[Ectopic acromegaly due to a bronchial carcinoid].
Tumours that cause ectopic acromegaly can do so through the secretion of GH or GHRH. One hundred cases of ectopic acromegaly due to secretion of GHRH have been described. Given the rarity of this pathology, we present a clinical case with the aim of contributing our diagnostic-therapeutic experience and the subsequent follow-up. We present the case of a patient with acromegaloid physical features that had evolved over several years. Concomitantly, he also presented other accompanying symptoms that were suggestive of a possible bronchial origin. Facing the clinical suspicion of acromegaly, we opted to confirm it biochemically and subsequently through image study. A hypophysary origin was ruled out, so we carried out screening for a bronchial neuroendocrine and/or gastrointestinal tumor as they are the most frequent localizations. The treatment of choice was surgical resection.


Clot Retraction: Cellular Mechanisms and Inhibitors, Measuring Methods, and Clinical Implications.
Platelets have important functions in hemostasis. Best investigated is the aggregation of platelets for primary hemostasis and their role as the surface for coagulation leading to fibrin- and clot-formation. Importantly, the function of platelets does not end with clot formation. Instead, platelets are responsible for clot retraction through the concerted action of the activated αIIbβ3 receptors on the surface of filopodia and the platelet's contractile apparatus binding and pulling at the fibrin strands. Meanwhile, the signal transduction events leading to clot retraction have been investigated thoroughly, and several targets to inhibit clot retraction have been demonstrated. Clot retraction is a physiologically important mechanism allowing: (1) the close contact of platelets in primary hemostasis, easing platelet aggregation and intercellular communication, (2) the reduction of wound size, (3) the compaction of red blood cells to a polyhedrocyte infection-barrier, and (4) reperfusion in case of thrombosis. Several methods have been developed to measure clot retraction that have been based on either the measurement of clot volume or platelet forces. Concerning the importance of clot retraction in inborn diseases, the failure of clot retraction in Glanzmann thrombasthenia is characterized by a bleeding phenotype. Concerning acquired diseases, altered clot retraction has been demonstrated in patients with coronary heart disease, stroke, bronchial asthma, uremia, lupus erythematodes, and other diseases. However, more studies on the diagnostic and prognostic value of clot retraction with methods that have to be standardized are necessary.


Psychosocial interventions for the diabetic patient.
Diabetes usually requires substantial life-long self-management by the patient. Psychological factors and the patient's health beliefs are important determinants of self-care behavior. Education has a modest influence on generating better self-care, but psychologically based interventions are clearly more effective. This review gives an overview of these interventions with some discussion of their basis in psychological theory. Some labels such as cognitive behavioral therapy and family therapy include a wide range of approaches. Randomized trials have generally produced improvement in measures of psychological well-being, but improved glycemic control has been more elusive. The influence on behavior can be very dependent on the individual therapist. Only a few trials have managed to sustain improvement in glycosylated hemoglobin beyond a year. Not all patients are prepared to engage and accept these forms of therapeutic intervention. We are still some way from moving psychological management from the trial situation into the diabetic clinic.


Effects of altered prenatal hormonal environment on expression of autoimmune disease in NZB/NZW mice.
F1 hybrid New Zealand Black (NZB) x New Zealand White (NZM) (NZB/NZW) mice spontaneously develop an autoimmune disease analogous to systemic lupus erythematosus (SLE). Testosterone experts a powerful suppressive effect on this disorder in adult NZB/NZW mice. A series of experiments was designed to determine if disease would also be suppressed by exposing fetal NZB/NZW mice to increased testosterone. A model was developed in which NZB dams carrying NZB/NZW fetuses were treated with testosterone in a dose adequate to masculinize the external genitalia in female fetuses. NZB/NZW mice that were derived from testosterone-treated dams and control NZB/NZW offspring were followed in a longevity study and had serial assays to assess development of SLE. Additional experiments were carried out to measure lymphocyte subsets and responses to mitogens. Results were compared with F1 hybrid offspring of C57BL/6 dams crossed with DBA/2 males, which are not autoimmune and do not develop SLE. Spleen cells from these groups were tested for Thy 1.2, CD4, CD8, and IgM receptors, and for responses to the mitogens Concanavalin A (ConA) and lipopolysaccharide. Control male NZB/NZW fetuses had unexpectedly high serum estradiol, which decreased significantly with maternal testosterone treatment. The testosterone-exposed male NZB/NZW fetuses developed into adults that lived longer than male NZB/NZW controls. Testosterone treatment of the dam was associated with elevated terminal anti-DNA levels but did not alter markers of renal diseases in adult NZB/NZW mice of either sex. Testosterone-exposed NZB/NZW females had altered T-lymphocyte subsets and testosterone-exposed males had increased response to ConA compared to controls. In male NZB/NZW fetuses whose mothers were administered testosterone, the naturally high level of circulating estradiol observed in untreated male fetuses was decreased significantly. This decrease was associated with an increase in longevity. This unique observation has important implications for fetal exposure to endocrine disruptors in the environment.


Von Willebrand's disease in the German shepherd dog.
Two litters of German shepherd dogs were evaluated for a haemorrhagic tendency that was characterised by excessive bleeding from the umbilicus at birth, haemorrhage and haematoma formation at vaccination, excessive bruising, and lameness due to haemarthrosis. Platelet counts, clotting times and Von Willebrand's factor (VWF) assays were assessed in all dogs. Factor VIII determination was performed in 1 puppy and its parents. Based on the clotting times and VWF assay, 6 puppies (4 male and 2 female) showed type I Von Willebrand's disease (VWD), 5 (4 male and 1 female) possible type II VWD, and 4 were unaffected. One puppy with possible type II VWD had very low factor VIII activity; its sire had a normal factor activity, whereas the dam was in the low-normal range. This article reports type I and possible type II VWD in 2 related litters of German shepherd dogs, the latter being rare in German shepherd dogs.


Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10.
A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.


Pathophysiological relevance of selenium.
The essential trace element selenium (Se) is a central constituent of 50-70 selenoprotein variants encoded by 25 human genes. Incorporation of the 21st proteinogenic amino acid selenocysteine occurs cotranslationally and requires peculiar features of the corresponding mRNA, a dedicated tRNA and a complex translational machinery for decoding UGA in this context. Thyroid hormone (TH) synthesis and protection of the thyroid gland from H2O2 and reactive oxygen species derived therefrom as well as TH activation and inactivation by deiodinase enzymes requires Se. Altered Se status has been associated with benign (goiter and autoimmune thyroid disease) and malignant thyroid maladies and several but not all Se supplementation studies reported on beneficial effects. Whether adequate or therapeutic Se supply is advantageous for the functional unit of the thyroid, the angiofollicular unit, or for the immune system or for both requires more controlled clinical trials and further in vitro and animal experimental studies. Development of proper diagnostic tests to monitor Se status of the thyroid gland and identification and validation of clinically useful thyroid-related biomarkers for Se action on the largest human endocrine gland are required. Several knockout and transgenic mouse models have revealed valuable insight into the role of Se and selenoprotein function for the thyroid. Recently, first human mutations in genes encoding a selenoprotein and a component involved in selenoprotein biosynthesis have been identified, the latter with marked impairment of TH homeostasis.


The Impact of Environmental Design on Teamwork and Communication in Healthcare Facilities: A Systematic Literature Review.
The purpose of this systematic review is to investigate the current knowledge about the impact of healthcare facility design on teamwork and communication by exploring the relevant literature. Teamwork and communication are behavioral factors that are impacted by physical design. However, the effects of environmental factors on teamwork and communication have not been investigated extensively in healthcare design literature. There are no published systematic reviews on the current topic. Searches were conducted in PubMed and Google Scholar databases in addition to targeted design journals including Health Environmental Research & Design, Environment and Behavior, Environmental Psychology, and Applied Ergonomics. Inclusion criteria were (a) full-text English language articles related to teamwork and communication and (b) involving any healthcare built environment and space design published in peer-reviewed journals between 1984 and 2017. Studies were extracted using defined inclusion and exclusion criteria. In the first phase, 26 of the 195 articles most relevant to teamwork and 19 studies of the 147 were identified and reviewed to understand the impact of communication in healthcare facilities. The literature regarding the impact of built environment on teamwork and communication were reviewed and explored in detail. Eighteen studies were selected and succinctly summarized as the final product of this review. Environmental design, which involves nurses, support staff, and physicians, is one of the critical factors that promotes the efficiency of teamwork and collaborative communication. Layout design, visibility, and accessibility levels are the most cited aspects of design which can affect the level of communication and teamwork in healthcare facilities.


Influence of high concentration monovalent cations on the protein partitioning in polyethyleneglycol 1500-phosphate aqueous two-phase systems.
The influence of chloride salts of Na+, Rb+ and Cs+ at concentrations from 0.15 to 1.2M was studied with bovine albumin, trypsin, ovoalbumin and lysozyme partitioning in an aqueous two-phase system formed by polyethyleneglycol 1500 and potassium phosphate at pH 7.4. Monovalent cations favoured the protein transfer to the polyethyleneglycol rich phase in the following order: Rb+ > Na+ > Cs+. Structure making cations as Na+ induced a poor loss of structured water, producing little diminution of the molar partial specific volume of polyethyleneglycol, while Rb+ and Cs+, structure breaking cations, induced a significant decrease in the specific volume of the polyethylene glycol. The increase of available solution free volume in the top phase favours the protein transfer to the polyethyleneglycol rich phase. Na+ and Rb+ induced a slight decrease in the alpha helix content of the proteins, while Cs+ increased the secondary structure for all the proteins. All the cations induced a decrease in the hydrophobic surface of the proteins, this effect was more significant in the presence of Cs+.


Exercise myocardial perfusion SPECT in patients without known coronary artery disease: incremental prognostic value and use in risk stratification.
We evaluated the incremental prognostic value, the role in risk stratification, and the impact on patient management of myocardial perfusion single-photon emission computed tomography (SPECT) in a population of patients without prior myocardial infarction, catheterization, or revascularization. We examined 2200 consecutive patients who at the time of their dual-isotope SPECT had not undergone catheterization, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty and had no known history of previous myocardial infarction. Follow-up was performed at a mean of 566 +/- 142 days (97% complete) for hard events (cardiac death and myocardial infarction) and for referral to cardiac catheterization or revascularization within 60 days after nuclear testing. Examination of clinical, exercise, and nuclear models by use of pre-exercise tolerance test (ETT), post-ETT, and nuclear information using a stepwise Cox proportional hazards model and receiver-operating characteristic curve analysis revealed that nuclear testing added incremental prognostic value after inclusion of the most predictive clinical and exercise variables (global chi2 = 12 for clinical variables; 31 for clinical + exercise variables; 169 for nuclear variables; gain in chi2, P < .0001 for all; receiver-operating characteristic areas: 0.66 +/- 0.04 for clinical, 0.73 +/- 0.04 for clinical + exercise variables, 0.87 +/- 0.03 for nuclear variables, P = .03 for gain in area with exercise variables; P < .001 for increase with nuclear variables). Multiple logistic regression analysis revealed that scan information contributed 95% of the information regarding referral to catheterization with further additional information provided by presenting symptoms and exercise-induced ischemia. Referral rates to early catheterization and revascularization paralleled the hard event rates in all scan categories - very low referral rates in patients with normal scans and significant increases in referral rates as a function of worsening scan results. Even after stratification by clinical and exercise variables such as the Duke treadmill score, pre- and post-ETT likelihood of coronary artery disease, presenting symptoms, sex, and age, the nuclear scan results further risk-stratified the patient subgroups, thus demonstrating clinical incremental value. In a patient population with no evidence of previous coronary artery disease at overall low risk (1.8% hard event rate), myocardial perfusion SPECT adds incremental prognostic information and risk-stratifies patients even after clinical and exercise information is known. It appears that referring physicians use this test in an appropriate manner in selecting patients to be referred to catheterization or revascularization.


The use of cyclosporin A and prednisone in cadaver kidney transplantation.
Eighteen patients were treated with primary cadaveric renal transplantation using cyclosporin A therapy, and four more patients undersent cadaveric retransplantation. Eleven of the 22 recipients were conditioned with lymphoid depletion before transplantation, using thoracic duct drainage or lymphapheresis for two to eight and one-half weeks. Cyclosporin A was begun a few hours before grafting. The other 11 patients were pretreated with cyclosporin A for from one day to 18 days. After transplantation, the majority of patients in both subgroups of 11 had rejection develop, but in most, the immunologic process was readily controlled with relatively small dosages of prednisone. After follow-up periods of two to four and one-half months, one patient has died of the complications of a coronary artery reconstruction that was not related to the transplantation. Another graft was lost from rejection, and a third organ was removed because of ureteral necrosis. Nineteen of the original 22 cadaveric kidneys are functioning, including 17 of the 18 kidneys given to patients who were undergoing transplantation for the first time. The only loss in the latter group of 18 patients was in the patient who died after an open heart operation. Results of these studies have shown that cyclosporin A is a superior and safe immunosuppressive drug but that, for optimal use in cadaveric transplantation, it usually should not be given alone. Steroid therapy greatly amplified the value of cyclosporin A. Unless major delayed morbidity develops which is not obvious so far, this drug combination should permit revolutionary advances in the transplantation of all organs. Other adjuncts to the cyclosporin A-steroid combination, including lymphoid depletion techniques, will require further investigation.


Antioxidant and hepatoprotective effects of A. cerana honey against acute alcohol-induced liver damage in mice.
A. cerana honey, gathered from Apis cerana Fabricius (A. cerana), has not been fully studied. Samples of honey originating from six geographical regions (mainly in the Qinling Mountains of China) were investigated to determine their antioxidant and hepatoprotective effects against acute alcohol-induced liver damage. The results showed that A. cerana honeys from the Qinling Mountains had high total phenolic contents (345.1-502.1mgGAkg-1), ascorbic acid contents (153.8-368.4mgkg-1), and strong antioxidant activities in DPPH radical scavenging activity assays (87.5-136.2IC50mgmL-1), ferric reducing antioxidant powers (191.8-317.4mgTroloxkg-1), and ferrous ion-chelating activities (27.5-35.5mgNa2EDTAkg-1). Pretreatment with A. cerana honey (Qinling Mountains) at 5, 10, or 20gkg-1 twice daily for 12weeks significantly inhibited serum lipoprotein oxidation and increased serum radical absorbance capacity (ORAC) (P<0.05). Moreover, A. cerana honey inhibited acute alcohol-induced increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum (P<0.05), reduced the production of hepatic malondialdehyde (MDA) (P<0.05), and promoted superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities (P<0.05). More importantly, it also remarkably inhibited the level of TGF-β1 in the serum and liver (P<0.05). The results of this study indicate that administration of A. cerana honey prevents acute alcohol-induced liver damage likely because of its antioxidant properties and ability to prevent oxidative stress.


Expression and purification of Arg196 and Lys272 mutants of mevalonate kinase from Methanococcus jannaschii.
In microorganisms and plants, mevalonate kinase is involved in the biosynthesis of isoprenoid derivatives, one of the largest groups of natural products. We subcloned the gene of mevalonate kinase from Methanococcus jannaschii into a bacterial expression vector pLM1 with six continuous histidine codons attached to the 5' end of the gene. A variety of mutant expression plasmids including pMMK(R196K), pMMK(R196Q), pMMK(R196V), pMMK(K272R), and pMMK(K272A) have been constructed using site-directed mutagenesis. The wild-type protein and mutants were overexpressed and purified with a nickel HiTrap chelating metal affinity column to homogeneity. CD spectroscopy of wild-type protein and mutants indicates that none of the above mutations induces significant secondary structural changes. The results from kinetic studies showed that Arg196 is an essential residue for the function of the enzyme. Kinetic studies of Lys272 mutants indicate that salt bridge Lys272-Glu14 plays an important role in maintaining the active site microenvironment that is essential for catalytic activity of the enzyme.


Efficient Computation of Structural and Electronic Properties of Halide Perovskites Using Density Functional Tight Binding: GFN1-xTB Method.
In recent years, metal halide perovskites (MHPs) for optoelectronic applications have attracted the attention of the scientific community due to their outstanding performance. The fundamental understanding of their physicochemical properties is essential for improving their efficiency and stability. Atomistic and molecular simulations have played an essential role in the description of the optoelectronic properties and dynamical behavior of MHPs, respectively. However, the complex interplay of the dynamical and optoelectronic properties in MHPs requires the simultaneous modeling of electrons and ions in relatively large systems, which entails a high computational cost, sometimes not affordable by the standard quantum mechanics methods, such as density functional theory (DFT). Here, we explore the suitability of the recently developed density functional tight binding method, GFN1-xTB, for simulating MHPs with the aim of exploring an efficient alternative to DFT. The performance of GFN1-xTB for computing structural, vibrational, and optoelectronic properties of several MHPs is benchmarked against experiments and DFT calculations. In general, this method produces accurate predictions for many of the properties of the studied MHPs, which are comparable to DFT and experiments. We also identify further challenges in the computation of specific geometries and chemical compositions. Nevertheless, we believe that the tunability of GFN1-xTB offers opportunities to resolve these issues and we propose specific strategies for the further refinement of the parameters, which will turn this method into a powerful computational tool for the study of MHPs and beyond.


Tapered silicon core fibers with nano-spikes for optical coupling via spliced silica fibers.
Reported here is the fabrication of tapered silicon core fibers possessing a nano-spike input that facilitates their seamless splicing to conventional single mode fibers. A proof-of-concept 30 µm cladding diameter fiber-based device is demonstrated with nano-spike coupling and propagation losses below 4 dB and 2 dB/cm, respectively. Finite-element-method-based simulations show that the nano-spike coupling losses could be reduced to below 1 dB by decreasing the cladding diameters down to 10 µm. Such efficient and robust integration of the silicon core fibers with standard fiber devices will help to overcome significant barriers for all-fiber nonlinear photonics and optoelectronics.


Two types of achalasia in the same patient. Is this really the case? An unusual finding in a single study.
Within the functional tests, the High Resolution Manometry has been a great improvement in the diagnosis of esophageal motor disorders, especially those that cause obstruction or difficulty for the normal progress of the alimentary content. We present the case of a patient with dysphagia to which a manometry is performed in the diagnostic process, where the presence of two types of Acalasia is present in the same tracing.


The Effectiveness of Different Treatment Modalities of Cutaneous Angiosarcoma: Results From Meta-Analysis and Observational Data From SEER Database.
Cutaneous angiosarcoma (cAS) is an aggressive vascular tumor that originates from vascular or lymphatic epithelial cells. To date, the cAS literature has been limited in a small number with single-center experiences or reports due to its rarity and the optimal treatment strategy is still in dispute. This study aimed to conduct a systematic review and compare the effect of available treatments retrieved from observational studies and Surveillance, Epidemiology, and End Results (SEER) program. The authors performed a systematic review in the PubMed, Embase and MEDLINE database identifying the researches assessing the treatment for cAS patients. Clinical and treatment information of patients who had been diagnosed with a primary cAS were also obtained from the SEER program. Thirty-two studies were eligible but only 5 of which with 276 patients were included in meta-analysis since the unclear or unavailable information. The risk ratio of 5-year death for surgery, surgery with radiotherapy and surgery with chemotherapy were 0.84, 0.96, and 0.69. Meanwhile, in SEER database, there are 291 metastatic and 437 localized patients with cAS. The localized patients receiving surgery showed a significantly worse overall survival result when compared with the surgery combined with RT: hazard ratio: 1.6, 95% confidential interval: 1.05, 2.42, P = 0.03. In conclusion, our study provided a detailed picture of the effectiveness of present treatments for localized and metastatic cAS patients. The CT could be inappropriate in localized patients. For metastatic patients, the surgery combined RT was recommended compared with surgery alone since its enhanced OS prognosis. Yet, more novel-designed clinical trials with specific targeted populations and rigorous conducting are needed for a solid conclusion on which would be a better treatment strategy.


Ectoparasite performance when feeding on reproducing mammalian females: an unexpected decrease when on pregnant hosts.
Reproduction is an energy-demanding activity in mammalian females, with increased energy requirements during pregnancy and, especially, during lactation. To better understand the interactions between parasitism and host reproduction, we investigated feeding and reproductive performance of fleas (Xenopsylla ramesis) parasitizing non-reproducing, pregnant or lactating gerbilline rodents (Meriones crassus). Based on energetic considerations, we predicted that feeding and reproductive performance of fleas would be lowest on non-breeding females, moderate on pregnant females and highest on lactating females. We estimated feeding performance of the fleas via absolute and mass-specific bloodmeal size and reproductive performance via egg production and latency to peak oviposition. Host reproductive status had no effect on either absolute or mass-specific bloodmeal size or the day of peak oviposition, but significantly affected the daily number of eggs produced by a female flea. Surprisingly, and contrary to our predictions, egg production of fleas fed on pregnant rodents was significantly lower than that of fleas on non-reproducing and lactating rodents, while no difference in egg production between fleas feeding on non-reproducing and lactating hosts was found. Our results suggest that differences in parasite reproduction when feeding on hosts of different reproductive status are not associated with the different energy requirements of the hosts at non-breeding, pregnancy and lactation but rather with variation in hormonal and/or immune status during these periods.


Associations between Serum Omega-3 Fatty Acid Levels and Cognitive Functions among Community-Dwelling Octogenarians in Okinawa, Japan: The KOCOA Study.
Epidemiological studies have found frequent consumption of fatty fish is protective against cognitive decline. However, the association between circulating omega-3 polyunsaturated fatty acid (PUFA) levels and cognitive functions among the oldest old is not well known. To examine the association between serum PUFA levels and cognitive function among community-dwelling, non-demented elderly aged over 80 years old. The data came from the Keys to Optimal Cognitive Aging (KOCOA) study; an ongoing cohort of relatively healthy volunteers aged over 80 years old, living in Okinawa, Japan. One hundred eighty five participants (mean age 84.1±3.4 years) assessed in 2011 who were free from frank dementia (defined as Clinical Dementia Rating <1.0) were used for the current cross-sectional study. We examined whether serum omega-3 PUFAs (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), arachidonic acid (AA), EPA/AA ratio, DHA/AA ratio, and DHA+EPA are associated with (1) age and (2) global cognitive function (Japanese MMSE) and executive function (Verbal Fluency Letter). Data was analyzed univariately by t-test and multivariately by cumulative logistic regression models controlling for age, gender, years of education, obesity, hypertension, diabetes, and dyslipidemia. Serum DHA levels decreased with increasing age (p = 0.04). Higher global cognitive function was associated with higher levels of serum EPA (p = 0.03) and DHA + EPA (p = 0.03) after controlling for confounders. Higher serum EPA and DHA + EPA levels were independently associated with better scores on global cognitive function among the oldest old, free from dementia. Longitudinal follow-up studies are warranted.


Hypercrosslinked phenolic polymers with well-developed mesoporous frameworks.
A soft chemistry synthetic strategy based on a Friedel-Crafts alkylation reaction is developed for the textural engineering of phenolic resin (PR) with a robust mesoporous framework to avoid serious framework shrinkage and maximize retention of organic functional moieties. By taking advantage of the structural benefits of molecular bridges, the resultant sample maintains a bimodal micro-mesoporous architecture with well-preserved organic functional groups, which is effective for carbon capture. Moreover, this soft chemistry synthetic protocol can be further extended to nanotexture other arene-based polymers with robust frameworks.


The genetic structure of Aedes aegypti populations is driven by boat traffic in the Peruvian Amazon.
In the Americas, as in much of the rest of the world, the dengue virus vector Aedes aegypti is found in close association with human habitations, often leading to high population densities of mosquitoes in urban settings. In the Peruvian Amazon, this vector has been expanding to rural communities over the last 10-15 years, but to date, the population genetic structure of Ae. aegypti in this region has not been characterized. To investigate the relationship between Ae. aegypti gene flow and human transportation networks, we characterized mosquito population structure using a panel of 8 microsatellite markers and linked results to various potential mechanisms for long-distance dispersal. Adult and immature Ae. aegypti (>20 individuals per site) were collected from Iquitos city and from six neighboring riverine communities, i.e., Nauta, Indiana, Mazan, Barrio Florida, Tamshiaco, and Aucayo. FST statistics indicate significant, but low to moderate differentiation for the majority of study site pairs. Population structure of Ae. aegypti is not correlated with the geographic distance between towns, suggesting that human transportation networks provide a reasonable explanation for the high levels of population mixing. Our results indicate that Ae. aegypti gene flow among sub-populations is greatest between locations with heavy boat traffic, such as Iquitos-Tamshiaco and Iquitos-Indiana-Mazan, and lowest between locations with little or no boat/road traffic between them such as Barrio Florida-Iquitos. Bayesian clustering analysis showed ancestral admixture among three genetic clusters; no single cluster was exclusive to any site. Our results are consistent with the hypothesis that human transportation networks, particularly riverways, are responsible for the geographic spread of Ae. aegypti in the Peruvian Amazon. Our findings are applicable to other regions of the world characterized by networks of urban islands connected by fluvial transport routes.


[Has the discovery of Helicobacter pylori actually made a revolution in gastroenterology?].
Part 1 of this paper presents a brief description of the results of 25 year investigations of H. pylori infection and its contribution to the development of gastroduodenal pathology (chronic hepatitis, ulcer disease, stomach cancer, gastric maltoma) with reference to its diagnostics, strategy and efficacy of eradication therapy. Part 2 contains arguments and facts that contradict opinions in favour of the leading role of H. pylori infection in pathogenesis of major gastro-duodenal disorders as well as results of the studies of normal and anomalous gastric mucosal microflora comprising numerous bacteria, besides H. pylori, exhibiting such properties as adhesiveness, invasiveness (unlike H. pylori), virulence, and urease activity. The causes behind the failure of eradication therapy are discussed with reference to the decrease of its effectiveness to the critical level attributable largely to misjudgements of the authors of Maastricht recommendations.


Regulation of Opsin Gene Expression by DNA Methylation and Histone Acetylation.
One important role of epigenetic regulation is controlling gene expression in development and homeostasis. However, little is known about epigenetics' role in regulating opsin expression. Cell cultures (HEK 293, Y79, and WERI) producing different levels of opsins were treated with 5-aza-2'-deoxycytidine (5-Aza-dc) and/or sodium butyrate (SB) or suberoylanilide hydroxamic acid (SAHA) for 72 h. Global DNA methylation, site-specific methylation, and expressions of opsins were measured by LUMA assay, bisulfite pyrosequencing, and qPCR, respectively. Mouse retinal explants from wild-type P0/P1 pups were ex vivo cultured with/without 5-Aza-dc or SAHA for 6 days. The morphology of explants, DNA methylation, and expressions of opsins was examined. The drugs induced global DNA hypomethylation or increased histone acetylation in cells, including DNA hypomethylation of rhodopsin (RHO) and L-opsin (OPN1LW) and a concomitant increase in their expression. Further upregulation of RHO and/or OPN1LW in HEK 293 or WERI cells was observed with 5-Aza-dc and either SB or SAHA combination treatment. Mouse retinal explants developed normally but had drug-dependent differential DNA methylation and expression patterns of opsins. DNA methylation and histone acetylation directly regulate opsin expression both in vitro and ex vivo. The ability to manipulate opsin expression using epigenetic modifiers enables further study into the role of epigenetics in eye development and disease.


Practice management: observations, issues, and empirical evidence.
The primary objective of this study is to provide objective, empirical, evidence-based practice management information. This is a hitherto under-researched area of considerable interest for both the practitioner and educator. A questionnaire eliciting a mix of structured and free text responses was administered to a random sample of 480 practitioners who are members of the American Academy of Periodontology. Potential respondents not in private practice were excluded and the next listed person substituted. The results provide demographic and descriptive information about some of the main issues and problems facing practice managers, central to which are information technology (IT), financial, people management, and marketing. Human resource and marketing management appear to represent the biggest challenges. Periodontists running practices would prefer more information, development, and support in dealing with IT, finance, marketing, and people management. The empirical evidence reported here suggests that although tailored educational programs on key management issues at both undergraduate and postgraduate levels have become ubiquitous, nevertheless some respondents seek further training opportunities. Evidence-based practice management information will be invaluable to the clinician considering strategic and marketing planning, and also for those responsible for the design and conduct of predoctoral and postdoctoral programs.


Monitoring the acetohydroxy acid synthase reaction and related carboligations by circular dichroism spectroscopy.
Acetohydroxy acid synthase (AHAS) and related enzymes catalyze the production of chiral compounds [(S)-acetolactate, (S)-acetohydroxybutyrate, or (R)-phenylacetylcarbinol] from achiral substrates (pyruvate, 2-ketobutyrate, or benzaldehyde). The common methods for the determination of AHAS activity have shortcomings. The colorimetric method for detection of acyloins formed from the products is tedious and does not allow time-resolved measurements. The continuous assay for consumption of pyruvate based on its absorbance at 333 nm, though convenient, is limited by the extremely small extinction coefficient of pyruvate, which results in a low signal-to-noise ratio and sensitivity to interfering absorbing compounds. Here, we report the use of circular dichroism spectroscopy for monitoring AHAS activity. This method, which exploits the optical activity of reaction products, displays a high signal-to-noise ratio and is easy to perform both in time-resolved and in commercial modes. In addition to AHAS, we examined the determination of activity of glyoxylate carboligase. This enzyme catalyzes the condensation of two molecules of glyoxylate to chiral tartronic acid semialdehyde. The use of circular dichroism also identifies the product of glyoxylate carboligase as being in the (R) configuration.


Correlation of cognitive and social outcomes among children with autism spectrum disorder in a randomized trial of behavioral intervention.
Although social impairments are considered the hallmark deficit of autism, many behavioral intervention studies rely on cognitive functioning as a primary outcome. Fewer studies have examined whether changes in cognition are associated with changes in social functioning. This study examined whether cognitive gains among 192 students from 47 kindergarten-through-second-grade autism support classrooms participating in a year-long behavioral intervention study were associated with gains in social functioning. Children's gains in cognitive ability were modestly associated with independent assessors' and teachers' evaluations of social functioning but were not associated with changes in parent ratings. Observed social gains were not commensurate with gains in cognition, suggesting the need both for interventions that directly target social functioning and relevant field measures of social functioning.


LOV to BLUF: flavoprotein contributions to the optogenetic toolkit.
Optogenetics is an emerging field that combines optical and genetic approaches to non-invasively interfere with cellular events with exquisite spatiotemporal control. Although it arose originally from neuroscience, optogenetics is widely applicable to the study of many different biological systems and the range of applications arising from this technology continues to increase. Moreover, the repertoire of light-sensitive proteins used for devising new optogenetic tools is rapidly expanding. Light, Oxygen, or Voltage sensing (LOV) and Blue-Light-Utilizing flavin adenine dinucleotide (FAD) (BLUF) domains represent new contributors to the optogenetic toolkit. These small (100-140-amino acids) flavoprotein modules are derived from plant and bacterial photoreceptors that respond to UV-A/blue light. In recent years, considerable progress has been made in uncovering the photoactivation mechanisms of both LOV and BLUF domains. This knowledge has been applied in the design of synthetic photoswitches and fluorescent reporters with applications in cell biology and biotechnology. In this review, we summarize the photochemical properties of LOV and BLUF photosensors and highlight some of the recent advances in how these flavoproteins are being employed to artificially regulate and image a variety of biological processes.


Lewis acidity enhancement of triarylborane by appended phosphine oxide groups.
A series of mono-, di-, and tri-phosphine oxide substituted triarylboranes, Mes2BAr (1), MesBAr2 (2), and BAr3 (3) (Ar = 4-(Ph2PO)-2,6-Me2-C6H2) were prepared to investigate the effect of a phosphine oxide group (Ph2PO) on Lewis acidity enhancement of triarylboranes. The X-ray crystal structure of 3 revealed peripheral decoration of Ph2PO groups with a C3-axis perpendicular to the trigonal boron center. UV/Vis absorption and PL spectra indicated a significant contribution of π(Mes or phenylene) → pπ(B) charge transfer in the lower-energy electronic transition. The reduction potential measured by cyclic voltammetry showed apparent LUMO stabilization by introduction of phosphine oxide groups, the extent of which gradually increased with the increasing number of phosphine oxide groups. Lewis acidity enhancement was also supported by the gradual increase in fluoride ion affinity in the order 3 > 2 > 1. Theoretical calculations suggest that introduction of a Ph2PO group into a triarylborane significantly enhances the Lewis acidity of the boron center via an inductive electron-withdrawing effect and this effect is additive for multiple phosphine oxide groups.


Effect of the type of ion exchange membrane on performance, ion transport, and pH in biocatalyzed electrolysis of wastewater.
Previous studies have shown that the application of cation exchange membranes (CEMs) in bioelectrochemical systems running on wastewater can cause operational problems. In this paper the effect of alternative types of ion exchange membrane is studied in biocatalyzed electrolysis cells. Four types of ion exchange membranes are used: (i) a CEM, (ii) an anion exchange membrane (AEM), (iii) a bipolar membrane (BPM), and (iv) a charge mosaic membrane (CMM). With respect to the electrochemical performance of the four biocatalyzed electrolysis configurations, the ion exchange membranes are rated in the order AEM > CEM > CMM > BPM. However, with respect to the transport numbers for protons and/or hydroxyl ions (t(H/OH)) and the ability to prevent pH increase in the cathode chamber, the ion exchange membranes are rated in the order BPM > AEM > CMM > CEM.


[Bronchocentric granulomatosis (author's transl)].
A case report and a review of this recently described entity are presented. A feature of interest in our case is the presence of Aspergillus fumigatus at the pulmonary needle biopsy as well as in the surgical specimen. This finding is described for the first time in a non asthmatic patient.


Automated Image Acquisition for Low-Dose STEM at Atomic Resolution.
Beam damage is a major limitation in electron microscopy that becomes increasingly severe at higher resolution. One possible route to circumvent radiation damage, which forms the basis for single-particle electron microscopy and related techniques, is to distribute the dose over many identical copies of an object. For the acquisition of low-dose data, ideally no dose should be applied to the region of interest before the acquisition of data. We present an automated approach that can collect large amounts of data efficiently by acquiring images in a user-defined area-of-interest with atomic resolution. We demonstrate that the stage mechanics of the Nion UltraSTEM, combined with an intelligent algorithm to move the sample, allow the automated acquisition of atomically resolved images from micron-sized areas of a graphene substrate. Moving the sample stage automatically in a regular pattern over the area-of-interest enables the collection of data from pristine sample regions without exposing them to the electron beam before recording an image. Therefore, it is possible to obtain data with minimal dose (no prior exposure during focusing), which is only limited by the minimum signal needed for data processing. This enables us to minimize beam-induced damage in the sample and to acquire large data sets within a reasonable amount of time.


Neurophysiological modeling of voiding in rats: bladder pressure and postganglionic bladder nerve activity.
A model was developed that describes the relations between bladder pressure and both efferent and afferent nerve activity in postganglionic bladder nerves in urethan-anesthetized rats. Nerve activity was calculated as the 100-ms time integral of the rectified nerve signal. Afferent and efferent nerve signals were measured separately by crushing the nerve proximally or distally. A linear relation was found between bladder pressure and afferent nerve activity (fit error < 7%), and the relation between bladder pressure and efferent nerve activity was described by a low-pass filter (fit error < 90%). In most experiments, combined (efferent and afferent) nerve activity was measured. Absence of efferent nerve activity was assumed during the pressure decrease immediately after voiding. From this episode, the afferent nerve activity was estimated for the entire measurement. Efferent nerve activity was then estimated assuming linear addition in the bidirectionally conducting nerves. The model described the measured data very well (fit error < 7%), and the model parameters showed a good reproducibility in each rat (SD was approximately 30% of the mean).


KBH-A42, a histone deacetylase inhibitor, inhibits the growth of doxorubicin-resistant leukemia cells expressing P-glycoprotein.
Multidrug resistance mediated by the drug efflux protein, P-glycoprotein (P-gp), is one of the principal mechanisms by which tumor cells escape the cell death induced by chemotherapeutic agents. In our previous study, we demonstrated that KBH-A42 [N-hydroxy-3-(2-oxo-1-(3-phenylpropyl)-1,2,5,6-tetrahydropyridin-3-yl)propanamide], a synthetic histone deacetylase inhibitor, effectively inhibited the growth of several human cancer cell lines. In this study, we attempted to determine whether KBH-A42 was also capable of inhibiting the growth of multidrug-resistant cells. Doxorubicin dose-dependently inhibited the growth of P-gp-negative K562 human leukemia cells, but did not show substantial inhibition on the growth of P-gp-positive K562/ADR cells even at 10 microM, the highest concentration of KBH-A42 used, which increased the acetylation of histones in these leukemia cells, dose-dependently and effectively inhibited the cell growth, regardless of the presence of P-gp in the cells. KBH-A42 mediated G0/G1 cell cycle arrest, probably as the result of the down-regulation of CDK2, CDK4 and CDK6 and the up-regulation of p21WAF1. When the expression of p21WAF1 was ablated by a specific siRNA, the inhibition of cell growth by KBH-A42 was partly reduced in both cell lines. In addition to the cell cycle arrest, KBH-A42 also induced apoptosis in these cells, which was accompanied by the activation of caspases, including caspase-9, caspase-8 and caspase-3. The pan-caspase inhibitor, Z-VAD-fmk, partially blocked the cell death induced by KBH-A42. These results indicate that KBH-A42 induces cell cycle arrest and apoptosis via the up-regulation of p21WAF1 and caspase activation, respectively, regardless of the presence of P-gp in the leukemia cells.


Comparison between the 6-minute walk tests performed in patients with chronic obstructive pulmonary disease at different altitudes.
To evaluate the influence of the altitude on the 6-minute walking test in patients with moderate to severe pulmonary disease. Twenty-nine patients performed the 6-minute walk test at a pulmonary rehabilitation clinic in Santo André (above sea level), in São Paulo State, and at the Enseada Beach, in Guarujá (at sea level), also in São Paulo State. Of these 29 patients, 8 did the test both on hard sand and on asphalt to analyze if there were differences in performance during the tests. Data such as heart rate, oxygen saturation, test distance, and Borg scale were compared. We found no statistical difference in relation to oxygen saturation at rest before the beginning of the walking test in Santo André 94.67±2.26% and at sea level 95.56±2% (p=0.71). The minimum saturation measured during the test was 87.27±6.54% in Santo André and 89.10±5.41% in Guarujá (p=0.098). There were no differences in the performed distance between the different kinds of terrains; the distance on sand was 387.75±5.02m and on asphalt it was 375.00±6.54m (p=0.654). Regarding oxygen saturation during walking, the pulse oximetry on sand was 95.12±1.80% and on asphalt it was 96.87±1.64% (p=1.05). Altitude did not affect the performance of the walking test in patients with moderate to severe pulmonary disease and the results were similar in both cases, on sand and on asphalt.


Synergistic anticancer effects of combined γ-tocotrienol with statin or receptor tyrosine kinase inhibitor treatment.
Systemic chemotherapy is the only current method of treatment that provides some chance for long-term survival in patients with advanced or metastatic cancer. γ-Tocotrienol is a natural form of vitamin E found in high concentrations in palm oil and displays potent anticancer effects, but limited absorption and transport of by the body has made it difficult to obtain and sustain therapeutic levels in the blood and target tissues. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase and are an example of a promising cancer chemotherapeutic agent whose clinical usefulness has been limited due to high-dose toxicity. Similarly, erlotinib and gefitinib are anticancer agents that inhibit the activation of individual HER/ErbB receptor subtypes, but have shown limited clinical success because of heterodimerization between different EGF receptor family members that can rescue cancer cells from agents directed against a single receptor subtype. Recent studies have investigated the anticancer effectiveness of low-dose treatment of various statins or EGF receptor inhibitors alone and in combination with γ-tocotrienol on highly malignant +SA mouse mammary epithelial cells in vitro. Combined treatment with subeffective doses of γ-tocotrienol with these other chemotherapeutic agents resulted in a synergistic inhibition of +SA cell growth and viability. These findings strongly suggest that combined treatment of γ-tocotrienol with other anticancer agents may not only provide an enhanced therapeutic response but also provide a means to avoid the toxicity, low bioavailability, or limited therapeutic action associated with high-dose monotherapy.


A molecular mechanism for the effect of lithium on development.
Lithium, one of the most effective drugs for the treatment of bipolar (manic-depressive) disorder, also has dramatic effects on morphogenesis in the early development of numerous organisms. How lithium exerts these diverse effects is unclear, but the favored hypothesis is that lithium acts through inhibition of inositol monophosphatase (IMPase). We show here that complete inhibition of IMPase has no effect on the morphogenesis of Xenopus embryos and present a different hypothesis to explain the broad action of lithium. Our results suggest that lithium acts through inhibition of glycogen synthase kinase-3 beta (GSK-3 beta), which regulates cell fate determination in diverse organisms including Dictyostelium, Drosophila, and Xenopus. Lithium potently inhibits GSK-3 beta activity (Ki = 2 mM), but is not a general inhibitor of other protein kinases. In support of this hypothesis, lithium treatment phenocopies loss of GSK-3 beta function in Xenopus and Dictyostelium. These observations help explain the effect of lithium on cell-fate determination and could provide insights into the pathogenesis and treatment of bipolar disorder.


Antivertigo medications and drug-induced vertigo. A pharmacological review.
The approach to drug treatment of vertigo is almost exclusively symptomatic. There are 3 major goals for drug treatment of vertigo. The first one is to eliminate the hallucination of motion. Drugs with vestibular 'suppressant' properties are used for this purpose. The major vestibular suppressants are anticholinergic and antihistamine drugs. The second goal is to reduce the accompanying neurovegetative and psychoaffective signs (nausea, vomiting, anxiety). Antidopaminergics are used for this purpose. The third goal is to enhance the process of 'vestibular compensation' to allow the brain to find a new sensory equilibrium in spite of the vestibular lesion. Until now, the pharmacological manipulation of vestibular compensation has been assessed in animals but not in humans with vestibular lesions. Vestibular suppressant drugs delay rather than enhance compensation. A variety of other drugs is also used in the treatment of vertigo, including benzodiazepines, histaminergic agents, sympathomimetics and calcium antagonists. Their mechanism of action is poorly understood. The data base derived from clinical trials evaluating antivertigo medications is often questionable because of methodological limitations. This explains why habits of prescription are mainly empirical, and why striking differences can be noticed from one country to another. We can hope that new treatments may emerge from the present interest in receptor subclasses and neuromodulators of the vestibular system, and we must be ready to evaluate these potential new pharmacological agents with reliable clinical methods in humans.


Feasibility and Measurement Value of Pancreatic 2-D Shear Wave Elastography in Healthy Adults: Evaluation, Influencing Factors, Reference Range, Measurement Stability and Reproducibility.
The present study was aimed at assessing the success rate and measurement value, determining the influencing factors and reference range and examining the intra-operator stability and inter-operator reproducibility of pancreatic 2-D shear wave elastography (SWE) measurement in healthy adults. In 2022, 387 healthy adults were prospectively recruited. Logistic regression and linear regression analyses were used to explore the factors influencing the success rate and the measurement value of pancreatic 2-D SWE measurement, respectively. A two-sided 95% reference range was estimated accordingly. The intraclass correlation coefficient was calculated to evaluate the intra-operator stability and inter-operator reproducibility of the pancreatic 2-D SWE measurement. The pancreatic body (89.6%) bore the highest while the tail (72.8%) bore the lowest success rate of pancreatic 2-D SWE measurement. Sex and body mass index (BMI) were the independent factors influencing measurement success rate in all three parts of the pancreas. Mean measurement values (Emean) were not the same in the three parts of the pancreas of the same participant. BMI and image depth were the independent factors influencing Emean in the pancreatic body, while region of interest depth and BMI were the only independent factors influencing Emean in the pancreatic head and tail, respectively. The intra-operator stability of pancreatic 2-D SWE measurement was found to be excellent, whereas its inter-operator reproducibility was poor to good. Pancreatic 2-D SWE is a reliable technique for evaluating pancreatic stiffness in healthy adults, but its success rate and measurement value are influenced by multiple factors.


Atypical response to bacterial coinfection and persistent neutrophilic bronchoalveolar inflammation distinguish critical COVID-19 from influenza.
Neutrophils are recognized as important circulating effector cells in the pathophysiology of severe coronavirus disease 2019 (COVID-19). However, their role within the inflamed lungs is incompletely understood. Here, we collected bronchoalveolar lavage (BAL) fluids and parallel blood samples of critically ill COVID-19 patients requiring invasive mechanical ventilation and compared BAL fluid parameters with those of mechanically ventilated patients with influenza, as a non-COVID-19 viral pneumonia cohort. Compared with those of patients with influenza, BAL fluids of patients with COVID-19 contained increased numbers of hyperactivated degranulating neutrophils and elevated concentrations of the cytokines IL-1β, IL-1RA, IL-17A, TNF-α, and G-CSF; the chemokines CCL7, CXCL1, CXCL8, CXCL11, and CXCL12α; and the protease inhibitors elafin, secretory leukocyte protease inhibitor, and tissue inhibitor of metalloproteinases 1. In contrast, α-1 antitrypsin levels and net proteolytic activity were comparable in COVID-19 and influenza BAL fluids. During antibiotic treatment for bacterial coinfections, increased BAL fluid levels of several activating and chemotactic factors for monocytes, lymphocytes, and NK cells were detected in patients with COVID-19 whereas concentrations tended to decrease in patients with influenza, highlighting the persistent immunological response to coinfections in COVID-19. Finally, the high proteolytic activity in COVID-19 lungs suggests considering protease inhibitors as a treatment option.


A conundrum for randomized controlled trials: experience from a small hepatocellular carcinoma trial.
The aim of this study was to explore why patients accepted or declined to participate in a randomized clinical trial, which was subsequently discontinued because of a low recruitment rate. Forty-one patients were invited to participate in a randomized clinical trial that aimed to compare local ablation therapies and surgery to treat small asymptomatic hepatocellular carcinomas. These patients were then asked to answer a questionnaire that assessed patient perception and reasons for accepting or declining to enroll in the randomized clinical trial. When patients had a strong preference for a specific treatment, the questionnaire assessed why, how and when they had chosen it. The response rate was 6/6 (100%) and 30/35 (86%) for the participant and non-participant groups, respectively. Among the 30 non-participants, 23 had a strong preference for local ablation therapies, which was less invasive and offered shorter hospitalization. Patient preference for a specific treatment often stemmed from their consultations with a clinician who referred them to a specialist hospital. Patients without strong preference for a specific treatment participated in the randomized clinical trial because of altruistic motivations. When new treatments that are innovative and less burdensome become widespread, they are difficult to compare with standard therapy utilizing a well-designed randomized clinical trial. Consequently, when an innovative treatment is developed, investigators should consider designing a randomized clinical trial as early as possible.


Study of the sensitivity of neonates to digoxin: contribution of erythrocyte 86rubidium uptake test.
In general, there is little agreement how digoxin should be used in newborn, and the results of studies in this field seem contradictory. This study attempts a quantitative assessment of the number and the sensitivity of cellular receptors for digoxin in the organism, by the in vitro measurement of erythrocyte 86Rubidium uptake in neonates compared with adults and old people. Red blood cells are first incubated with differing concentrations of digoxin, and then incubated with 86Rb. The initial level of 86Rb uptake (Rbi) is that observed in the absence of digoxin. The 50% index of captation (IC50) is the digoxin concentration in nanograms per ml at which 86Rb uptake is half Rbi. Three groups of patients were studied: Group I: 12 neonates, less than 5 days old; Group II: 11 adults (26 to 57 years old); Group III: 9 elderly people (71 to 82 years old). Rbi was significantly lower in neonates (Mean +/- SD: 25.8% +/- 3.5, P less than 0.001) and in the elderly (29.9% +/- 3.1) than in adults (36.8% +/- 4.6). IC50 was significantly lower in the elderly (12.1 ng/ml +/- 2.4) than in the adult patients (20.5 ng/ml +/- 5.5, P less than 0.001). In the newborns, values of IC50 were widely scattered (16.2 ng/ml +/- 7.2). The authors suggest that since Rbi reflects Na+, K+-ATPase activity, this activity is diminished in newborn and old people, and indicates that they have fewer cellular receptors for digoxin than adults. In the elderly, the low IC50 would imply increased sensitivity to digoxin. In neonates, the wide range of values for IC50 suggests considerable individual variation in sensitivity to digoxin. The results are consistent with the recently recommended lower dosages of digoxin in neonates.


[Lymphocytes B and NK in respiratory allergy].
High affinity immunoglobulin E (IgE) receptors may activate the mast cell degradation; on the other hand, the ones of low affinity may activate B lymphocytes so they act as antigen-presenting cells and as producers of the same immunoglobulin. As allergic patients produce a great quantity of IgE they are prone to get an infection. To quantify the IgE increase in 28 patients with allergic rhinitis or asthma, or both without having received a previous treatment. 38 patients with allergic rhinitis, bronchial asthma, allergic conjunctivitis or atopic dermatitis diagnosis were included. B lymphocytes and NK cells immunophenotypification was made. Flow cytometry was used for cells lecture. Data were analyzed with descriptive statistics applying central tendency measurements. No variations were found in the values of any cell lineage. Proliferation and activation of B lymphocytes should be considered in allergic diseases as its quantification in serum may be a measurement parameter of allergic activity.


Characterization of two cDNAs encoding cysteine proteinases from the soybean cyst nematode Heterodera glycines.
Two cDNAs encoding cysteine proteinases were isolated from a cDNA library constructed from feeding females of Heterodera glycines. The library was screened with a cysteine proteinase gene fragment originally amplified from cDNA of H. glycines. Database searches predict that 1 cDNA (hgcp-I) encodes a cathepsin L-like proteinase, while the second (hgcp-II) encodes a cathepsin S-like enzyme. Both predicted proteins contain a short secretion signal sequence, a long propeptide and a mature protein of 219 amino acids. Southern blot analysis suggests that the cathepsin S-like enzyme, HGCP-II, is encoded by a single-copy gene in contrast to the cathepsin L-like proteinase, HGCP-I which may have 2 homologues. The regions encoding the mature proteinases were cloned into an expression vector and recombinant protein produced in E. coli. HGCP-I was shown, after refolding, to cleave the synthetic peptide Z-Phe-Arg-AMC, and this activity could be inhibited by the engineered rice cystatin Oc-I delta D86. HGCP-II showed no activity against the synthetic substrates tested. The knowledge gained from these studies will improve our understanding of plant nematode proteinases and aid the development of a rational proteinase inhibitor-based approach to plant nematode resistance.


Are new nurses work ready - The impact of preceptorship. An integrative systematic review.
The aim of this integrative systematic review was to systematically search, critically appraise, and summarise reported research related to readiness to practice and types of clinical support offered to newly registered nurses and preregistration nurses (such as, mentoring, preceptorship, or clinical facilitation). The review was undertaken in February 2017. The databases of Medline, CINAHL, Academic Search Complete, and Cochrane Library were searched. The search returned 137 articles. The final number of papers (after screening and exclusions) was 15 articles related to the topic. Key findings that influence work readiness for newly registered nurses were - Importance of Preceptors for Facilitating Work Readiness with the sub themes of Positive relationships between the preceptors and the student or newly registered nurse, Preparing and supporting the preceptor for the role and Using a model to guide preceptorship of students, the second theme was related to Clincal exposure, including a sub theme of Adequate clinical exposure and clinical competence. Work readiness has been attributed to many factors and this review has revealed a number of key factors that contribute to newly registered nurses' work readiness such as preparation of the preceptor, positive relationships and adequate clinical exposure.


Lambda: the local aligner for massive biological data.
Next-generation sequencing technologies produce unprecedented amounts of data, leading to completely new research fields. One of these is metagenomics, the study of large-size DNA samples containing a multitude of diverse organisms. A key problem in metagenomics is to functionally and taxonomically classify the sequenced DNA, to which end the well-known BLAST program is usually used. But BLAST has dramatic resource requirements at metagenomic scales of data, imposing a high financial or technical burden on the researcher. Multiple attempts have been made to overcome these limitations and present a viable alternative to BLAST. In this work we present Lambda, our own alternative for BLAST in the context of sequence classification. In our tests, Lambda often outperforms the best tools at reproducing BLAST's results and is the fastest compared with the current state of the art at comparable levels of sensitivity. Lambda was implemented in the SeqAn open-source C++ library for sequence analysis and is publicly available for download at http://www.seqan.de/projects/lambda. Supplementary data are available at Bioinformatics online.


The two-track model of bereavement: overview, retrospect, and prospect.
Sustaining meaning in life, maintaining emotional well-being, and balancing attachments to the living and the deceased are features associated with the psychological (and often private) impact of loss. In the Two-Track Model of Bereavement, the loss process is conceptualized along two distinct but interactive axes that attend to these overt and covert aspects of the response to loss. Whereas Track I is concerned with biopsychosocial functioning in the wake of loss, it is Track II that focuses on the bereaved's ongoing emotional attachment and relationship to the deceased. The contributions of the model to theory and research can serve to clarify our thinking about bereavement as a process resonating throughout one's life. Initially, research and clinical findings from bereaved parents are presented to illustrate the Two-Track Model and its contribution to the deepening of our understanding of loss throughout the life cycle. The contributions of the model to clinical practice are then considered for their ability to clarify our thinking and interventions. Two clinical cases illustrate situations where a predominant focus is on one or the other of these tracks. Ultimately, the Two-Track Model of Bereavement's use extends to the organization and clarification of theory, research, and clinical work.


Protective effect of Embelia ribes Burm on methionine-induced hyperhomocysteinemia and oxidative stress in rat brain.
The present study was aimed to find out the protective effect of ethanolic extract of E. ribes fruits on homocysteine, lactate dehydrogenase (LDH) and lipid profile in serum, lipid peroxidation (LPO) and non-enzymatic antioxidant glutathione (GSH) levels in brain homogenates and histopathological examination of brain tissue in methionine (1 g/kg body weight, orally for 30 days) induced hyperhomocysteinemic rats. A significant increase in homocysteine, LDH, total cholesterol, triglycerides, low density lipoprotein (LDL-C) and very low density lipoprotein (VLDL-C) levels was observed in serum. Increased LPO levels in brain homogenates with reduced serum high density lipoprotein (HDL-C) levels and decreased GSH content were other salient features observed in methionine treated pathogenic control rats. Administration of ethanolic E. ribes extract (100 mg/kg body weight, orally) for 30 days to methionine-induced hyperhomocysteinemic rats produced a significant decrease in the levels of homocysteine, LDH, total cholesterol, triglycerides, LDL-C, VLDL-C in serum and LPO levels in brain homogenates with significant increase in serum HDL-C levels and GSH content in brain homogenates, when compared with pathogenic control rats. Biochemical observations were further substantiated with histological examination of brain. Degenerative changes of neuronal cells in methionine treated rats were minimized to near normal morphology by ethanolic E. ribes extract administration as evident by histopathological examination. The results provide clear evidence for the first time, that ethanolic E. ribes extract treatment enhances the antioxidant defense against methionine-induced hyperhomocysteinemia and oxidative stress in brain.


Maternal left ventricular dimension in pregnancies complicated by fetal growth retardation.
Previous studies using two-dimensional chest radiographs have found a significant correlation between prematurity, fetal growth retardation, and the size of the maternal heart. Accordingly, we evaluated maternal left ventricular size and function by M-mode echocardiography near the end of gestation in 42 women with suspected fetal growth retardation and in 79 women whose pregnancies were normal. No significant differences were found between the two groups, implying that maternal left ventricular size and function is adequate in pregnancies complicated by "idiopathic" fetal growth retardation.


Estimation of nicotine content in popular Indian brands of smoking and chewing tobacco products.
To estimate the nicotine content of some popular Indian brands of smoking tobacco (cigarettes and bidis) and pan masalas (chewable tobacco). Commercially available cigarettes, bidis, and pan masalas (chewable tobacco) were obtained from local retail outlets for the study. Nicotine was estimated using gas-liquid chromatography. The analyses showed relatively higher levels of nicotine in tobacco from bidis (26.9 mg gm) as compared to cigarettes(15 mg/gm); the difference is statistically significant ( P P > 0.01). Nicotine concentration in chewing tobacco was 3.4 mg/gm. The study concludes that the nicotine content of Indian brands of smoking tobacco was slightly high compared to other international brands. Higher concentration of nicotine was found in bidis compared to cigarettes. The nicotine content in commercially available chewing tobacco products was found to be much lower than in the smoking form of tobacco, but the average daily consumption made it comparable to the smoking form.


Highly dispersible PEGylated graphene/Au composites as gene delivery vector and potential cancer therapeutic agent.
Graphene/Au composites with a high positive charge, which is advantageous for the binding and condensation of negatively charged siRNA, are synthesized via an in situ reduction method, using PEI as a reductant and protective reagent. Owing to the sufficient amounts of amino groups, PEI-grafted graphene/Au composites can be further modified with methoxyl-PEG to acquire low cytotoxicity, novel blood compatibility, and optimal dispersibility in physiological environments. The obtained PEGylated PEI-grafted graphene/Au composites (PPGA) allow efficient loading of siRNA, forming PPGA/siRNA complexes to transport into HL-60 cells and downregulated anti-apoptosis Bcl-2 protein, indicating PPGA is a suitable platform for gene delivery. Moreover, PPGA display an enhanced photothermal response with respect to PPG under NIR laser irradiation, suggesting that PPGA can be used as an efficient photothermal agent.


Current Issues in the Use of fMRI-Based Neurofeedback to Relieve Psychiatric Symptoms.
fMRI-based neurofeedback (fMRI-NF) is a non-invasive technique that allows participants to achieve control of their own brain activity using the real-time feedback of the activity (measured indirectly based on the BOLD signal) of a particular brain region or network. The feasibility of fMRI-NF in healthy subjects has been documented for a variety of brain areas and neural systems, and this technique has also been proposed for the treatment of psychiatric disorders in recent years. Through a systematic review of the scientific literature this paper probes the rationale and expected applications of fMRI-NF in psychiatry, discusses issues that must be addressed in the use of this technique to treat mental disorders. Six relevant references and five ongoing studies were identified according to our inclusion criteria. These studies show that in most psychiatric disorders (major depressive disorder, schizophrenia, personality disorders, addiction), patients are able to learn voluntary control of the neuronal activity of the targeted brain region(s). Interestingly, in some cases, this learning is associated with clinical improvement, showing that fMRI-NF can potentially be developed into a therapeutic tool. However, only low-level evidence is available to support the use of this relatively new technique in clinical practice. Notably, no randomized, controlled trial is currently available in this field of research. Finally, methodological issues and clinical perspectives (especially the potential use of pattern recognition in fMRI-NF protocols) are discussed.


Delayed Chemical Defense: Timely Expulsion of Herbivores Can Reduce Competition with Neighboring Plants.
Time delays in plant responses to insect herbivory are thought to be the principal disadvantage of induced over constitutive defenses, suggesting that there should be strong selection for rapid responses. However, observed time delays between the onset of herbivory and defense induction vary considerably among plants. We postulate that strong competition with conspecifics is an important codeterminant of the cost-benefit balance for induced responses. There may be a benefit to the plant to delay mounting a full defense response until the herbivore larvae are mobile enough to leave and large enough to cause severe damage to neighboring plants. Thus, delayed responses could reduce the competitive pressure on the focal plant. To explore this idea, we developed an individual-based model using data from wild tobacco, Nicotiana attenuata, and its specialized herbivore, Manduca sexta. Chemical defense was assumed to be costly in terms of reduced plant growth. We used a genetic algorithm with the plant's delay time as a heritable trait. A stationary distribution of delay times emerged, which under high herbivore densities peaked at higher values, which were related to the time larvae need to grow large enough to severely damage neighboring plants. Plants may thus tip the competitive balance by expelling insect herbivores to move to adjacent plants when the herbivores are most damaging. Thus, herbivores become part of a plant's strategy for reducing competition and increasing fitness.


Performance of the pediatric glasgow coma scale in children with blunt head trauma.
To compare the accuracy of a pediatric Glasgow Coma Scale (GCS) score in preverbal children with blunt head trauma with the standard GCS score in older children. The authors prospectively enrolled children younger than 18 years with blunt head trauma. Patients were divided into cohorts of those 2 years and younger and those older than 2 years. The authors assigned a pediatric GCS score to the younger cohort and the standard GCS score to the older cohort. Outcomes were 1) traumatic brain injury (TBI) on computed tomography (CT) scan or 2) TBI in need of acute intervention. The authors created and compared receiver operating characteristic (ROC) curves between the age cohorts for the association of GCS scores and TBI. The authors enrolled 2,043 children, and 327 were 2 years and younger. Among these 327, 15 (7.7%; 95% confidence interval [CI] = 4.4% to 12.4%) of 194 who underwent imaging with CT had TBI visible and nine (2.8%; 95% CI = 1.3% to 5.2%) had TBI needing acute intervention. In children older than 2 years, 83 (7.7%; 95% CI = 6.2% to 9.5%) of the 1,077 who underwent imaging with CT had TBI visible and 96 (5.6%; 95% CI = 4.6% to 6.8%) had TBI needing acute intervention. For the pediatric GCS in children 2 years and younger, the area under the ROC curve was 0.72 (95% CI = 0.56 to 0.87) for TBI on CT scan and 0.97 (95% CI = 0.94 to 1.00) for TBI needing acute intervention. For the standard GCS in older children, the area under the ROC curve was 0.82 (95% CI = 0.76 to 0.87) for TBI on CT scan and 0.87 (95% CI = 0.83 to 0.92) for TBI needing acute intervention. This pediatric GCS for children 2 years and younger compares favorably with the standard GCS in the evaluation of children with blunt head trauma. The pediatric GCS is particularly accurate in evaluating preverbal children with blunt head trauma with regard to the need for acute intervention.


DNA zip codes control an ancient mechanism for gene targeting to the nuclear periphery.
Many genes in Saccharomyces cerevisiae are recruited to the nuclear periphery after transcriptional activation. We have identified two gene recruitment sequences (GRS I and II) from the promoter of the INO1 gene that target the gene to the nuclear periphery. These GRSs function as DNA zip codes and are sufficient to target a nucleoplasmic locus to the nuclear periphery. Targeting requires components of the nuclear pore complex (NPC) and a GRS is sufficient to confer a physical interaction with the NPC. GRS I elements are enriched in promoters of genes that interact with the NPC, and genes that are induced by protein folding stress. Full transcriptional activation of INO1 and another GRS-containing gene requires GRS-mediated targeting of the promoter to the nuclear periphery. Finally, GRS I also functions as a DNA zip code in Schizosaccharomyces pombe, suggesting that this mechanism of targeting to the nuclear periphery has been conserved over approximately one billion years of evolution.


Exosomal and non-exosomal miRNA expression levels in patients with HCV-related cirrhosis and liver cancer.
Patients with HCV-related cirrhosis are at risk for liver cancer development. For these patients miRNAs may serve as preclinical markers, which expression levels are deregulated in cancer and which are stable to the damaging factors partly through complex formation with proteins or packaging into exosomes. In this research we have tried to identify what miRNA fraction in plasma - exosomal or not packed into exosomes (non-exosomal) - is stronger associated with primary liver cancer. The second question was whether saliva miRNA expression levels - both exosomal and non-exosomal - are associated with primary liver cancer. We evaluated exosomal and non-exosomal miRNAs - let-7a-5p, -16-5p, -18a-5p, -21-5p, -22-3p, -34a-5p, -103a-3p, -122-5p, -221-3p, -222-3p - in plasma and saliva of patients with HCV-related liver cirrhosis (n = 24), primary liver cancer (n = 24) and healthy volunteers (n = 21). Relative expression level was calculated with normalization of exosomal miRNA to exosomal miRNA-16-5p, non-exosomal miRNA to non-exosomal miRNA-16-5p and as a ratio of exosomal miRNA to non-exosomal miRNA. In this study, non-exosomal miRNAs (let-7a, miRNA-21-5p, -22-3p, -103a, -122-5p, -221-3p and 222-3p) normalized to non-exosomal miRNA-16-5p showed strong association with liver cancer in plasma. Three miRNAs, those with the mostly pronounced change of expression levels in plasma, - miRNA-21-5p, 122-5p, 221-3p - were detected in saliva. In contrast, exosomal miRNAs show stronger association with primary liver over non-exosomal miRNAs when working with saliva. Thus, depending on the examined biological material both miRNA fractions may serve as a valuable source for diagnostic and prognostic data.


Risk factors for vitamin D inadequacy among women with osteoporosis: an international epidemiological study.
A serum 25-hydroxyvitamin D [25(OH)D] level of 75 nmol/l (30 ng/ml) has been proposed as the minimum for adequate vitamin D nutrition as lower levels are associated with increases in serum parathyroid hormone in otherwise healthy adults. Amongst 2589 community-dwelling, postmenopausal women with osteoporosis from 18 countries, recruited to determine risk factors for vitamin D inadequacy, 64% had vitamin D inadequacy. General health, education, ethnicity, sun exposure, skin reactivity, diet, recent travel to sunny climates, vitamin D supplementation, body mass index (BMI), season and latitude were assessed using logistic regression models. Asian ethnicity, BMI >or=30 kg/m(2), living in non-equatorial countries, inadequate vitamin D supplementation, poor/fair health, no education about vitamin D, skin reactivity and no recent travel to sunny areas were significant predictors. Several modifiable risk factors are associated with vitamin D inadequacy worldwide, suggesting potentially simple ways to increase vitamin D and improve bone health in postmenopausal women.


[The antiviral activity of the adamantane derivatives against the influenza virus A (H1N1) pdm2009 model in vivo].
For the first time in vivo, the model of the viral pneumonia in mice was used to study the antiviral activity against influenza A virus (H1N1) pdm09 synthetic derivatives of adamantane series including the amino acid residues and lipoid acid. It was found that the adamantane derivatives with histidine, serine, and lipoid acid could inhibit the rimantadine-resistant strain of the influenza A (H1N1) pdm09. As a result, the lifespan of the mice infected with the virus has increased by 1.6 times with respect to viral control. Thus, the possibility of restoration of antiviral properties of rimantadine both in vitro and in vivo by introducing into its molecular structure new functionally active groups was tested.


Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma.
Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET (REarranged during Transfection) proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC. We conducted a phase I/II trial of vandetanib for children (5-12 years) and adolescents (13-18 years) with MTC to define a recommended dose and assess antitumor activity. The starting dose was 100 mg/m(2) administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m(2)/d after two cycles. Radiographic response to vandetanib was quantified using RECIST (v1.0), biomarker response was measured by comparing posttreatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient-reported outcome was used to assess clinical benefit. Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2-52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n = 15) the confirmed objective partial response rate was 47% (exact 95% confidence intervals, 21%-75%). Biomarker partial response was confirmed for calcitonin in 12 subjects and for CEA in 8 subjects. Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m(2)/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.


Recovery from sleep disturbance precedes that of depression and anxiety following mild traumatic brain injury: a 6-week follow-up study.
The detailed course of mental disorders at the acute and subacute stages of mild traumatic brain injury (mTBI), especially with regard to recovery from sleep disturbances, has not been well characterised. The aim of this study was to determine the course of depression, anxiety and sleep disturbance, following an mTBI. We recruited patients with mTBI from three university hospitals in Taipei and healthy participants as control group for this study. 100 patients with mTBI (35 men) who were older than 20 years, with a Glasgow Coma Scale score of 13-15 and loss of consciousness for <30 min, completed the baseline and 6-week follow-up assessments. 137 controls (47 men) without TBI were recruited in the study. None of the participants had a history of cerebrovascular disease, mental retardation, previous TBI, epilepsy or severe systemic medical illness. The Beck Anxiety Inventory (BAI), the Beck Depression Inventory II (BDI), the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI) were assessed for the patients with mTBI at baseline and 6 weeks after mTBI and for the controls. The ESS scores were not significantly different between the mTBI at baseline or at 6 weeks after mTBI and controls. Although the BAI, BDI and PSQI scores of the mTBI group were significantly different than those of the control group at baseline, all had improved significantly 6 weeks later. However, only the PSQI score improved to a level that was not significantly different from that of the control group. Daytime sleepiness is not affected by mTBI. However, mTBI causes depression and anxiety and diminished sleep quality. Although all these conditions improve significantly within 6 weeks post-mTBI, only sleep quality improves to a pre-mTBI level. Thus, recovery from mTBI-induced sleep disturbance occurs more rapidly than that of mTBI-induced depression and anxiety.


A Unitary-Transformative Nursing Science: From Angst to Appreciation.
The discord within nursing regarding the definition of nursing science has created great angst, particularly for those who view nursing science as a body of knowledge derived from theories specific to its unique concerns. The purpose of this brief article is to suggest a perspective and process grounded in appreciation of wholeness that may offer a way forward for proponents of a unitary-transformative nursing science that transcends the discord. This way forward is guided by principles of fostering dissent without contempt, generating a well-imagined future, and garnering appreciatively inspired action for change.


O2 adsorption dependent photoluminescence emission from metal oxide nanoparticles.
Optical properties of metal oxide nanoparticles are subject to synthesis related defects and impurities. Using photoluminescence spectroscopy and UV diffuse reflectance in conjunction with Auger electron spectroscopic surface analysis we investigated the effect of surface composition and oxygen adsorption on the photoluminescence properties of vapor phase grown ZnO and MgO nanoparticles. On hydroxylated MgO nanoparticles as a reference system, intense photoluminescence features exclusively originate from surface excitons, the radiative deactivation of which results in collisional quenching in an O2 atmosphere. Conversely, on as-prepared ZnO nanoparticles a broad yellow emission feature centered at hνEm = 2.1 eV exhibits an O2 induced intensity increase. Attributed to oxygen interstitials as recombination centers this enhancement effect originates from adsorbate-induced band bending, which is pertinent to the photoluminescence active region of the nanoparticles. Annealing induced trends in the optical properties of the two prototypical metal oxide nanoparticle systems, ZnO and MgO, are explained by changes in the surface composition and underline that particle surface and interface changes that result from handling and processing of nanoparticles critically affect luminescence.


The Direct and Indirect Associations between Childhood Socioeconomic Disadvantage and Adolescent Gun Violence.
We examined whether childhood socioeconomic disadvantage was associated with adolescent gun violence and whether early symptoms of conduct disorder and/or exposure to delinquent peers accounted for the linkage. Participants were 503 predominately Black and White boys who were recruited in 1st grade from Pittsburgh public schools. Multi-informant assessments were conducted regularly from approximately ages 7 to 20. A latent socioeconomic disadvantage factor was estimated with census-tract and parent-reported data when boys were about age 7½. Latent growth curve models assessed parent/teacher-reported conduct problems and youth-reported peer delinquency from about ages 7½ to 10. The outcome was youth-reported engagement in gun violence by about age 20. We also controlled for race. Analyses examined whether the association between childhood socioeconomic disadvantage and adolescent gun violence was mediated through early conduct problems and/or increased exposure to delinquent peers. Childhood socioeconomic disadvantage was associated with adolescent gun violence, and some of this effect was mediated through peer delinquency and conduct problems. Specifically, childhood socioeconomic disadvantage was associated with greater affiliation with delinquent peers in early childhood, and early peer delinquency promoted a greater increase in conduct problems across childhood, and these conduct problems, in turn, led to an increased risk for adolescent gun violence. In summary, this study found that early socioeconomic disadvantage was directly and indirectly related to adolescent gun violence. Results suggest that interventions that aim to reduce conduct problems and deviant peer group affiliation in childhood might be important windows of opportunity for reducing gun violence in impoverished neighborhoods.


Gene 33 is an endogenous inhibitor of epidermal growth factor (EGF) receptor signaling and mediates dexamethasone-induced suppression of EGF function.
We report a mechanism by which the adapter protein Gene 33 (also called RALT and MIG6) regulates epidermal growth factor receptor (EGFR) signaling. We find that Gene 33 inhibits EGFR autophosphorylation and specifically blunts epidermal growth factor (EGF)-induced activation and/or phosphorylation of Ras, ERK, JNK, Akt/PKB, and retinoblastoma protein. The Ack homology domain of Gene 33, which contains the previously identified EGFR binding domain, is both necessary and sufficient for this inhibition of EGFR autophosphorylation. The endogenous Gene 33 polypeptide is induced by EGF, platelet-derived growth factor, serum, and dexamethasone (Dex) in Rat 2 rat fibroblasts. Dex induces Gene 33 expression and inhibits EGFR phosphorylation and EGF signaling. RNA interference-mediated silencing of Gene 33 significantly reverses this effect. Overexpression of Gene 33 completely blocks EGF-induced protein and DNA synthesis in Rat 2 cells, whereas gene 33 RNA interference substantially enhances EGF-induced protein and DNA synthesis in Rat 2 cells. Our results indicate that Gene 33 is a physiological feedback inhibitor of the EGFR, functioning to inhibit EGFR phosphorylation and all events induced by EGFR activation. Our results also indicate a role for Gene 33 in the suppression, by Dex, of EGF signaling pathways. We propose that Gene 33 may function in the cross-talk between EGF signaling and other mitogenic and/or stress signaling pathways.


A unifying hypothesis for the renin-angiotensin system and hematopoiesis: sticking the pieces together with the JAK-STAT pathway.
JAK-STAT pathway is a recently encountered intracellular signal transduction system. The pathway is utilized by numerous cytokines, growth factors, and hormones for gene expression and a variety of biological activities. Hematopoiesis is regulated by many cytokines and growth factors that support the proliferation and differentiation of progenitor cells in the bone marrow. JAK-STAT pathway arises as the most common signalling cascade of a wide range of cytokines and/or growth factors in propagation of physiological and pathological/neoplastic hematopoiesis. On the other side, renin-angiotensin system (RAS) includes not only the classic circulating endocrine system controlling blood pressure and electrolyte homeostasis, but also tissue-specific RASs with autocrine and/or paracrine functions. Preliminary data suggest the involvement of the RAS components in normal and pathologic hematopoiesis, although the precise mechanism of action has not been elucidated yet. We have hypothesized, in this report, that JAK-STAT pathway serves as a point of crosstalk between the components of the locally present RAS in the bone marrow and hematopoiesis. Demonstration of a local RAS in the bone marrow with clarification of the postreceptor signalling events may play a consequential role not only for further clarification of normal hematopoiesis but also novel therapeutic approaches in pathologic/neoplastic conditions.


Risks and benefits of renal artery stenting in fibromuscular dysplasia: Lessons from the ARCADIA-POL study.
Although renal stenting is the standard revascularization method for atherosclerotic renal artery stenosis (RAS) (FMD-RAS), stenting in fibromuscular dysplasia (FMD) RAS is usually limited to periprocedural complications of angioplasty and primary arterial dissection. The main aim of the study was to retrospectively analyze the immediate and long-term results of renal stenting versus angioplasty in patients with FMD. Of 343 patients in the ARCADIA-POL registry, 58 patients underwent percutaneous treatment due to FMD-RAS (in 70 arteries). Percutaneous transluminal renal angioplasty (PTRA) was performed as an initial treatment in 61 arteries (PTRA-group), whereas primary stenting was undertaken in nine arteries (stent-group). Stent-related complications were defined as: in-stent restenosis > 50% (ISR); stent fracture; under-expansion; or migration. In the PTRA-group, the initial restenosis rate was 50.8%. A second procedure was then performed in 22 arteries: re-PTRA (12 arteries) or stenting (10 arteries). The incidence of recurrent restenosis after re-PTRA was 41.7%. Complications occurred in seven of 10 (70%) arteries secondarily treated by stenting: two with under-expansion and five with ISR. In the stent-group, stent under-expansion occurred in one case (11.1%) and ISR in three of nine stents (33.3%). In combined analysis of stented arteries, either primarily or secondarily, stent-related complications occurred in 11/19 stenting procedures (57.9%): three due to under-expansion and eight due to ISRs. Finally, despite several revascularization attempts, four of 19 (21%) stented arteries were totally occluded and one was significantly stenosed at follow-up imaging. Our study indicates that renal stenting in FMD-RAS may carry a high risk of late complications, including stent occlusion. Further observational data from large-scale registries are required.


Connective tissue growth factor/CCN2 attenuates β-adrenergic receptor responsiveness and cardiotoxicity by induction of G protein-coupled receptor kinase-5 in cardiomyocytes.
Myocardial connective tissue growth factor (CTGF/CCN2) is induced in heart failure, a condition associated with diminution of β-adrenergic receptor (β-AR) responsiveness. Accordingly, we aimed to investigate whether CTGF could play a mechanistic role in regulation of β-AR responsiveness. Concentration-response curves of isoproterenol-stimulated cAMP generation in cardiomyocytes from transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) or cardiomyocytes pretreated with recombinant human CTGF (rec-hCTGF) revealed marked reduction of both β₁-AR and β₂-AR responsiveness. Consistently, ventricular muscle strips from Tg-CTGF mice stimulated with isoproterenol displayed attenuation of maximal inotropic responses. However, no differences of maximal inotropic responses of myocardial fibers from Tg-CTGF mice and nontransgenic littermate control (NLC) mice were discerned when stimulated with supramaximal concentrations of dibutyryl-cAMP, indicating preserved downstream responsiveness to cAMP. Congruent with a mechanism of desensitization of β-ARs, mRNA and protein levels of G protein-coupled receptor kinase 5 (GRK5) were found isoform-selective upregulated in both cardiomyocytes from Tg-CTGF mice and cardiomyocytes exposed to rec-hCTGF. Corroborating a mechanism of GRK5 in CTGF-mediated control of β-AR sensitivity, Chinese hamster ovary cells pretreated with rec-hCTGF displayed increased agonist- and biased ligand-stimulated β-arrestin binding to β-ARs. Despite increased sensitivity of cardiomyocytes from GRK5-knockout (KO) mice to β-adrenergic agonists, pretreatment of GRK5-KO cardiomyocytes with rec-hCTGF, as opposed to cardiomyocytes from wild-type mice, did not alter β-AR responsiveness. Finally, Tg-CTGF mice subjected to chronic exposure (14 days) to isoproterenol revealed blunted myocardial hypertrophy and preserved cardiac function versus NLC mice. In conclusion, this study uncovers a novel mechanism controlling β-AR responsiveness in cardiomyocytes involving CTGF-mediated regulation of GRK5.


Prognostic value of elevated high-sensitivity cardiac troponin T in patients admitted to an emergency department with atrial fibrillation.
Elevated levels of high-sensitivity cardiac troponin T (hsTnT) indicate underlying heart disease and are known to predict adverse outcomes in various patient populations. Their role in atrial fibrillation (AF) is still under debate. This retrospective study included 2898 consecutive patients presenting with AF to the emergency department of the Department of Cardiology, Heidelberg University Hospital. Multivariable Cox regression was used to assess associations between hsTnT and mortality. Elevated hsTnT levels were associated with increased risk of all-cause mortality in all patients with AF, as well as in each subtype of AF. After adjustment for multiple risk factors, both detectable hsTnT below the 99th percentile (5-14 ng/L, adjusted hazard ratio (HR): 4.86 [95% CI: 1.77-13.34], P = 0.002) and elevated hsTnT (>14 ng/L, adjusted HR: 13.42 [95% CI: 4.95-36.40], P < 0.001) were associated with a higher risk of mortality in patients with AF, compared to undetectable hsTnT (<5 ng/L). Elevated hsTnT was also associated with higher mortality after exclusion of patients with myocardial infarction, as well as in the subgroup of patients with AF as main admission diagnosis. The inclusion of hsTnT significantly improved the performance of the multivariable model for mortality prediction. Elevated hsTnT levels are associated with higher mortality in patients with AF, and provide added prognostic information independent of major cardiovascular risk factors and clinical characteristics. Measurement of hsTnT should be considered for risk assessment in patients presenting to an emergency department with AF. http://www.clinicaltrials.gov; Unique identifier: NCT02542189.