-Yo antibodies, were absent. The patient received steroid pulse therapy, oral prednisolone therapy, and concurrent radiochemotherapy. Chorea and high-signal lesions in the corpus striatum bilaterally on MRI improved quickly, and the mediastinal lymph node swelling also improved. The patient has been stable for 3 years since the onset of his symptoms. As the prognosis of paraneoplastic chorea is relatively favorable in some patients, it should be considered in the differential diagnosis of patients with chorea.


Chronic heart failure in patients undergoing major head and neck surgery: A hospital-based study.
To investigate the effects of chronic heart failure on various post-operative outcomes in head and neck cancer patients undergoing major cancer surgery. For this retrospective cohort study of patients undergoing major head and neck cancer surgery, a sample of 10,002 patients between 2017 and 2019 were identified through the Nationwide Inpatient Sample. Patients were selected as undergoing major head and neck cancer surgery, defined as laryngectomy, pharyngectomy, glossectomy, neck dissection, mandibulectomy, and maxillectomy, then separated based on pre-surgical diagnosis of chronic heart failure. The effects of pre-operative chronic heart failure on post-surgical outcomes in these patients were investigated by univariable and multivariable logistic regression using ICD-10 codes and SPSS. A diagnosis of chronic heart failure was observed in 265 patients (2.6 %). Patients with chronic heart failure had more preexisting comorbidities when compared to patients without chronic heart failure (mean ± SD; 4 ± 1 vs. 2 ± 1). Multivariable logistic regression showed that chronic heart failure patients had significantly greater odds of dying during hospitalization (OR 2.86, 95 % CI 1.38-5.91) and experiencing non-routine discharge from admission (OR 1.89, 95 % CI 1.41-2.54) after undergoing major head and neck cancer surgery. Chronic heart failure is associated with greater length of stay and hospital charges among head and neck cancer patients undergoing major head and neck cancer surgeries. Chronic heart failure patients have significantly greater rates of unfavorable post-operative outcomes, including death during hospitalization and non-routine discharge from admission.


Wheatgrass Juice Administration and Immune Measures during Adjuvant Chemotherapy in Colon Cancer Patients: Preliminary Results.
Adjuvant chemotherapy is recommended in high-risk stage II-III colorectal cancer (CC). We examine the effect of daily wheatgrass juice (WGJ) intake in addition to chemotherapy on immune parameters, including IL-6, IL-8, IL-10, IL-12, and white blood cells (WBCs) among CC patients. In a controlled prospective trial, 100 stage II-III CC patients were enrolled. According to patient preference, they were divided into two subgroups, control group and intervention group, 50 patients each, all of whom received the same standard postoperative adjuvant chemotherapy, plus consumption of 60 cc WGJ daily in the intervention group. Blood samples were collected at baseline (T0) and upon treatment termination, 5-6 months later (T1). Cytokine concentrations were assessed using ELISA kits. Anti-inflammatory cytokine IL-10 concentrations were significantly higher in the WGJ group than in the control group at T1. The decline in WBC counts between T0 and T1 was significantly lower in the WGJ group. No significant differences were observed in IL-6, IL-8, and IL-12 concentrations between the study groups. The higher levels of IL-10 and the attenuating of WBC decline during chemotherapy may constitute preliminary evidence of the beneficial effects of WGJ on immune parameters, when given as a supplement to standard care. In light of these preliminary results, WGJ supports immunological parameters during adjuvant chemotherapy. Nevertheless, future studies are needed in order to translate those results to clinical recommendations for cancer survivors.


Acquired chiari malformation type I associated with a fatty terminal filum. Case report.
The authors report the case of a 3-year-old girl with a Chiari malformation Type I (CM-I) and concomitant fatty terminal filum. This child was examined prior to the onset of CM-I as well as after, and the authors present magnetic resonance (MR) images documenting that the malformation was acquired as the child grew in height. This case contributes to the literature describing an acquired CM-I associated with a fatty filum and is the first published account to include MR imaging obtained before and after the onset of the malformation.


Effects of naratriptan versus naproxen on daily functioning in the acute treatment of migraine: a randomized, double-blind, double-dummy, crossover study.
To evaluate the effect of acute treatment on ictal behavioral functioning of patients with migraine via ambulatory accelerometry. The inability to carry out daily activities often complicates migraine attacks. Research into the effects of pharmacological drugs on this outcome parameter in the acute treatment of migraine has been based on subjective reports only. In a double-blind, double-dummy, crossover study, 12 patients with migraine treated 2 migraine attacks with the nonspecific antimigraine drug, naproxen (500-mg capsule) or the more specific antimigraine drug, naratriptan (2.5-mg tablet). The clinical symptoms of headache, nausea, vomiting, photophobia, and phonophobia, and the subjective symptoms reflecting mood, sleepiness, and level of functioning were measured by use of a daily log. During the first 6 hours after intake of the study medication, the objective behavioral parameters showed no significant effect of time and no significant differences between naproxen and naratriptan, but naratriptan was significantly more efficacious than naproxen in relieving headache, nausea, and vomiting; the interval between treatment and relief was significantly shorter after intake of naratriptan. Consciously perceived clinical and subjective symptoms do not necessarily run in parallel with their behavioral equivalents. It, thus, may be important to assess the effects of treatment on behavioral functioning in the evaluation of the general efficacy of antimigraine drugs in the acute treatment of a migraine attack.


Generational differences among newly licensed registered nurses.
Responses of 2369 newly licensed registered nurses from 3 generational cohorts-Baby Boomers, Generation X, and Generation Y-were studied to identify differences in their characteristics, work-related experiences, and attitudes. These responses revealed significant differences among generations in: job satisfaction, organizational commitment, work motivation, work-to-family conflict, family-to-work conflict, distributive justice, promotional opportunities, supervisory support, mentor support, procedural justice, and perceptions of local job opportunities. Health organizations and their leaders need to anticipate intergenerational differences among newly licensed nurses and should provide for supportive working environments that recognize those differences. Orientation and residency programs for newly licensed nurses should be tailored to the varying needs of different generations. Future research should focus on evaluating the effectiveness of orientation and residency programs with regard to different generations so that these programs can be tailored to meet the varying needs of newly licensed nurses at the start of their careers.


Light-dependent magnetoreception in birds: increasing intensity of monochromatic light changes the nature of the response.
The Radical Pair model proposes that magnetoreception is a light-dependent process. Under low monochromatic light from the short-wavelength part of the visual spectrum, migratory birds show orientation in their migratory direction. Under monochromatic light of higher intensity, however, they showed unusual preferences for other directions or axial preferences. To determine whether or not these responses are still controlled by the respective light regimes, European robins, Erithacus rubecula, were tested under UV, Blue, Turquoise and Green light at increasing intensities, with orientation in migratory direction serving as a criterion whether or not magnetoreception works in the normal way. The birds were well oriented in their seasonally appropriate migratory direction under 424 nm Blue, 502 nm Turquoise and 565 nm Green light of low intensity with a quantal flux of 8 x 10(15) quanta s(-1) m(-2), indicating unimpaired magnetoreception. Under 373 nm UV of the same quantal flux, they were not oriented in migratory direction, showing a preference for the east-west axis instead, but they were well oriented in migratory direction under UV of lower intensity. Intensities of above 36 x 10(15) quanta s(-1) m(-2) of Blue, Turquoise and Green light elicited a variety of responses: disorientation, headings along the east-west axis, headings along the north-south axis or 'fixed' direction tendencies. These responses changed as the intensity was increased from 36 x 10(15) quanta s(-1) m(-2) to 54 and 72 x 10(15) quanta s(-1) m(-2). The specific manifestation of responses in directions other than the migratory direction clearly depends on the ambient light regime. This implies that even when the mechanisms normally providing magnetic compass information seem disrupted, processes that are activated by light still control the behavior. It suggests complex interactions between different types of receptors, magnetic and visual. The nature of the receptors involved and details of their connections are not yet known; however, a role of the color cones in the processes mediating magnetic input is suggested.


Comparison Of Pre-Operative Curvature With Postoperative Curvature In Root Canals Treated With K-3 Rotary Systems.
With root canal treatment, the organic debris and micro-organisms from pulp space is removed and an ideal canal preparation is achieved that is conducive of hermetic obturation. The purpose of this study was to correlate the pre-operative canal curvature with the postoperative curvature in human extracted teeth prepared with K-3 rotary systems. The root canal preparation was carried out on extracted human molars and premolars using K-3 endodontic rotary files. A pre and post-operative image of the teeth using digital radiograph were taken in order to compare pre and post-operative canal curvature. The images were saved in an images retrieval system (Gendex software, USA). Change in the canal curvature was measured using the software measuring tool (Vixwin software, USA). Student paired t-test and Pearson correlation test was applied at 0.05 level of significance. There is a statistically significant difference between pre-operative and post-operative canal curvature (p-value <0.001) and a strong positive correlation (91% correlation) between pre-operative and post-operative canal curvature in teeth prepared with the K-3 rotary files. A significant difference between pre and post instrumentation curvature was found. Degree of canal curvature was not correlated with time taken for canal preparation.