Toxicity of gutkha, a smokeless tobacco product gone global: is there more to the toxicity than nicotine?
The popularity of smokeless tobacco (ST) is growing rapidly and its prevalence of use is rising globally. Consumption of Gutkha, an addictive form of ST, is particularly common amongst South Asian communities throughout the World. This includes within the US, following large-scale immigration into the country. However, there exists a lack of knowledge concerning these alternative tobacco products. To this end, a study was carried out to determine the toxicity of gutkha, and what role, if any, nicotine contributes to the effects. Adult male mice were treated daily for 3-week (5 day/week, once/day), via the oral mucosa, with equal volumes (50 μL) of either sterile water (control), a solution of nicotine dissolved in water (0.24 mg of nicotine), or a solution of lyophilized guthka dissolved in water (21 mg lyophilized gutkha). Serum cotinine, measured weekly, was 36 and 48 ng/mL in gutkha- and nicotine-treated mice, respectively. Results demonstrated that exposure to nicotine and gutkha reduced heart weight, while exposure to gutkha, but not nicotine, decreased liver weight, body weight, and serum testosterone levels (compared to controls). These findings suggest that short-term guhtka use adversely impacts growth and circulating testosterone levels, and that gutkha toxicity may be driven by components other than nicotine. As use of guthka increases worldwide, future studies are needed to further delineate toxicological implications such that appropriate policy decisions can be made.


Evaluation of histopathology, PCR, and qPCR to detect Mikrocytos mackini in oysters Crassostrea gigas using Bayesian latent class analysis.
Latent class analysis (LCA) is a common method to evaluate the diagnostic sensitivity (DSe) and specificity (DSp) for pathogen detection assays in the absence of a perfect reference standard. Here we used LCA to evaluate the diagnostic accuracy of 3 tests for the detection of Mikrocytos mackini in Pacific oysters Crassostrea gigas: conventional polymerase chain reaction (PCR), real-time quantitative PCR (qPCR), and histopathology. A total of 802 Pacific oysters collected over 12 sampling events from 9 locations were assessed. Preliminary investigations indicated that standard LCA assumptions of test independence and constant detection accuracy across locations were likely unrealistic. This was mitigated by restructuring the LCA in a Bayesian framework to include test-derived knowledge about pathogen prevalence and load for categorizing populations into 2 classes of infection severity (low or high) and assessing separate DSe and DSp estimates for each class. Median DSp estimates were high (>96%) for all 3 tests in both population classes. DSe estimates varied between tests and population classes but were consistently highest for qPCR (87-99%) and lowest for histopathology (21-51%). Acknowledging that detection of M. mackini may be fitted to multiple diagnostic and management purposes, qPCR had the highest DSe while maintaining similar DSp to both conventional PCR and histopathology and thus is generally well-suited to most applications.


The Incidence and Effect of Cytomegalovirus Disease on Mortality in Transplant Recipients and General Population: Real-world Nationwide Cohort Data.
Background: In addition to the conventional opportunistic infections in solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT) recipients, cytomegalovirus (CMV) infection is associated with various chronic inflammatory diseases or poor outcomes in non-immunocompromised critically ill patients. To evaluate the burden or outcome of CMV replication in non-transplant individuals, we compared the incidence rates (IRs) for CMV disease and all-cause mortality between SOT recipients, HSCT recipients, and non-transplant population. Methods: The SOT (N=16,368) and HSCT (N=10,206) cohorts between 2010 and 2015 were established using the WHO ICD-10 from the whole population-based large database of the Health Insurance Review & Assessment Service (HIRA). CMV cases, defined as symptomatic disease with isolation of virus, DNA, pp65 antigen, and pathology except CMV syndrome, were extracted with the unique codes for relief of medical costs of HIRA in the same dataset. Cox's proportional hazard regression analyses and log-rank test in the Kaplan-Meier curves were performed to compare all-cause mortality between the three groups. Results: The CMV IRs adjusted by age and sex were significantly higher in the SOT (adjusted IR [95% confidence intervals], 33.1 [28.8-38.0] per 1,000 person-years) and HSCT recipients (5.1 [4.6-6.1] per 1,000 person-years) than in the whole population (0.58 [0.49-0.67] per 100,000 person-years). However, SOT recipients with CMV (18/283, 6.4%) had significantly lower all-cause mortality than non-transplant individuals with CMV (207/1,258, 16.5%) (adjusted hazard ratio [95% CI], 0.42 [0.25-0.67], log-rank P < 0.001). Conclusion: These data suggest that CMV disease in patients without transplants is associated with poor outcomes.


Assessing Errors Inherent in OCT-Derived Macular Thickness Maps.
SD-OCT has become an essential tool for evaluating macular pathology; however several aspects of data collection and analysis affect the accuracy of retinal thickness measurements. Here we evaluated sampling density, scan centering, and axial length compensation as factors affecting the accuracy of macular thickness maps. Forty-three patients with various retinal pathologies and 113 normal subjects were imaged using Cirrus HD-OCT. Reduced B-scan density was associated with increased interpolation error in ETDRS macular thickness plots. Correcting for individual differences in axial length revealed modest errors in retinal thickness maps, while more pronounced errors were observed when the ETDRS plot was not positioned at the center of the fovea (which can occur as a result of errant fixation). Cumulative error can exceed hundreds of microns, even under "ideal observer" conditions. This preventable error is particularly relevant when attempting to compare macular thickness maps to normative databases or measuring the area or volume of retinal features.


Yeast homotypic vacuole fusion requires the Ccz1-Mon1 complex during the tethering/docking stage.
The function of the yeast lysosome/vacuole is critically linked with the morphology of the organelle. Accordingly, highly regulated processes control vacuolar fission and fusion events. Analysis of homotypic vacuole fusion demonstrated that vacuoles from strains defective in the CCZ1 and MON1 genes could not fuse. Morphological evidence suggested that these mutant vacuoles could not proceed to the tethering/docking stage. Ccz1 and Mon1 form a stable protein complex that binds the vacuole membrane. In the absence of the Ccz1-Mon1 complex, the integrity of vacuole SNARE pairing and the unpaired SNARE class C Vps/HOPS complex interaction were both impaired. The Ccz1-Mon1 complex colocalized with other fusion components on the vacuole as part of the cis-SNARE complex, and the association of the Ccz1-Mon1 complex with the vacuole appeared to be regulated by the class C Vps/HOPS complex proteins. Accordingly, we propose that the Ccz1-Mon1 complex is critical for the Ypt7-dependent tethering/docking stage leading to the formation of a trans-SNARE complex and subsequent vacuole fusion.


Age and sex differences in presentation of symptoms among patients with acute coronary disease: the REACT Trial. Rapid Early Action for Coronary Treatment.
There are few data on possible age and sex differences in presentation of symptoms for patients with acute coronary disease. To investigate demographic differences in presentation of symptoms at the time of hospital presentation for acute myocardial infarction (AMI) and unstable angina. The medical records of patients who presented with chest pain and who also had diagnoses of AMI (n = 889) or unstable angina (n = 893) on discharge from 43 hospitals were reviewed as part of data collection activities of the Rapid Early Action for Coronary Treatment trial based in 10 pair-matched communities throughout the USA. Dyspnea (49%), arm pain (46%), sweating (35%), and nausea (33%) were commonly reported by men and women of all ages in addition to the presenting complaint of chest pain. After we had controlled for various characteristics through regression modeling, older persons with AMI were significantly less likely than were younger persons to complain of arm pain and sweating, and men were significantly less likely to report vomiting than were women. Among persons with unstable angina, arm pain and sweating were reported significantly less often by elderly patients. Nausea and back, neck, and jaw pain were more common complaints of women. Results of this study suggest that there are differences between symptoms at presentation of men and women, and those in various age groups, hospitalized with acute coronary disease. Clinicians should be aware of these differences when diagnosing and managing patients suspected to have coronary heart disease.


History and status of embryology and developmental biology at Polish Medical Faculties and Schools.
In Poland, medical embryology (both scientific research and teaching of the subject) has traditionally involved Chairs of Histology and Embryology rather than Obstetrics and Gynecology. Before World War II, the most buoyant centers for embryological research among the five universities at the time (in Warsaw, Krakow, Poznan, Lvov and Vilnius), were the Chairs of Embryology and Histology at Medical Faculties of the Jagiellonian University in Krakow and the University of Vilnius. After World War II, eleven Medical Academies (Universities of Medicine) came into being (Warsaw, Krakow, Poznan, Lodz, Gdansk, Bialystok, Bydgoszcz, Szczecin, Wroclaw, Katowice and Lublin). They conduct scientific research on normal development of the human embryo as well as teratology studies. In the XX century, eminent medicine-related embryologist included professors Emil Godlewski Jr., Stanislaw Hiller and Stefan Baginski.


Mouse interferon produced in vivo does not inhibit the development of preimplantation mouse embryos.
Mouse embryos were cultured in vitro in medium with serum containing interferon which had been induced in vivo by intravenous administration of polyinosine-polycytidylic acid. Two-cell and blastocyst-stage embryos were incubated for 72 and 24 h respectively before embryo transfer, or fixation to determine cell number. Further, blastocysts were outgrown on coverslips in embryo culture medium with fetal calf serum and interferon. Expression of an intermediate filament protein (Mr 55 000) in blastocyst outgrowths was examined with a monoclonal antibody. Embryos appeared morphologically normal and after treatment the mean cell number did not differ from that of controls. Implantation was unaffected by any of the treatments, but culture before transfer in medium containing mouse serum reduced the number of normal fetuses recovered on Day 14 of gestation compared to those cultured in medium without serum. Exposure to interferon did not modify the expression of filaments in the outgrown blastocyst. It is therefore unlikely that interferon induced by viral infection during pregnancy is responsible for preimplantation embryonic loss.


Traumatic separation of epiphyses. An experimental study in rats.
Four types of physeal fracture-separations, defined by the Salter-Harris classification, were created experimentally in the proximal physis of the right tibia of immature rats. The four types are: Type I, pure epiphyseal separation; Type II, separation of the epiphysis with a metaphyseal fracture; Type III, partial epiphyseal separation with a vertical fracture of the epiphysis; and Type IV, vertical epiphyseal and metaphyseal fractures. A sham operation performed on the left tibia served as the control. The animals were killed at various intervals up to 25 days after the operation. The findings were assessed by roentgenographic, histologic, and vessel injection methods. For Types I and II morphometric analyses were also performed. The influence of various types of lesions on the growth rate and the healing process was documented. For Types I and II lesions there was a transitory growth arrest and an increased thickening of the zone of hypertrophic cells. The alterations regressed after Day 15, and by day 25, a nearly normal plate was seen. For Type III lesions an angular deformity of the tibia occurred that increased with time. For Type IV lesions, a step-off developed on the articular surface that became more severe with time. Early vascular anastomoses between the epiphysis and the metaphysis led to the formation of bone bridges in Type III and Type IV lesions.


Neurotoxicity of e-cigarettes.
It appears that electronic cigarettes (EC) are a less harmful alternative to conventional cigarette (CC) smoking, as they generate substantially lower levels of harmful carcinogens and other toxic compounds. Thus, switching from CC to EC may be beneficial for smokers. However, recent accounts of EC- or vaping-associated lung injury (EVALI) has raised concerns regarding their adverse health effects. Additionally, the increasing popularity of EC among vulnerable populations, such as adolescents and pregnant women, calls for further EC safety evaluation. In this state-of-the-art review, we provide an update on recent findings regarding the neurological effects induced by EC exposure. Moreover, we discuss possible neurotoxic effects of nicotine and numerous other chemicals which are inherent both to e-liquids and EC aerosols. We conclude that in recognizing pertinent issues associated with EC usage, both government and scientific researchers must address this public health issue with utmost urgency.


Evaluating the clinical efficacy and limitations of indocyanine green fluorescence-guided surgery in childhood hepatoblastoma: A retrospective study.
Indocyanine green (ICG) fluorescence guided surgery has been used to treat childhood hepatoblastoma (HB), but the advantages and disadvantages of this technique have not been fully discussed. The purpose of this study is to summarize the experience and to explore the clinical value of this technique for children with HB. 45 children with HB who underwent ICG fluorescence guided surgery (n = 22) and general surgery (n = 23) in our center from January 2020 to December 2022 were enrolled retrospectively. All the liver tumors in the ICG group showed hyperfluorescence, including total and partial fluorescent types. With the help of ICG navigation, minimally invasive surgery was performed in 3 cases. 18.2 % of cases with tumors could not be accurately identified under white light, but could be identified by fluorescence imaging. The fluorescent cutting lines of 59.1 % of cases were consistent with the safe cutting lines. In 36.4 % of cases, the fluorescence boundary was not clear because of tumor necrosis. In 36.4 % of cases, the fluorescence could not be detected on the inner edge of the tumors because of the depth. A total of 29 ICG (+) suspicious lesions were found during the operations, of which 5 were true positive lesions. ICG fluorescence guided surgery is safe and feasible in children with HB. This technique is helpful for locating tumors, determining margin and finding small lesions with negative imaging, especially in minimally invasive surgery. However, preoperative chemotherapy, tumor necrosis, tumor depth, and ICG administration impact the effect of fluorescence imaging.


Not just fun and games: applications of virtual reality in the identification and rehabilitation of cognitive disorders of the elderly.
To outline the evidence in the published medical literature suggesting the potential applications of virtual reality (VR) for the identification and rehabilitation of cognitive disorders of the elderly. Non-systematic literature review. VR, despite its more common usage by younger persons, is a potentially promising source of techniques useful in the identification and rehabilitation of cognitive disorders of the elderly. Systems employing VR can include desktop and head-mounted visual displays among other devices. Thus far, published studies have described VR-based applications in the identification and treatment of deficits in navigational skills in ambulation and driving. In addition, VR has been utilised to enhance the ability to perform activities of daily living in patients with dementia, stroke, and Parkinson's Disease. Such investigations have thus far been small, and unblinded. VR-based applications can potentially offer more versatile, comprehensive, and safer assessments of function. However, they also might be more expensive, complex and more difficult to use by elderly patients. Side effects of head-mounted visual displays include nausea and disorientation, but, have not been reported specifically in older subjects.


Effects of dairy consumption on SIRT1 and mitochondrial biogenesis in adipocytes and muscle cells.
Recent data from this laboratory suggest that components of dairy foods may serve as activators of SIRT1 (Silent Information Regulator Transcript 1), and thereby participate in regulation of glucose and lipid metabolism. In this study, an ex-vivo/in-vitro approach was used to examine the integrated effects of dairy diets on SIRT1 activation in two key target tissues (adipose and muscle tissue). Serum from overweight and obese subjects fed low or high dairy diets for 28 days was added to culture medium (similar to conditioned media) to treat cultured adipocytes and muscle cells for 48 hours. Treatment with high dairy group conditioned media resulted in 40% increased SIRT1 gene expression in both tissues (p < 0.01) and 13% increased enzyme activity in adipose tissue compared to baseline. This was associated with increased gene expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF1), cytochrome oxidase c subunit 7 (Cox 7), NADH dehydrogenase and uncoupling protein 2 (UCP2) in adipocytes as well as uncoupling protein 3 (UCP3), NRF1 and Cox 7 in muscle cells (p < 0.05). Further, direct incubation of physiological concentrations of leucine and its metabolites α-Ketoisocaproic acid (KIC) and β-hydroxy-methylbuteric acid (HMB) with recombinant human SIRT1 enzyme resulted in 30 to 50% increase of SIRT1 activity (p < 0.05). These data indicate that dairy consumption leads to systemic effects, which may promote mitochondrial biogenesis in key target tissues such as muscle and adipose tissue both by direct activation of SIRT1 as well as by SIRT1-independent pathways.


An overview of paediatric leishmaniasis.
Leishmaniasis, a parasitic disease transmitted by the bite of some species of sandflies affects various age groups depending on the infecting Leishmania species, geographic location, disease reservoir, and host immunocompetence. Visceral leishmaniasis is the most severe form of the disease affecting children. The extent and presentation of the disease depend on several factors, including the humoral and cell-mediated immune response of the host, the virulence of the infecting species, and the parasite burden. Children are at greater risk than adults in endemic areas. Malnutrition contributes to the development of disease, and incomplete therapy of initial disease is a risk factor for recurrence of leishmaniasis. Children usually present with intermittent fever, paleness, refusal to feed or anorexia, weight loss, and abdominal distension. Splenomegaly, hepatomegaly, lymph node enlargement, thrombocytopaenia, anaemia, leukopaenia and hypergammaglobulinemia are the most common findings in Paediatric leishmaniasis. Molecular methods appear to offer the promise of accurate non-invasive tools for the diagnosis of Leishmaniasis. Till these methods are evaluated, definite diagnosis will rely on the demonstration of the infecting parasite in various tissues. World-wide, with the notable exception of India, pentavalent antimonial compounds remain the most effective and the most affordable therapy for this disease. Lipid formulations of amphotericin B were assessed as short duration treatment and were proved to be effective. However, their cost precludes their wide use in developing countries. Miltefosine, a new oral agent, might prove effective, safe, and affordable. Strategies aimed at control of the micro-population of sandflies, eradication of canine leishmaniasis, and offering personal protection against sandfly bites, together with health education programs in developing countries, can help control the disease. Development of an effective vaccine remains a priority.


Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline.
The aim was to formulate practice guidelines for endocrine treatment of transsexual persons. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence, which was low or very low. Committees and members of The Endocrine Society, European Society of Endocrinology, European Society for Paediatric Endocrinology, Lawson Wilkins Pediatric Endocrine Society, and World Professional Association for Transgender Health commented on preliminary drafts of these guidelines. Transsexual persons seeking to develop the physical characteristics of the desired gender require a safe, effective hormone regimen that will 1) suppress endogenous hormone secretion determined by the person's genetic/biologic sex and 2) maintain sex hormone levels within the normal range for the person's desired gender. A mental health professional (MHP) must recommend endocrine treatment and participate in ongoing care throughout the endocrine transition and decision for surgical sex reassignment. The endocrinologist must confirm the diagnostic criteria the MHP used to make these recommendations. Because a diagnosis of transsexualism in a prepubertal child cannot be made with certainty, we do not recommend endocrine treatment of prepubertal children. We recommend treating transsexual adolescents (Tanner stage 2) by suppressing puberty with GnRH analogues until age 16 years old, after which cross-sex hormones may be given. We suggest suppressing endogenous sex hormones, maintaining physiologic levels of gender-appropriate sex hormones and monitoring for known risks in adult transsexual persons.


Non-opsonic phagocytosis of Legionella pneumophila by macrophages is mediated by phosphatidylinositol 3-kinase.
Legionella pneumophila, is an intracellular pathogen that causes Legionnaires' disease in humans, a potentially lethal pneumonia. L. pneumophila has the ability to enter and replicate in the host and is essential for pathogenesis. Phagocytosis was measured by cell invasion assays. Construction of PI3K mutant by PCR cloning and expression of dominant negative mutant was detected by Western blot. PI3K activity was measured by 32P labeling and detection of phospholipids products by thin layer chromatography. Infection of macrophages with virulent L. pneumophila stimulated the formation of phosphatidylinositol 3-phosphate (PIP3), a phosphorylated lipid product of PI3K whereas two structurally distinct phosphatidylinositol 3 kinase (PI3K) inhibitors, wortmannin and LY294002, reduced L. pneumophila entry into macrophages in a dose-dependent fashion. Furthermore, PI3K activation led to Akt stimulation, a serine/threonine kinase, which was also inhibited by wortmannin and LY294002. In contrast, PI3K and protein kinase B (PKB/Akt) activities were lower in macrophages infected with an avirulent bacterial strain. Only virulent L. pneumophila increased lipid kinase activity present in immunoprecipitates of the p85alpha subunit of class I PI3K and tyrosine phosphorylated proteins. In addition, macrophages expressing a specific dominant negative mutant of PI3K reduced L. pneumophila entry into these cells. Entry of L. pneumophila is mediated by PI3K/Akt signaling pathway. These results suggest an important role for PI3K and Akt in the L. pneumophila infection process. They point to possible novel strategies for undermining L. pneumophila host uptake and reducing pathogenesis of Legionnaires' disease.


Multi-generational imputation of single nucleotide polymorphism marker genotypes and accuracy of genomic selection.
Availability of high-density single nucleotide polymorphism (SNP) genotyping platforms provided unprecedented opportunities to enhance breeding programmes in livestock, poultry and plant species, and to better understand the genetic basis of complex traits. Using this genomic information, genomic breeding values (GEBVs), which are more accurate than conventional breeding values. The superiority of genomic selection is possible only when high-density SNP panels are used to track genes and QTLs affecting the trait. Unfortunately, even with the continuous decrease in genotyping costs, only a small fraction of the population has been genotyped with these high-density panels. It is often the case that a larger portion of the population is genotyped with low-density and low-cost SNP panels and then imputed to a higher density. Accuracy of SNP genotype imputation tends to be high when minimum requirements are met. Nevertheless, a certain rate of genotype imputation errors is unavoidable. Thus, it is reasonable to assume that the accuracy of GEBVs will be affected by imputation errors; especially, their cumulative effects over time. To evaluate the impact of multi-generational selection on the accuracy of SNP genotypes imputation and the reliability of resulting GEBVs, a simulation was carried out under varying updating of the reference population, distance between the reference and testing sets, and the approach used for the estimation of GEBVs. Using fixed reference populations, imputation accuracy decayed by about 0.5% per generation. In fact, after 25 generations, the accuracy was only 7% lower than the first generation. When the reference population was updated by either 1% or 5% of the top animals in the previous generations, decay of imputation accuracy was substantially reduced. These results indicate that low-density panels are useful, especially when the generational interval between reference and testing population is small. As the generational interval increases, the imputation accuracies decay, although not at an alarming rate. In absence of updating of the reference population, accuracy of GEBVs decays substantially in one or two generations at the rate of 20% to 25% per generation. When the reference population is updated by 1% or 5% every generation, the decay in accuracy was 8% to 11% after seven generations using true and imputed genotypes. These results indicate that imputed genotypes provide a viable alternative, even after several generations, as long the reference and training populations are appropriately updated to reflect the genetic change in the population.


Comparison of Pheochromocytoma-Specific Morbidity and Mortality Among Adults With Bilateral Pheochromocytomas Undergoing Total Adrenalectomy vs Cortical-Sparing Adrenalectomy.
Large studies investigating long-term outcomes of patients with bilateral pheochromocytomas treated with either total or cortical-sparing adrenalectomies are needed to inform clinical management. To determine the association of total vs cortical-sparing adrenalectomy with pheochromocytoma-specific mortality, the burden of primary adrenal insufficiency after bilateral adrenalectomy, and the risk of pheochromocytoma recurrence. This cohort study used data from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018. Data were analyzed from September 1, 2018, to June 1, 2019. Total or cortical-sparing adrenalectomy. Primary adrenal insufficiency, recurrent pheochromocytoma, and mortality. Of 625 patients (300 [48%] female) with a median (interquartile range [IQR]) age of 30 (22-40) years at diagnosis, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas and 224 (36%) were diagnosed with metachronous pheochromocytomas (median [IQR] interval to second adrenalectomy, 6 [1-13] years). In 505 of 526 tested patients (96%), germline mutations were detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]). Of 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical sparing and were successful in 248 of 324 patients (76.5%). Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy. A third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing syndrome. Of 377 patients who became steroid dependent, 67 (18%) developed at least 1 adrenal crisis and 50 (13%) developed iatrogenic Cushing syndrome during median (IQR) follow-up of 8 (3-25) years. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median (IQR) of 8 (4-13) years, all of which were successfully treated with another surgery. Cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma: of 63 patients who died, only 3 (5%) died of metastatic pheochromocytoma. Patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. Cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma.


Chemical Space of FLT3 Inhibitors as Potential Anti-AML Drugs.
FLT3 is a member of receptor tyrosine kinase III family, mainly expressed in hematopoietic cells. The aberrant expression and function of FLT3 are strongly related to leukemia, especially acute myeloid leukemia. Its varieties of amino-acid residues mutations, such as FLT3-ITDs and -TKDs, can induce constant proliferation of hematological tumor cells with poor prognosis. Hence FLT3 serves as a promising target in AML chemotherapy. This review focused on the progress of FLT3 inhibitors study including those that have entered clinical trials or were reported in numerous patents all over the world. Thus, we provided a useful reference for the development of new anti-leukemia drugs. Through a comprehensive retrospective study, FLT3 inhibitors in several patent applications were identified and classified into five categories, including quinolone-related, indole-related, ureas, pyrimidines and other compounds. For each category of compounds, the structural feature, SAR, biological activity and current research status were thoroughly reviewed and analyzed. Although some of those compounds expressed potent bioactivities and have reached the advanced clinical trials for the treatment of leukemia, there are still several problems need to be faced before they enter the market eventually, especially the drug resistance issue. The improvement of therapeutic potency for FLT3 inhibitors might depend on the useful combination therapy and further refinement of the intrinsic properties of FLT3 inhibitors.


High-throughput sequence analysis of small RNAs in grapevine (Vitis vinifera L.) affected by grapevine leafroll disease.
Grapevine leafroll disease (GLRD) is one of the most economically important virus diseases of grapevine (Vitis spp.) worldwide. In this study, we used high-throughput sequencing of cDNA libraries made from small RNAs (sRNAs) to compare profiles of sRNA populations recovered from own-rooted Merlot grapevines with and without GLRD symptoms. The data revealed the presence of sRNAs specific to Grapevine leafroll-associated virus 3, Hop stunt viroid (HpSVd), Grapevine yellow speckle viroid 1 (GYSVd-1) and Grapevine yellow speckle viroid 2 (GYSVd-2) in symptomatic grapevines and sRNAs specific only to HpSVd, GYSVd-1 and GYSVd-2 in nonsymptomatic grapevines. In addition to 135 previously identified conserved microRNAs in grapevine (Vvi-miRs), we identified 10 novel and several candidate Vvi-miRs in both symptomatic and nonsymptomatic grapevine leaves based on the cloning of miRNA star sequences. Quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) of selected conserved Vvi-miRs indicated that individual members of an miRNA family are differentially expressed in symptomatic and nonsymptomatic leaves. The high-resolution mapping of sRNAs specific to an ampelovirus and three viroids in mixed infections, the identification of novel Vvi-miRs and the modulation of certain conserved Vvi-miRs offers resources for the further elucidation of compatible host-pathogen interactions and for the provision of ecologically relevant information to better understand host-pathogen-environment interactions in a perennial fruit crop.


New evidence of illicit cigarette consumption and government revenue loss in Indonesia.
Illicit cigarettes because of their affordability could increase smoking prevalence, especially among young people. They also cause a large revenue loss for the government. This study aims to estimate illicit cigarette consumption and government revenue loss in Indonesia, a country with a very high smoking prevalence, especially among males. We estimated illicit cigarette trade in terms of volume and revenue loss. Illicit trade was estimated as the discrepancy between legal cigarette sales and domestic consumption recorded by national representative surveys. Data sources included Basic Health Research Survey, Global Adult Tobacco Survey, National Socioeconomic Survey, and data from Ministry of Finance. We found that illicit cigarette consumption fluctuated from 19 billion sticks in 2007 to 14 billion sticks in 2013, and sharply increased to 59 billion sticks in 2018. Relative to cigarette consumption, illicit cigarettes were the lowest at 5% in 2013 and highest at 19% of consumption in 2018 (assuming 0% underreporting). The estimated government revenue loss ranged from IDR 24.2 to 42.0 trillion (US$ 1668 to 2897 million), which corresponds to 15.8% to 27.5% of cigarette excise revenue in 2018. In Indonesia, illicit cigarette consumption was found to be high and increasing, which contributed to a large government revenue loss (almost onethird of tobacco excise tax revenue). To reduce illegal cigarette production and smuggling, the government should increase resources to enforce the regulation on the excise tax system including stronger penalties, especially related to illicit cigarette production.


Optimization of neural networks using variable structure systems.
This paper proposes a new mixed training algorithm consisting of error backpropagation (EBP) and variable structure systems (VSSs) to optimize parameter updating of neural networks. For the optimization of the number of neurons in the hidden layer, a new term based on the output of the hidden layer is added to the cost function as a penalty term to make optimal use of hidden units related to weights corresponding to each unit in the hidden layer. VSS is used to control the dynamic model of the training process, whereas EBP attempts to minimize the cost function. In addition to the analysis of the imposed dynamics of the EBP technique, the global stability of the mixed training methodology and constraints on the design parameters are considered. The advantages of the proposed technique are guaranteed convergence, improved robustness, and lower sensitivity to initial weights of the neural network.


[The teaching of play/therapeutic play in nursing schools in São Paulo State].
This study is a descriptive and quantitative research that aims to characterize the toy/therapeutic toy teaching and analyze the facilities and difficulties of its development in the graduation courses in nursing in Sao Paulo State. The data was collected in 40 institutions, where there were 76 participant professors. The results showed that the theme is approached in the programmatic content of Pediatric Nursing in most of these institutions, in the third, more effectively in the last ten years, both in the theoretical and practical teaching. The theoretical load time had a variation of one to 20 hours, using expositive and participative class and the written test prevailed in the theoretical evaluation strategies and in the practical, the students observation. Some difficulties and facilities mentioned refer to valorization and to infra structure favorable to these resources.


Platelet count in healthy full-term Nigerian neonates.
633 platelet counts are reported on 338 full-term healthy Nigerian babies aged 1 hour to 28 days. Platelet counts for the first week (207,000 +/- 72,000 cumm) are significantly lower (P less than .001) than in the subsequent 3 weeks (282,000 +/- 94,000 cumm). Platelet counts of 100,000-400,000/cumm during the first week and 100,000-450,000/cumm during the rest of the neonatal period include 95% of the respective age groups of Nigerian infants studied and these ranges can therefore be regarded as standard for healthy Nigerian neonates. Platelet counts in Nigerian neonates are essentially similar to those reported elsewhere but significantly higher than in Nigerian adults.


Reduced expression of a rhomboid protease, EhROM1, correlates with changes in the submembrane distribution and size of the Gal/GalNAc lectin subunits in the human protozoan parasite, Entamoeba histolytica.
Entamoeba histolytica is a food- and waterborne parasite that causes amebic dysentery and amoebic liver abscesses. Adhesion is one of the most important virulence functions as it facilitates motility, colonization of host, destruction of host tissue, and uptake of nutrients by the parasite. The parasite cell surface adhesin, the Gal/GalNAc lectin, facilitates parasite-host interaction by binding to galactose or N-acetylgalactosamine residues on host components. It is composed of heavy (Hgl), intermediate (Igl), and light (Lgl) subunits. Igl is constitutively localized to lipid rafts (cholesterol-rich membrane domains), whereas Hgl and Lgl transiently associate with rafts. When all three subunits are localized to rafts, galactose-sensitive adhesion is enhanced. Thus, submembrane location may regulate the function of this adhesion. Rhomboid proteases are a conserved family of intramembrane proteases that also participate in the regulation of parasite-host interactions. In E. histolytica, one rhomboid protease, EhROM1, cleaves Hgl as a substrate, and knockdown of its expression inhibits parasite-host interactions. Since rhomboid proteases are found within membranes, it is not surprising that lipid composition regulates their activity and enzyme-substrate binding. Given the importance of the lipid environment for both rhomboid proteases and the Gal/GalNAc lectin, we sought to gain insight into the relationship between rhomboid proteases and submembrane location of the lectin in E. histolytica. We demonstrated that EhROM1, itself, is enriched in highly buoyant triton-insoluble membranes reminiscent of rafts. Reducing rhomboid protease activity, either pharmacologically or genetically, correlated with an enrichment of Hgl and Lgl in rafts. In a mutant cell line with reduced EhROM1 expression, there was also a significant augmentation of the level of all three Gal/GalNAc subunits on the cell surface and an increase in the molecular weight of Hgl and Lgl. Overall, the study provides insight into the molecular mechanisms governing parasite-host adhesion for this pathogen.


Setting standards for product selection: allergy prevention.
It is axiomatic to state that if products made of natural rubber latex were not used in health care settings then there would be no problems of acquired hypersensitivity from such products. Although synthetic materials are available they do not currently possess the same technical qualities of elasticity and comfort, nor do they deliver the desired degree of protection against biological agents as gloves made out of natural rubber latex. Selection of gloves either for non-sterile procedures or sterile surgical use should be based on this understanding, and gloves with minimal levels of extractable latex proteins should be used.


[Light-emitting diodes (LED) technology applied to the photopolymerization of resin composites].
An adequate polymerization of resin composites can significantly contribute to increase the longevity of a restoration. In this field, the choice of the operative technique and the characteristics of the lamp are very important. The aim of this review was to evaluate the effectiveness of cure of the light-emitting diodes (LED) lamps comparing them to the others currently available for resin composites photopolymerization. At present, halogen lamps are the most commonly used light sources, but this technology does not allow further developments; even plasma arc and laser lamps have some drawbacks. The innovative LED technology, based on semiconductors, opened new and interesting views in the field of photopolymerization; to the advantages of a soft-start polymerization they add the safety, efficiency, economy and long lifetime of LED light. A careful review of the literature revealed that, although their lower emission of light, these lamps are capable of a polymerization qualitatively comparable to other light sources. Physical and mechanical properties, degree of conversion, depth of cure and final hardness of the composites cured with a LED light are similar to the values achieved with the halogen lamp, whereas the temperature increase is significantly lower and does not pose a threat to the pulp tissue. Undoubtedly, more tests of the mechanical properties of composites processed with LED units need to be carried out but, as the technology improves, LED curing will become an interesting alternative to existing curing methods.


Illumina and PacBio DNA sequencing data, de novo assembly and annotation of the genome of Aurantiochytrium limacinum strain CCAP_4062/1.
The complete genome of the thraustochytrid Aurantiochytrium limacinum strain CCAP_4062/1 was sequenced using both Illumina Novaseq 6000 and third generation sequencing technology PacBio RSII in order to obtain trustworthy assembly and annotation. The reads from both platforms were combined at multiple levels in order to obtain a reliable assembly, then compared to the A. limacinum ATCCⓇ MYA1381™ reference genome. The final assembly was annotated with the help of strain CCAP_4062/1 RNAseq data. A. limacinum strain CCAP_4062/1 is an industrial strain used for the production of very long chain polyunsaturated fatty acids, like the docosahexaenoic acid that is an essential fatty acid synthesised only at very low pace in humans and vertebrates . Thraustochytrids in general and Aurantiochytrium more specifically, are used for carotenoid and squalene production as well. Beside their biotechnological interest, thraustochytrids play a crucial role in both inshore and oceanic basins ecosystems. Genome sequences will foster biotechnological as well as ecological studies.


Selective extraction of persistent organic pollutants from environmental matrices.
An attempt is made to determine the bioavailability of persistent organic pollutants (POP's) in environmental matrices. The approach is based on the use of the Hildebrand Solubility Parameter, and its individual parameters of hydrogen bonding, dispersion and polarity to select weak and strong solvents to extract POP's from soil matrices. The approach has been applied to both spiked soils and certified reference materials. Initial results indicate that it is possible to fractionate POP's from soil matrices based on their ability to be extracted from soil by particular solvents.


Using machine learning to understand age and gender classification based on infant temperament.
Age and gender differences are prominent in the temperament literature, with the former particularly salient in infancy and the latter noted as early as the first year of life. This study represents a meta-analysis utilizing Infant Behavior Questionnaire-Revised (IBQ-R) data collected across multiple laboratories (N = 4438) to overcome limitations of smaller samples in elucidating links among temperament, age, and gender in early childhood. Algorithmic modeling techniques were leveraged to discern the extent to which the 14 IBQ-R subscale scores accurately classified participating children as boys (n = 2,298) and girls (n = 2,093), and into three age groups: youngest (< 24 weeks; n = 1,102), mid-range (24 to 48 weeks; n = 2,557), and oldest (> 48 weeks; n = 779). Additionally, simultaneous classification into age and gender categories was performed, providing an opportunity to consider the extent to which gender differences in temperament are informed by infant age. Results indicated that overall age group classification was more accurate than child gender models, suggesting that age-related changes are more salient than gender differences in early childhood with respect to temperament attributes. However, gender-based classification was superior in the oldest age group, suggesting temperament differences between boys and girls are accentuated with development. Fear emerged as the subscale contributing to accurate classifications most notably overall. This study leads infancy research and meta-analytic investigations more broadly in a new direction as a methodological demonstration, and also provides most optimal comparative data for the IBQ-R based on the largest and most representative dataset to date.


The Mechanisms Underlying Helicobacter Pylori-Mediated Protection against Allergic Asthma.
Helicobacter pylori, a gram negative pathogen, infects the stomach and gastrointestinal tract and causes pathological damage to these organs. H. pylori infection is more prevalent among people living in developing countries. Allergic asthma is a chronic inflammatory disease of the airways. Hyperinflation, hyperresponsiveness, and abnormal immunological and inflammatory processes in respiratory airways typically occur during an asthma attack. The results of recent studies have suggested an association between H. pylori and asthma risk. However, the role of H. pylori infection in the pathophysiology of asthma is still a matter of debate. The results of some studies indicate an association between H. pylori infection and protection against allergic asthma. Exposure to infectious agents might educate the immune system and provide protection against allergic diseases. H. pylori inflammation also changes gastric hormonal levels and could influence the autonomic nervous system. T-regs could be influenced by the immunological response to H. pylori and then inhibit the Th-2-mediated allergic response. Therefore, H. pylori might play a protective role against asthma. H. pylori can also reduce gastro-esophageal reflux, which is an asthma stimulator. High loads of H. pylori are not always present during infection. It is not definitely clear whether H. pylori is a pathogen or simply an opportunist. It has been suggested that early exposure to H. pylori prevents development of pediatric asthma. Therefore, it is possible that therapeutic products made from H. pylori can be used for the treatment or prevention of asthma.


Visible Light Induced Copper-Catalyzed Enantioselective Deaminative Arylation of Amino Acid Derivatives Assisted by Phenol.
The exploration of value-added conversions of naturally abundant amino acids has received considerable attention from the synthetic community. Compared with the well-established asymmetric decarboxylative transformation, the asymmetric deaminative transformation of amino acids still remains a formidable challenge, mainly due to the lack of effective strategies for the C-N bond activation and the potential incompatibility with chiral catalysts. Here, we disclose a photoinduced Cu-catalyzed asymmetric deaminative coupling reaction of amino acids with arylboronic acids. This new protocol provides a series of significant chiral phenylacetamides in generally good yields and excellent stereoselectivity under mild and green conditions (42-85 % yields, up to 97 % ee). Experimental investigations and theoretical calculations were performed to reveal the crucial role of additional phenols in improving catalytic efficiency and enantiocontrol.


Chloroplast-like organelles were found in enucleate sieve elements of transgenic plants overexpressing a proteinase inhibitor.
SaPIN2a, a plant proteinase inhibitor from nightshade (Solanum americanum), was located to the enucleate sieve elements (SEs) of phloem. The expressed SaPIN2a in transgenic lettuce showed inhibition of plant endogenous trypsin- and chymotrypsin-like activities, suggesting that SaPIN2a can regulate proteolysis in plant cells. To further investigate the physiological role of SaPIN2a, we produced transgenic nightshade and lettuce plants overexpressing SaPIN2a from the cauliflower mosaic virus (CaMV) 35S promoter using Agrobacterium-mediated transformation. Overexpression of SaPIN2a in transgenic plants was demonstrated by northern blot and western blot analysis. SaPIN2a-overexpressing transgenic nightshade plants showed significantly lower height than wild-type plants. Transmission electron microscopy analysis showed that chloroplast-like organelles with thylakoids, which are not present in enucleate SEs of wild-type plants, were present in the enucleate SEs of SaPIN2a-overexpressing transgenic plants. This finding is discussed in terms of the possible role played by SaPIN2a in the regulation of proteolysis in SEs.


Nickel-Catalyzed Enantioselective Synthesis of Dienyl Sulfoxide.
Sulfoxides are widely used in the pharmaceutical industry and as ligands in asymmetric catalysis. However, the efficient asymmetric synthesis of this structural motif remains limited. In this study, we disclosed a Ni-catalyzed enantioconvergent reaction that utilizes both racemic allenyl carbonates and β-sulfinyl esters. Our method employs cheap and more sustainable Ni(II) as a precatalyst and successfully overcomes the challenging poisoning effect and instability of sulfenate generated in situ. This enables the synthesis of a series of dienyl sulfoxides with enantioselectivity of up to 98% ee. The product exhibit tremendous potential in various applications, including diastereoselective Diels-Alder reactions coordination with transition metals, and incorporation into medicinal compounds, among others. Using a combination of experimental and computational methods, we have uncovered an interesting associated outersphere mechanism that contrasts with conventional mechanisms commonly observed in asymmetric transition metal catalysis.


Binaural integration: a challenge to overcome for children with hearing loss.
Access to bilateral hearing can be provided to children with hearing loss by fitting appropriate hearing devices to each affected ear. It is not clear, however, that bilateral input is properly integrated through hearing devices to promote binaural hearing. In the present review, we examine evidence indicating that abnormal binaural hearing continues to be a challenge for children with hearing loss despite early access to bilateral input. Behavioral responses and electrophysiological data in children, combined with data from developing animal models, reveal that deafness in early life disrupts binaural hearing and that present hearing devices are unable to reverse these changes and/or promote expected development. Possible limitations of hearing devices include mismatches in binaural place, level, and timing of stimulation. Such mismatches could be common in children with hearing loss. One potential solution is to modify present device fitting beyond providing audibility to each ear by implementing binaural fitting targets. Efforts to better integrate bilateral input could improve spatial hearing in children with hearing loss.


Remodeling dynamics of bone supporting rigidly fixed titanium implants: a histomorphometric comparison in four species including humans.
The long-term maintenance of a rigid bone-implant interface (osseointegration) is the clinical goal of most dental implant systems, although the biological mechanism for retaining a foreign object in living bone is unclear. Little data are available on the physiological turnover (remodeling) of the supporting osseous tissue. The objective of this study was to histomorphometrically assess bone remodeling surrounding rigidly integrated titanium implants in multiple species. Implants, in place from 6 months to 5 years, were recovered from human, monkey, dog, and rabbit subjects. With the use of stereological point-hit and linear-intercept methods, indices of bone formation and resorption were determined. Remarkably similar patterns emerged among all investigated species. Repeated-measures ANOVA showed a 3 to 9 fold increase in remodeling within 1 mm of the bone-implant interface (P<0.001; data expressed as percent turnover / month, mean +/- SEM for n = 3-11). All morphometric indices (percent new bone, percent fluorochrome-labeled bone, percent resorption space) showed similar trends. These data suggest that the physiological mechanism for maintaining rigid osseous integration (osseointegration) is a sustained elevation of remodeling adjacent to the bone-implant interface.


nm23, TOP2A and VEGF expression: Potential prognostic biologic factors in peripheral T-cell lymphoma, not otherwise specified.
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is an aggressive lymphoma associated with a poor outcome. To date, the factor consistently associated with prognosis is the International Prognostic Index (IPI) score; however, it is considered that the IPI score cannot be beneficial for guiding potential targeted therapies. New scoring systems have recently been developed. The aim of the present study was to observe the expression of NME/NM23 nucleoside diphosphate kinase 1 (nm23), nuclear DNA topoisomerase 2-α (TOP2A), multiple myeloma oncogene-1 (MUM-1) and vascular endothelial growth factor (VEGF), and evaluate their prognostic value in PTCL-NOS. A retrospective analysis of 124 cases of PTCL-NOS showed that 70/122 (57.4%) cases were positive for nm23, 71/122 (58.2%) for TOP2A, 30/119 (25.2%) for MUM-1 and 64/122 (52.5%) for VEGF. Of note, 50/122 cases concurrently expressed nm23, TOP2A and VEGF. The univariate analysis results revealed that the nm23 (P=0.012), TOP2A (P=0.002) and VEGF (P=0.008) expression had a negative prognostic effect in patients with PTCL-NOS, while the MUM-1 expression did not have a significant prognostic value (P=0.918). In addition, the concurrent expression of nm23, TOP2A and VEGF was significantly associated with a worse prognosis (P=0.002). However, in multivariate Cox regression analysis, the concurrent expression of nm23, TOP2A and VEGF tended to predict a worse prognosis, however the P-value was borderline (hazard ratio, 1.495; 95% confidence interval, 0.993-2.250; P=0.054). It is speculated that there may be an association among the expression of nm23, TOP2A and VEGF, and that their expression may serve as a promising prognostic factor for PTCL-NOS.


The interaction between stimulus and reinforcer control on remembering.
In a symbolic matching-to-sample task, 6 pigeons obtained food by pecking a red side key when the brighter of two white lights had been presented on the center key and by pecking a green side key when the dimmer of two white lights had been presented on the center key. Across Part 1 and Parts 6 to 10, the delay between sample-stimulus presentation and the availability of the choice keys was varied between 0 s and 25 s. Across Parts 1 to 5, the delay between the emission of a correct choice and the delivery of a reinforcer was varied between 0 s and 30 s. Although increasing both types of delay decreased stimulus discriminability, lengthening the stimulus-choice delay produced a greater decrement in choice accuracy than did lengthening the choice-reinforcer delay. Additionally, the relative reinforcer rate for correct choice was varied across both types of delay. The sensitivity of behavior to the distribution of reinforcers decreased as discriminability decreased under both procedures. These data are consistent with the view, based on the generalized matching law, that sample stimuli and reinforcers interact in their control over remembering.


Synovial fibroblasts infected with Salmonella enterica serovar Typhimurium mediate osteoclast differentiation and activation.
The mechanisms whereby arthritogenic organisms may induce cartilage and bone erosions in infection-triggered arthritis remain unknown. In this study, we asked whether an arthritogenic organism could contribute to osteoclast differentiation and activation through regulation of the receptor activator of NF-kappaB ligand (RANKL) in synovial fibroblasts. Rat synovial fibroblasts were infected in vitro with Salmonella enterica serovar Typhimurium and monitored over time. The expression of RANKL in resting and infected synovial fibroblasts was quantified by reverse transcription-PCR and Western blotting. Osteoclast progenitors, isolated from femurs of 8-week-old rats and cultured in the presence of macrophage colony-stimulating factor, were cocultured with either infected or noninfected synovial fibroblasts for 2 to 4 days. Differentiation and maturation of osteoclasts were determined by morphology and tartrate-resistant acid phosphatase (TRAP) staining and by a bone resorption bioassay. RANKL expression was undetectable in resting synovial fibroblasts but was dose-dependently upregulated in cells after Salmonella infection. Osteoprotegerin was constitutively expressed by synovial fibroblasts and was not upregulated by infection. Further, we observed the formation of multinucleated TRAP-positive cells and formation of bone resorption pits in cocultures of bone marrow-derived osteoclast precursors with synovial fibroblasts infected with Salmonella but not with heat-killed Salmonella or noninfected cells. Arthritogenic bacteria may alter bone structure via synovial fibroblast intermediaries, since infected synovial fibroblasts (i) upregulate RANKL expression and (ii) enhance osteoclast precursor maturation into multinucleated, TRAP-positive, bone-resorbing, osteoclast-like cells. These data provide a link between infection and osteoclastogenesis. A better understanding of infection-mediated osteoclast differentiation and activation may provide new therapeutic strategies for inflammatory joint disease.


Comparison of Efficacy and Safety of CT-Guided Radiofrequency Thermocoagulation Through Foramen Rotundum Versus Foramen Ovale for V2 Primary Trigeminal Neuralgia.
Primary trigeminal neuralgia (TN) is one of the most severe facial pain syndromes. TN affects patients' quality of life and, when severe, can lead to depression and increase social burden. This retrospective study aimed to compare efficacy and safety of computed tomographic (CT)-guided percutaneous radiofrequency thermocoagulation (RFT) through the foramen rotundum (FR) versus through the foramen ovale (FO) for treatment of maxillary division (V2) TN. A prospective study. Shengjing Hospital of China Medical University. Seventy patients with V2 TN were randomly assigned to 2 groups: RFT-FR group (n = 35) and RFT-FO group (n = 35). Visual Analog Scale (VAS), the Medical Outcomes Study 36-Item Short-Form Health Survey, the total efficacy, complications, and recurrence rate were assessed before and after surgery at different time points. Compared with the preoperative VAS, the postoperative VAS in the RFT-FR and RFT-FO groups both decreased significantly (P < 0.05). There was no significant difference in VAS between the 2 groups (P > 0.05); in both groups quality of life improved to varying degrees after RFT. In the RFT-FO group, the physical component summary (PCS) and mental component summary (MCS) were significantly lower than in the RFT-FR group at 1 week, 2 weeks and 1 month (P < 0.05). After 3 months, the PCS and MCS of the RFT-FO group gradually increased, so the 2 groups no longer differed significantly (P > 0.05). The total incidence of complications in the RFT-FR and RFT-FO groups was 20.0% (7/35) and 62.9% (22/35), respectively, and differed significantly (P < 0.05). This study cohort size is small, but we will gradually increase the number of patients later. Second, there may be acquiescence bias or response bias. Third, the punctures under the more commonly used C-arm imaging guidance deserve to be evaluated in the future. CT-guided RFT through the FR and FO are both an effective, minimally invasive treatments for V2 TN that can relieve pain effectively.


Developmental skills between kindergarten children with handwriting difficulties in Chinese and/or English.
This study aimed to examine the differences in developmental skills between children with and without handwriting difficulties in their last year of kindergarten education. Standardised tests on handwriting performance and developmental skills were administered to 20 typically developing children, 21 children with handwriting difficulties in Chinese and 23 children with handwriting difficulties in both Chinese and English. We used one-way MANOVA, univariate ANOVA and post hoc comparisons, to compare the developmental skills between children with and without handwriting difficulties. Multiple regression analysis was used to identify the significant predictors of developmental skills for Chinese and English handwriting performance. Higher proportion of children faced handwriting difficulties in Chinese than in English. Their major problem in Chinese handwriting was on stroke formation, while the results did not indicate the key factor leading to English handwriting difficulties. The results also showed that children with handwriting difficulties had significantly poorer visual motor integration, some aspects of visual perception and fine motor skills than typically developing children. Reading skills were not a key factor contributing to handwriting performance. In addition, visual and fine motor integration and spatial relationship were the significant predictors of Chinese and English handwriting performance, which accounted for 39.7 and 43.6% of the variance respectively. First, the results suggested that more resources should be devoted to coaching children to learn Chinese than English handwriting. Second, besides direct repetitive practice on handwriting, there is a need to incorporate learning activities to facilitate the development of visual motor skills, visual perception, and fine motor skills as a preparation for learning to write or in improving handwriting performance among kindergarten children.


The Structural Duality of Nucleobases in Guanine Quadruplexes Controls Their Low-Energy Photoionization.
Guanine quadruplexes are four-stranded DNA/RNA structures composed of a guanine core (vertically stacked guanine tetrads) and peripheral groups (dangling ends and/or loops). Such a dual structural arrangement of the nucleobases favors their photoionization at energies significantly lower than the guanine ionization potential. This effect is important with respect to the oxidative DNA damage and for applications in the field of optoelectronics. Photoionization quantum yields, determined at 266 nm by nanosecond transient absorption spectroscopy, strongly depend on both the type and position of the peripheral nucleobases. The highest value (1.5 × 10-2) is found for the tetramolecular structure (AG4A)4 in which adenines are intermittently stacked on the adjacent guanine tetrads, as determined by nuclear magnetic resonance spectroscopy. Quantum chemistry calculations show that peripheral nucleobases interfere in a key step preceding electron ejection: charge separation, initiated by the population of charge transfer states during the relaxation of electronic excited states.


Resuscitative transesophageal echocardiography in emergency departments in the United States and Canada: A cross-sectional survey.
Over the past two decades, transesophageal echocardiography (TEE) has been used with increasing frequency to evaluate critically ill patients outside of traditional settings. The purpose of this study was to characterize the number of programs, users, practice characteristics, training and competency requirements and barriers for the current use of resuscitative transesophageal echocardiography (TEE) in Emergency Departments (EDs) in the United States and Canada. A closed internet-based, cross-sectional, point-prevalence survey was administered via email to 120 program directors of emergency ultrasound fellowships (EUSF) and 43 physicians from EDs without EUSF from the United States and Canada. Ninety-eight percent of surveyed participants responded. Twenty percent of respondents reported having active resuscitative TEE programs. The majority of participating hospitals (70%) were academic centers with residency programs. A total of 33 programs reported using resuscitative TEE in their ED and of those, 82% were programs with EUSF. Most programs performing TEE (79%) had less than five attending physicians performing TEE. Evaluation of patients during resuscitation from cardiac arrest (100%) and post-arrest care (76%) are the two most frequent indications for TEE in the ED. The most common core elements of resuscitative TEE protocols used are: assessment of left ventricular (LV) systolic function (97%), assessment of right ventricular (RV) function (88%), evaluation of pericardial effusion / tamponade (52%). All programs reported using formal didactics in their training programs, 94% reported using high-fidelity simulation, and 79% live scanning of patients. Financial concerns were the most common barrier use of TEE in the ED (58%), followed by maintenance of equipment (30%), and credentialing/privileges (30%). This study provides a snapshot of the practice of resuscitative TEE in EDs in the United States and Canada revealing the existence of 33 programs using this emerging modality in the care of critically ill patients.


Requirement for a complex of Wiskott-Aldrich syndrome protein (WASP) with WASP interacting protein in podosome formation in macrophages.
Chemotactic migration of macrophages is critical for the recruitment of leukocytes to inflamed tissues. Macrophages use a specialized adhesive structure called a podosome to migrate. Podosome formation requires the Wiskott-Aldrich syndrome protein (WASP), which is a product of the gene defective in an X-linked inherited immunodeficiency disorder, the Wiskott-Aldrich syndrome. Macrophages from WASP-deficient Wiskott-Aldrich syndrome patients lack podosomes, resulting in defective chemotactic migration. However, the molecular basis for podosome formation is not fully understood. I have shown that the WASP interacting protein (WIP), a binding partner of WASP, plays an important role in podosome formation in macrophages. I showed that WASP bound WIP to form a complex at podosomes and that the knockdown of WIP impairs podosome formation. When WASP binding to WIP was blocked, podosome formation was also impaired. When WASP expression was reduced by small interfering RNA transfection, the amount of the complex of WASP with WIP decreased, resulting in reduced podosome formation. Podosomes were restored by reconstitution of the WASP-WIP complex in WASP knockdown cells. These results indicate that the WASP-WIP complex is required for podosome formation in macrophages. When podosome formation was reduced by blocking WASP binding to WIP, transendothelial migration of macrophages, the most crucial process in macrophage trafficking, was impaired. These results suggest that a complex of WASP with WIP plays a critical role in podosome formation, thereby mediating efficient transendothelial migration of macrophages.


The relationship of neighborhood demographic characteristics to point-of-sale tobacco advertising and marketing.
Exposure to tobacco marketing has been associated with an increased likelihood that youth start smoking and may interfere with tobacco cessation. We aimed to describe the prevalence, placement, and features of tobacco advertising at the point of sale by race, ethnicity, and other neighborhood demographics, as well as by store type. A cross-sectional assessment of the advertising environment in establishments that held tobacco licenses in our study region (a metropolitan area in the Midwest USA) was conducted in 2007. Stores were geocoded and linked with block group demographic data taken from the Year 2000 US census. We calculated associations between our hypothesized predictors, race, ethnicity, and other neighborhood demographics, and two types of outcomes (1) amount and (2) characteristics of the advertising. Tobacco advertising at the point of sale was most common in gas stations/convenience stores, liquor stores, and tobacco stores. A 10% difference in a block group's African-American/Black population was associated with 9% (95% confidence interval [CI]=3%, 16%) more ads as well as a greater likelihood that ads would be close to the ground (prevalence ratio [PR]=1.15 [95% CI=1.04, 1.28]). Block groups with greater African-American/Black, Asian, people on public assistance or below 150% of the poverty threshold, or people under the age of 18 years had more ads for menthol brands. Block groups with greater proportions of Whites were more likely to have ads that used health words, such as 'light' or 'natural' (PR for 10% difference in White population=1.41 [95% CI=1.17-1.70]). Chain stores were more likely to have greater amounts of advertising, ads close to the ground, ads for price deals, or ads that use words that imply health. Tobacco advertising targets communities with various racial and ethnic profiles in different ways. Now that US Food and Drug Administration has the authority to regulate the marketing and sale of tobacco products, there is new opportunity to reduce the harmful impact of tobacco advertising.


Production and isolation of azaspiracid-1 and -2 from Azadinium spinosum culture in pilot scale photobioreactors.
Azaspiracid (AZA) poisoning has been reported following consumption of contaminated shellfish, and is of human health concern. Hence, it is important to have sustainable amounts of the causative toxins available for toxicological studies and for instrument calibration in monitoring programs, without having to rely on natural toxin events. Continuous pilot scale culturing was carried out to evaluate the feasibility of AZA production using Azadinium spinosum cultures. Algae were harvested using tangential flow filtration or continuous centrifugation. AZAs were extracted using solid phase extraction (SPE) procedures, and subsequently purified. When coupling two stirred photobioreactors in series, cell concentrations reached 190,000 and 210,000 cell · mL(-1) at steady state in bioreactors 1 and 2, respectively. The AZA cell quota decreased as the dilution rate increased from 0.15 to 0.3 day(-1), with optimum toxin production at 0.25 day(-1). After optimization, SPE procedures allowed for the recovery of 79 ± 9% of AZAs. The preparative isolation procedure previously developed for shellfish was optimized for algal extracts, such that only four steps were necessary to obtain purified AZA1 and -2. A purification efficiency of more than 70% was achieved, and isolation from 1200 L of culture yielded 9.3 mg of AZA1 and 2.2 mg of AZA2 of >95% purity. This work demonstrated the feasibility of sustainably producing AZA1 and -2 from A. spinosum cultures.


Effects of feeding Spodoptera littoralis on lima bean leaves. I. Membrane potentials, intracellular calcium variations, oral secretions, and regurgitate components.
Membrane potentials (V(m)) and intracellular calcium variations were studied in Lima bean (Phaseolus lunatus) leaves when the Mediterranean climbing cutworm (Spodoptera littoralis) was attacking the plants. In addition to the effect of the feeding insect the impact of several N-acyl Glns (volicitin, N-palmitoyl-Gln, N-linolenoyl-Gln) from the larval oral secretion was studied. The results showed that the early events upon herbivore attack were: a) a strong V(m) depolarization at the bite zone and an isotropic wave of V(m) depolarization spreading throughout the entire attacked leaf; b) a V(m) depolarization observed for the regurgitant but not with volicitin [N-(17-hydroxy-linolenoyl)-Gln] alone; c) an enhanced influx of Ca(2+) at the very edge of the bite, which is halved, if the Ca(2+) channel blocker Verapamil is used. Furthermore, the dose-dependence effects of N-acyl Gln conjugates-triggered influx of Ca(2+) studied in transgenic aequorin-expressing soybean (Glycine max) cells, showed: a) a concentration-dependent influx of Ca(2+); b) a configuration-independent effect concerning the stereochemistry of the amino acid moiety; c) a slightly reduced influx of Ca(2+) after modification of the fatty acid backbone by functionalization with oxygen and; d) a comparable effect with the detergent SDS. Finally, the herbivore wounding causes a response in the plant cells that cannot be mimicked by mechanical wounding. The involvement of Ca(2+) in signaling after herbivore wounding is discussed.


Effects of glucocorticoid treatment on focal and systemic bone loss in rheumatoid arthritis.
Rheumatoid arthritis (RA) is characterized by an extensive dysregulation in skeletal homeostasis recognized as 1) focal articular bone erosions, 2) iuxta-articular osteopenia, 3) systemic osteoporosis (OP) and fractures, as is well documented in both cross-sectional and prospective studies. The disease activity, as a consequence of new insights into the complex interaction between bone cells and a variety of cells of the immune system, has emerged as the main responsible for both focal and systemic bone loss. Given this background, the therapeutic approach to RA has become more aggressive, and a more widespread use of low-dose glucocorticoids (GC), recently categorized as disease modifying antirheumatic drugs (DMARD) because of their additional joint sparing effect on the long-term, has also been recommended from the early stages. Addressing the effects of GC on systemic bone loss in RA, GC are considered, in addition to inflammation and inactivity, the major risk factors for OP and fractures. As a consequence, among the most recent recommendations (i.e. dosing, timing, and tapering strategies) for patients receiving GC for more than 3 months, prevention and treatment of GC-induced OP (i.e. calcium, vitamin D, and bisphosphonates) are included. However, innovative GC, characterized by a more favorable risk/benefit profile such as selective GC receptor agonists (SEGRA), are currently in the pipeline. This article reviews the major points of evidence so far available, regarding the effects of GC on focal and systemic bone loss.


What is the purpose of launching World Journal of Gastrointestinal Pathophysiology?
The first issue of World Journal of Gastrointestinal Pathophysiology (WJGP), whose preparatory work was initiated in June, 2009, is published on April 15, 2010. The WJGP Editorial Board has now been established and consists of 154 distinguished experts from 27 countries. Our purpose of launching WJGP is to publish peer-reviewed, high-quality articles via an open-access online publishing model, thereby acting as a platform for communication between peers and the wider public, and maximizing the benefits to editorial board members, authors and readers.


Evolution: why all plumes and jets evolve to round cross sections.
Turbulent curtains of smoke rise initially as flat plumes and, above a certain height, they become round plumes. The same evolution of cross-sectional shape is exhibited by jets issuing from flat nozzles. Here we predict based on principle that all such flows should evolve their cross-sectional shapes from flat to round (and not the other way) at a critical distance downstream, which is predictable. The principle is that the prevailing flow architecture provides greater access to the flow of momentum from the moving core (plume, jet) to the still surroundings. For turbulent plumes and jets, the transition distance scales with the long dimensions (L) of the two-dimensional (flat) heat sources and nozzles that drive them. For laminar jets, the transition distance scales with L Re, where Re is the Reynolds number based on nozzle velocity and the smaller dimension of the nozzle cross section. These predictions are confirmed by full numerical experiments of the three-dimensional flow fields of turbulent and laminar jets covering the Re range 10-10(4).


Use of seat-belts in Port Moresby.
The number of deaths and serious injuries especially in young people from road traffic accidents is reaching epidemic proportions world-wide, and is especially high in developing countries, with Papua New Guinea (PNG) near the top of the list. A proportion of these deaths and injuries could be prevented by the use of seat-belts. In a study undertaken in Port Moresby the overall belt-wearing rate of front-seat occupants of cars was 11.4%. Small children were often carried unrestrained in the front seat. The projected loss to the country in human and economic terms from these accidents in the remaining years of this century is presented. A strong plea is made to make seat-belt fitting and wearing compulsory in PNG.


Assessing sustainability in real urban systems: the Greater Cincinnati Metropolitan Area in Ohio, Kentucky, and Indiana.
Urban systems have a number of factors (i.e., economic, social, and environmental) that can potentially impact growth, change, and transition. As such, assessing and managing these systems is a complex challenge. While, tracking trends of key variables may provide some insight, identifying the critical characteristics that truly impact the dynamic behavior of these systems is difficult. As an integrated approach to evaluate real urban systems, this work contributes to the research on scientific techniques for assessing sustainability. Specifically, it proposes a practical methodology based on the estimation of dynamic order, for identifying stable and unstable periods of sustainable or unsustainable trends with Fisher Information (FI) metric. As a test case, the dynamic behavior of the City, Suburbs, and Metropolitan Statistical Area (MSA) of Cincinnati was evaluated by using 29 social and 11 economic variables to characterize each system from 1970 to 2009. Air quality variables were also selected to describe the MSA's environmental component (1980-2009). Results indicate systems dynamic started to change from about 1995 for the social variables and about 2000 for the economic and environmental characteristics.


Inactivation of clostridial ferredoxin and pyruvate-ferredoxin oxidoreductase by sodium nitrite.
Clostridial ferredoxin and pyruvate-ferredoxin oxidoreductase activity was investigated after in vitro or in vivo treatment with sodium nitrite. In vitro treatment of commercially available Clostridium pasteurianum ferredoxin with sodium nitrite inhibited ferredoxin activity. Inhibition of ferredoxin activity increased with increasing levels of sodium nitrite. Ferredoxin was isolated from normal C. pasteurianum and Clostridium botulinum cultures and from cultures incubated with 1,000 micrograms of sodium nitrite per ml for 45 min. The activity of in vivo nitrite-treated ferredoxin was decreased compared with that of control ferredoxin. Pyruvate-ferredoxin oxidoreductase isolated from C. botulinum cultures incubated with 1,000 micrograms of sodium nitrite per ml showed less activity than did control oxidoreductase. It is concluded that the antibotulinal activity of nitrite is due at least in part to inactivation of ferredoxin and pyruvate-ferredoxin oxidoreductase.


Effects of formaldehyde inhalation on zinc, copper and iron concentrations in liver and kidney of male rats.
In the present study, adult Wistar albino male rats were exposed to formaldehyde at different periods (subacute and subchronic) and concentrations (5.0 and 10.0 ppm) in order to figure out the changes in the concentration of Zn, Cu and Fe. It was observed that the formaldehyde inhalation caused gradual decline of body weights in the experimental groups when compared with control groups. It was found that subacute (4-week) or subchronic (13-week) exposure to formaldehyde for rats may cause growth retardation. After inhalation procedure, concentration of copper, zinc and iron were determined in liver and kidney tissues of rats using atomic absorption spectrophotometer. In addition, concentrations of Cu, Zn and Fe changed by the effect of formaldehyde in subacute and subchronic groups.


Redistribution and enhanced protein kinase C-mediated phosphorylation of alpha- and gamma-adducin during renal tumor progression.
Tumor promotion/progression is known to be due in part to increased signaling through a variety of mitogenic pathways, including protein kinase C (PKC). To determine whether increased PKC activity could play a role in promotion and progression of renal cancer, we monitored PKC activity in normal and progressively transformed renal neoplasias from Eker rats. Eker rats carry a defect in the tumor suppressor TSC2 gene that predisposes them to renal carcinoma, whereas additional factors influence tumor promotion/progression in accordance with a "two-hit" model. We used the phosphorylation of adducins at Ser-660, a known PKC phosphorylation site, as a reporter for endogenous PKC activity. In normal proximal tubules, total adducin levels (measured with a phosphorylation state-insensitive antibody) were relatively high, whereas pSer660-adducin (measured with a phosphorylation state-sensitive antibody) levels were very low. In comparison, in renal carcinomas, total adducin levels were decreased, and pSer-660-adducin levels were increased. Changes in phosphorylation correlated with changes in localization. In normal tissue, alpha- and gamma-adducin are targeted to the apical and basal membranes of proximal tubules, respectively, implying unique functions for these related proteins. In early lesions (atypical tubules), differential targeting is lost, and both alpha- and gamma-adducins localize to the basal membrane. In more advanced lesions, staining in lateral membranes at cell-cell contacts becomes apparent. Furthermore, in cells that have lost basement membrane contact, plasma membrane targeting is no longer apparent. These changes in adducin expression levels, phosphorylation state, and localization parallel the increased growth potential and dedifferentiation of the progressive tumor phenotypes. These data demonstrate the utility of phosphorylation state-selective antibodies in immunohistochemical applications as reporters of endogenous PKC activity in tissue samples. We also provide the first evidence that increased PKC activity and phosphorylation of important target proteins occurs during progressive transformation in a non-phorbol ester tumor promotion model in vivo.


Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells.
To explore the initial steps by which transplanted mesenchymal stem cells (MSCs) interact with the vessel wall in the course of extravasation, we studied binding of human MSCs to endothelial cells (ECs). In a parallel plate flow chamber, MSCs bound to human umbilical vein ECs (HUVECs) similar to peripheral-blood mononuclear cells (PBMCs) or CD34(+) hematopoietic progenitors at shear stresses of up to 2 dynes/cm(2). This involved rapid extension of podia, rolling, and subsequent firm adhesion that was increased when ECs were prestimulated with TNF-alpha. MSC binding was suppressed when ECs were pretreated with function-blocking anti-P-selectin antibody, and rolling of MSCs was induced on immobilized P-selectin, indicating that P-selectin was involved in this process. Preincubation of HUVECs with anti-VCAM-1 or of MSCs with anti-VLA-4 antibodies suppressed binding of MSCs to HUVECs but did not enhance inhibition by anti-P-selectin, indicating that both P-selectin and VCAM-1 are equally required for this process. Intravital microscopy demonstrated the capacity of MSCs to roll and adhere to postcapillary venules in vivo in a mouse model in a P-selectin-dependent manner. Thus, MSCs interact in a coordinated fashion with ECs under shear flow, engaging P-selectin and VCAM-1/VLA-4.


Rectal fecal impaction treatment in childhood constipation: enemas versus high doses oral PEG.
We hypothesized that enemas and polyethylene glycol (PEG) would be equally effective in treating rectal fecal impaction (RFI) but enemas would be less well tolerated and colonic transit time (CTT) would improve during disimpaction. Children (4-16 years) with functional constipation and RFI participated. One week before disimpaction, a rectal examination was performed, symptoms of constipation were recorded, and the first CTT measurement was started. If RFI was determined, then patients were assigned randomly to receive enemas once daily or PEG (1.5 g/kg per day) for 6 consecutive days. During this period, the second CTT measurement was started and a child's behavior questionnaire was administered. Successful rectal disimpaction, defecation and fecal incontinence frequencies, occurrence of abdominal pain and watery stools, CTTs (before and after disimpaction), and behavior scores were assessed. Ninety-five patients were eligible, of whom 90 participated (male, n = 60; mean age: 7.5 +/- 2.8 years). Forty-six patients received enemas and 44 PEG, with 5 dropouts in each group. Successful disimpaction was achieved with enemas (80%) and PEG (68%; P = .28). Fecal incontinence and watery stools were reported more frequently with PEG (P < .01), but defecation frequency (P = .64), abdominal pain (P = .33), and behavior scores were comparable between groups. CTT normalized equally (P = .85) in the 2 groups. Enemas and PEG were equally effective in treating RFI in children. Compared with enemas, PEG caused more fecal incontinence, with comparable behavior scores. The treatments should be considered equally as first-line therapy for RFI.


Epigenetic variation in asexually reproducing organisms.
The role that epigenetic inheritance can play in adaptation may differ between sexuals and asexuals because (1) the dynamics of adaptation differ under sexual and asexual reproduction and the opportunities offered by epigenetic inheritance may affect these dynamics differently; and (2) in asexual reproduction epigenetic reprogramming mechanisms that are associated with meiosis can be bypassed, which could promote the buildup of epigenetic variation in asexuals. Here, we evaluate current evidence for an epigenetic contribution to adaptation in asexuals. We argue that two aspects of epigenetic variation should have particular relevance for asexuals, namely epigenetics-mediated phenotypic plasticity within and between generations, and heritable variation via stochastic epimutations. An evaluation of epigenetic reprogramming mechanisms suggests that some, but not all, forms of asexual reproduction enhance the likelihood of stable transmission of epigenetic marks across generations compared to sexual reproduction. However, direct tests of these predicted sexual-asexual differences are virtually lacking. Stable transmission of DNA methylation, transcriptomes, and phenotypes from parent to clonal offspring are demonstrated in various asexual species, and clonal genotypes from natural populations show habitat-specific DNA methylation. We discuss how these initial observations can be extended to demonstrate an epigenetic contribution to adaptation.


Bimodal magmatism produced by progressively inhibited crustal assimilation.
The origin of bimodal (mafic-felsic) rock suites is a fundamental question in volcanology. Here we use major and trace elements, high-resolution Sr, Nd and Pb isotope analyses, experimental petrology and thermodynamic modelling to investigate bimodal magmatism at the iconic Carlingford Igneous Centre, Ireland. We show that early microgranites are the result of extensive assimilation of trace element-enriched partial melts of local metasiltstones into mafic parent magmas. Melting experiments reveal the crust is very fusible, but thermodynamic modelling indicates repeated heating events rapidly lower its melt-production capacity. Granite generation ceased once enriched partial melts could no longer form and subsequent magmatism incorporated less fertile restite compositions only, producing mafic intrusions and a pronounced compositional gap. Considering the frequency of bimodal magma suites in the North Atlantic Igneous Province, and the ubiquity of suitable crustal compositions, we propose 'progressively inhibited crustal assimilation' (PICA) as a major cause of bimodality in continental volcanism.


The role of integrins alpha 2 beta 1 and alpha 3 beta 1 in cell-cell and cell-substrate adhesion of human epidermal cells.
We have examined cultures of neonatal human foreskin keratinocytes (HFKs) to determine the ligands and functions of integrins alpha 2 beta 1, and alpha 3 beta 1 in normal epidermal stratification and adhesion to the basement membrane zone (BMZ) in skin. We used three assay systems, HFK adhesion to purified extracellular matrix (ECM) ligands and endogenous secreted ECM, localization of integrins in focal adhesions (FAs), and inhibition of HFK adhesion with mAbs to conclude: (a) A new anti-alpha 3 beta 1 mAb, P1F2, localized alpha 3 beta 1 in FAs on purified laminin greater than fibronectin/collagen, indicating that laminin was the best exogeneous ligand for alpha 3 beta 1. However, in long term culture, alpha 3 beta 1 preferentially codistributed in and around FAs with secreted laminin-containing ECM, in preference to exogenous laminin. Anti-alpha 3 beta 1, mAb P1B5, detached prolonged cultures of HFKs from culture plates or from partially purified HFK ECM indicating that interaction of alpha 3 beta 1 with the secreted laminin-containing ECM was primarily responsible for HFK adhesion in long term culture. (b) In FA assays, alpha 2 beta 1 localized in FAs conincident with initial HFK adhesion to exogenous collagen, but not laminin or fibronectin. However, in inhibition assays, anti-alpha 2 beta 1 inhibited initial HFK adhesion to both laminin and collagen. Thus, alpha 2 beta 1 contributes to initial HFK adhesion to laminin but alpha 3 beta 1 is primarily responsible for long-term HFK adhesion to secreted laminin-containing ECM. (c) Serum or Ca2(+)-induced aggregation of HFKs resulted in relocation of alpha 2 beta 1 and alpha 3 beta 1 from FAs to cell-cell contacts. Further, cell-cell adhesion was inhibited by anti-alpha 3 beta 1 (P1B5) and a new anti-beta 1 mAb (P4C10). Thus, interaction of alpha 3 beta 1 with either ECM or membrane coreceptors at cell-cell contacts may facilitate Ca2(+)-induced HFK aggregation. (d) It is suggested that interaction of alpha 3 beta 1 with a secreted, laminin-containing ECM in cultured HFKs, duplicates the role of alpha 3 beta 1 in basal cell adhesion to the BMZ in skin. Further, relocation of alpha 2 beta 1 and alpha 3 beta 1 to cell-cell contacts may result in detachment of cells from the BMZ and increased cell-cell adhesion in the suprabasal cells contributing to stratification of the skin.


Factor structure, internal consistency and construct validity of the Sheehan Disability Scale in a Spanish primary care sample.
The Sheehan Disability Scale (SDS) is a three-item instrument that measures disability in three inter-related domains: work, family life/home responsibilities and social/leisure activities. The main objective of the present study was to examine the factor structure, reliability and construct validity of the SDS in a wide Spanish sample of primary care (PC) patients. One phase cross-sectional survey. A total of 3815 patients, aged 18 years or older attending PC for a medical visit, were interviewed between October 2005 and March 2006. The interviews included the Structured Clinical Interview for DSM-IV Axis I Disorders for depressive and anxiety disorders, the Mini-International Neuropsychiatric Interview for the rest of mental disorders, a medical conditions checklist, the 2.0 version of the 12-item Short-Form Health Survey (SF-12) for measuring quality of life and the SDS. The principal component analysis and the subsequent confirmatory factor analysis indicated that the SDS is one-dimensional (normed fit index = 0.990, non-normed fit index = 0.987, comparative fit index = 0.991, goodness-of-fit index = 0.993, standardized root mean-square residual = 0.037, root mean-square error of approximation = 0.053). The internal consistency of the scale was good (α = 0.83) and it was significantly associated with the physical and mental component of the SF-12. Concerning discriminative validity, patients with major depression or panic disorder scored higher on the SDS than patients with chronic medical conditions or with no chronic pathology. We also found that a cut-off point of 8 in the SDS adequately discriminated between patients with and without depression (area under the curve = 0.814, sensitivity = 81.60%, specificity = 70.60%). The SDS seems a reliable, valid and useful clinical tool for measuring disability in Spanish PC patients.


Studies of single aerosol particles containing malonic acid, glutaric acid, and their mixtures with sodium chloride. II. Liquid-state vapor pressures of the acids.
The vapor pressures of two dicarboxylic acids, malonic acid and glutaric acid, are determined by the measurement of the evaporation rate of the dicarboxylic acids from single levitated particles. Two laboratory methods were used to isolate single particles, an electrodynamic balance and optical tweezers (glutaric acid only). The declining sizes of individual aerosol particles over time were followed using elastic Mie scattering or cavity enhanced Raman scattering. Experiments were conducted over the temperature range of 280-304 K and a range of relative humidities. The subcooled liquid vapor pressures of malonic and glutaric acid at 298.15 K were found to be 6.7(-1.2)(+2.6) x 10(-4) and 11.2(-4.7)(+9.6) x 10(-4) Pa, respectively, and the standard enthalpies of vaporization were respectively 141.9 ± 19.9 and 100.8 ± 23.9 kJ mol(-1). The vapor pressures of both glutaric acid and malonic acid in single particles composed of mixed inorganic/organic composition were found to be independent of salt concentration within the uncertainty of the measurements. Results are compared with previous laboratory determinations and theoretical predictions.


Effects of IL-1β-Blocking Therapies in Type 2 Diabetes Mellitus: A Quantitative Systems Pharmacology Modeling Approach to Explore Underlying Mechanisms.
Recent clinical studies suggest sustained treatment effects of interleukin-1β (IL-1β)-blocking therapies in type 2 diabetes mellitus. The underlying mechanisms of these effects, however, remain underexplored. Using a quantitative systems pharmacology modeling approach, we combined ex vivo data of IL-1β effects on β-cell function and turnover with a disease progression model of the long-term interactions between insulin, glucose, and β-cell mass in type 2 diabetes mellitus. We then simulated treatment effects of the IL-1 receptor antagonist anakinra. The result was a substantial and partly sustained symptomatic improvement in β-cell function, and hence also in HbA1C, fasting plasma glucose, and proinsulin-insulin ratio, and a small increase in β-cell mass. We propose that improved β-cell function, rather than mass, is likely to explain the main IL-1β-blocking effects seen in current clinical data, but that improved β-cell mass might result in disease-modifying effects not clearly distinguishable until >1 year after treatment.


Anemia and its relationship to clinical outcome in heart failure.
Anemia is often observed in patients with chronic heart failure (CHF), but its implications for patient outcomes are not well understood. The goal of this study was to investigate the relationship between anemia, severity of CHF, and clinical outcomes. Hemoglobin concentration (Hb) was measured in 912 subjects with CHF enrolled in the Randomized Etanercept North American Strategy to Study Antagonism of Cytokines (RENAISSANCE) trial. In a subgroup of 69 subjects, cardiac MRI was performed at randomization and 24 weeks later. Anemia (Hb < or =12.0 g/dL) was present in 12% of subjects. Cox regression analysis indicated that for every 1-g/dL-higher baseline Hb, the risk of mortality was 15.8% lower (P=0.0009) and the risk of mortality or hospitalization for heart failure was 14.2% lower (P<0.0001). Greater CHF severity was associated with significantly lower Hb concentrations. An increase in Hb over time was associated with a decrease in left ventricular mass and lower mortality, whereas a decrease in Hb over time was associated with an increase in left ventricular mass and higher mortality. In multivariate analysis, anemia remained a significant, independent predictor of death or hospitalization for heart failure, with both outcomes being significantly higher in all NYHA classes. Anemia is frequently present in patients with CHF. Lower Hb is associated with greater disease severity, a greater left ventricular mass index, and higher hospitalization and mortality rates.