Colesevelam enhances the beneficial effects of brown fat activation on hyperlipidaemia and atherosclerosis development.
Brown fat activation accelerates the uptake of cholesterol-enriched remnants by the liver and thereby lowers plasma cholesterol, consequently protecting against atherosclerosis development. Hepatic cholesterol is then converted into bile acids (BAs) that are secreted into the intestine and largely maintained within the enterohepatic circulation. We now aimed to evaluate the effects of prolonged brown fat activation combined with inhibition of intestinal BA reabsorption on plasma cholesterol metabolism and atherosclerosis development. APOE*3-Leiden.CETP mice with humanized lipoprotein metabolism were treated for 9 weeks with the selective β3-adrenergic receptor (AR) agonist CL316,243 to substantially activate brown fat. Prolonged β3-AR agonism reduced faecal BA excretion (-31%), while markedly increasing plasma levels of total BAs (+258%), cholic acid-derived BAs (+295%), and chenodeoxycholic acid-derived BAs (+217%), and decreasing the expression of hepatic genes involved in BA production. In subsequent experiments, mice were additionally treated with the BA sequestrant Colesevelam to inhibit BA reabsorption. Concomitant intestinal BA sequestration increased faecal BA excretion, normalized plasma BA levels, and reduced hepatic cholesterol. Moreover, concomitant BA sequestration further reduced plasma total cholesterol (-49%) and non-high-density lipoprotein cholesterol (-56%), tended to further attenuate atherosclerotic lesion area (-54%). Concomitant BA sequestration further increased the proportion of lesion-free valves (+34%) and decreased the relative macrophage area within the lesion (-26%), thereby further increasing the plaque stability index (+44%). BA sequestration prevents the marked accumulation of plasma BAs as induced by prolonged brown fat activation, thereby further improving cholesterol metabolism and reducing atherosclerosis development. These data suggest that combining brown fat activation with BA sequestration is a promising new therapeutic strategy to reduce hyperlipidaemia and cardiovascular diseases.


Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors.
Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET.


A low-flicker scheme for the real-time measurement of phase noise.
This paper presents a new scheme for the measurement of phase noise in real time, based on carrier suppression and synchronous detection of the noise sidebands of the device being tested. In the instruments of the interferometric type, the carrier is suppressed by adding an equal and opposite signal that must be adjusted with a phase shifter and an attenuator. The proposed scheme makes use of a dual adjustment of the carrier suppression, coarse and fine. The former is by-step; the latter is continuous. Because of the higher stability of the by-step adjustment and the lower weight of the continuous adjustment in the suppression circuit, the instrument exhibits intrinsically low residual flicker and low microphonicity. A prototype shows a residual flicker as low as -160 dBrad2/Hz at 1 Hz off the 100 MHz carrier. Applications include the noise characterization of components and the design of innovative ultrastable oscillators.


Mechanism for the phosphaturia of NH4Cl: dependence on acidemia but not on diet PO4 or PTH.
The effects of metabolic acidosis on renal PO4 handling are controversial. Clearance experiments, therefore, were performed in fasted parathyroidectomized rats 1) to test the thesis that NH4Cl per se alters PO4 reabsorption, 2) to characterize the mechanisms responsible for these changes, and 3) to define the interaction of NH4Cl with parathyroid hormone (PTH) in PO4 deprivation. NH4Cl increased the clearance and fractional excretion of PO4 (FEPO4) without altering plasma PO4. Lactic acid and HCl, but not saline loading. NH4HCO3, or glutamine, produced similar effects. At steady-state phosphaturic effects of NH4Cl, neutralization of the acidemia by NaHCO3 abolished the increment. PTH (3.3 U.kg-1.h-1), superimposed on the maximal effective dose of NH4Cl (5.7 mmol.kg-1.h-1), further augmented FEPO4 (from 24.3 to 46.9%). The effects of NH4Cl (delta FEPO4 = 23 vs. 21%) and the synergism with PTH were not affected by PO4 deprivation. In both PO4 repletion and deprivation, NH4Cl increased basal and PTH-stimulated cAMP excretion, but the changes were poorly correlated with FEPO4. We conclude that NH4Cl inhibits PO4 reabsorption independent of PTH, extracellular fluid volume, natriuresis, NH4+ ion, plasma PO4, or the status of PO4 balance. The effects are mediated by mechanisms dependent on acidemia but are quite distinct from those of PTH. Our findings on cAMP are most compatible with the hypothesis that biochemical events beyond cAMP generation mediate both the phosphaturia of NH4Cl and its ability to restore PTH sensitivity in PO4 deprivation.


Peroxisome proliferator-activated receptor-gamma activates p53 gene promoter binding to the nuclear factor-kappaB sequence in human MCF7 breast cancer cells.
The aim of the present study was to provide new mechanistic insight into the growth arrest and apoptosis elicited by peroxisome proliferator-activated receptor (PPAR)gamma in breast cancer cells. We ascertained that PPARgamma mediates the inhibition of cycle progression in MCF7 cells exerted by the specific PPARgamma agonist rosiglitazone [BRL4653 (BRL)], because this response was no longer notable in the presence of the receptor antagonist GW9662. We also provided evidence that BRL is able to up-regulate mRNA and protein levels of the tumor suppressor gene p53 and its effector p21(WAF1/Cip1) in a time- and dose-dependent manner. Moreover, in transfection experiments with deletion mutants of the p53 gene promoter, we documented that the nuclear factor-kappaB sequence is required for the transcriptional response to BRL. Interestingly, EMSA showed that PPARgamma binds directly to the nuclear factor-kappaB site located in the promoter region of p53, and chromatin immunoprecipitation experiments demonstrated that BRL increases the recruitment of PPARgamma on the p53 promoter sequence. Next, both PPARgamma and p53 were involved in the cleavage of caspases-9 and DNA fragmentation induced by BRL, given that GW9662 and an expression vector for p53 antisense blunted these effects. Our findings provide evidence that the PPARgamma agonist BRL promotes the growth arrest and apoptosis in MCF7 cells, at least in part, through a cross talk between p53 and PPARgamma, which may be considered an additional target for novel therapeutic interventions in breast cancer patients.


Embryonic stem cell microenvironment suppresses the malignancy of cutaneous melanoma cells by down-regulating PI3K/AKT pathway.
Malignant cancer cells engage in a dynamic reciprocity with the tumor microenvironment (TME) that promotes tumor growth, development, and resistance to therapy. Early embryonic blastocyst microenvironments can reverse the tumorigenic phenotype of malignant cancer cells via ameliorating of TME. It is potential to apply embryonic stem cell (ESC) microenvironment to suppress the malignant behaviors of cancer cells. This study aimed to investigate a better method and the mechanism of ESC microenvironment supplied by ESCs on suppressing the malignancy of cutaneous melanoma cells. Cutaneous melanoma cell line A2058 were cultured and divided into four groups: (a) A2058-only (Control); (b) A2058 and ESCs continuously co-cultured (Group One); (c) A2058 co-cultured with daily refreshed ESCs (Group two); (d) Group one with VO-Ohpic, inhibitor of PTEN (VO-Ohpic Group). The results showed that, compared to control group, A2058 cells in group one exhibited decreased cellular proliferation, migration, invasiveness and vasculogenic mimicry concomitant with an increase in cell apoptosis, accompanied by down-regulation of PI3K/AKT pathway. Besides, the above mentioned anti-tumor effects on A2058 cells were significantly enhanced in group two but statistically weakened after administration of VO-Ohpic compared to group one. We demonstrate that ESC microenvironment reduces the malignancy of A2058 by down-regulating PI3K/AKT pathway. Notably, such anti-tumor effects can be enhanced by appropriately increasing the quality and quantity of ESCs in co-culture system. Our results suggest that ESC microenvironment could be an effective and safe approach to treating cancer.


Retrieving and applying knowledge to different examples promotes transfer of learning.
Introducing variability during learning often facilitates transfer to new contexts (i.e., generalization). The goal of the present study was to explore the concept of variability in an area of research where its effects have received little attention: learning through retrieval practice. In four experiments, we investigated whether retrieval practice with different examples of a concept promotes greater transfer than repeated retrieval practice with the same example. Participants watched video clips from a lecture about geological science and answered application questions about concepts: either the same question three times or three different questions. Experiments 3 and 4 also included conditions that involved repeatedly studying the information in the application questions (either the same example or three different examples). Two days later, participants took a final test with new application questions. All four experiments showed that variability during retrieval practice produced superior transfer of knowledge to new examples. Experiments 3 and 4 also showed a testing effect and a benefit from studying different examples. Overall, these findings suggest that repeatedly retrieving and applying knowledge to different examples is a powerful method for acquiring knowledge that will transfer to a variety of new contexts. (PsycINFO Database Record


FOXM1 expression predicts the prognosis in hepatocellular carcinoma patients after orthotopic liver transplantation combined with the Milan criteria.
Molecular biomarker has been proposed to improve patient selection and post-transplant prognostication, but rare achievement has been made. In the present study, Forkhead box M1 (FOXM1) expression and its prognostic role have been investigated in hepatocellular carcinoma (HCC) treated by orthotopic liver transplantation (OLT). We found that the notably higher level of FOXM1 in tumors was associated with malignant pathological features of HCC and unfavorable outcome after OLT. The status of FOXM1 expression combined with the Milan criteria could make the prognostication more accurate and may be of particular interest for expanding the criteria in selecting transplant candidates.


Pyrococcus furiosus Argonaute-mediated nucleic acid detection.
We demonstrate that short single-stranded DNA generated by Pyrococcus furiosus Argonaute (PfAgo) can initiate a second round of cleavage. Based on this principle, we established a molecular diagnostic method, termed PfAgo-mediated Nucleic acid Detection (PAND). This method could detect DNA at attomolar sensitivities, distinguish single-nucleotide mutants and accomplish multiplexed detection.


RHEGMATOGENOUS RETINAL DETACHMENT AFTER INITIATION OF PILOCARPINE HYDROCHLORIDE OPHTHALMIC SOLUTION 1.25% FOR TREATMENT OF PRESBYOPIA.
Retinal detachment has previously been reported in association with topical miotic use for the treatment of glaucoma. Pilocarpine hydrochloride 1.25% was recently approved by the Food and Drug Administration for the treatment of presbyopia, with no reports of associated retinal detachments in the clinical trial data. Case report. Two novel cases of unilateral retinal detachment occurring within 10 days of the initiation of pilocarpine 1.25% for the treatment of presbyopia were described. The patients were pseudophakic men in their 60s or 70s with preexisting retinal detachment risk factors, such as high myopia, lattice degeneration, and prior retinal detachment. Both affected eyes were treated with pars plana vitrectomy and gas endotamponade with an uncomplicated postoperative course. Retinal detachment may be associated with the use of pilocarpine 1.25%. Caution should be used when considering prescribing this medication in patients with preexisting retinal abnormality.


A potential mechanism of action of colloidal bismuth subcitrate: diffusion barrier to hydrochloric acid.
The mode of action of colloidal bismuth subcitrate (CBS), a colloidal bismuth preparation often used in the treatment of gastroduodenal ulcers, is unknown. The precipitation characteristics of CBS were determined by titration with hydrochloric acid and gastric juice. The precipitation pH were 4.0 and 3.5 respectively. Preoperative administration of CBS resulted in a preferential accumulation of bismuth in chronic gastric ulcers as determined by tissue bismuth assays. CBS and gastric glycoprotein formed an in vitro complex which markedly retarded the migration of H+. One of the mechanisms by which CBS promotes ulcer healing is through its behaviour as a diffusion barrier to hydrochloric acid.


Comparable outcomes using propylene glycol-free melphalan for autologous stem cell transplantation in multiple myeloma.
Autologous stem cell transplantation (ASCT) remains a mainstay in the treatment of multiple myeloma (MM). While the procedure is generally safe, toxicities associated with high-dose melphalan conditioning are common and significantly affect patient quality of life. Recently, a propylene glycol-free melphalan formulation (PG-free MEL; Evomela®) was approved by the United States Food and Drug Administration as an ASCT-conditioning regimen for MM. PG-free MEL is more soluble and stable than propylene glycol-solubilized melphalan (PG-solubilized MEL; Alkeran®). As such, there is speculation that it could decrease toxicities and increase the efficacy of ASCT. We compared the outcomes of patients conditioned with PG-free MEL (n = 216) to PG-solubilized MEL (n = 200) at our institution. The baseline characteristics were similar between the two groups. After Day +0, there were no differences in terms of hospitalizations, neutropenic fevers, intravenous granisetron requirement, World Health Organization grade ≥ 2 oral/esophageal mucositis, intravenous fluid requirement, or narcotic requirement. However, PG-free MEL patients had a higher incidence of diarrhea, which was mostly C. difficile-negative (82% vs. 71%, P = 0.015*). Day + 100 hematologic responses and progression-free survival after ASCT were comparable. In summary, we demonstrate that switching to PG-free MEL did not significantly reduce short-term complications of ASCT or improve outcomes in MM.


Evaluation of long-term efficacy of finasteride in Korean men with androgenetic alopecia using the basic and specific classification system.
Finasteride 1 mg is considered to be the standard treatment method for male androgenetic alopecia (AGA). However, there have only been a few studies investigating its long-term efficacy. Moreover, its effect on various types of AGA remains unknown. In this study, the authors investigated the 5-year efficacy of finasteride 1 mg in Korean men with AGA and analyzed the changes in hair growth according to the distribution of hair loss. The medical records of male AGA patients who were treated with oral finasteride for a period of at least 5 years at two university hospitals were retrospectively reviewed. Patients' photographs were evaluated using the basic and specific (BASP) classification and investigator's global assessment. Of the total 126 patients, 108 (85.7%) showed improvement after 5 years of treatment. According to the BASP classification, hair loss of the anterior hair line (basic type), vertex (V type), and frontal area (F type) was improved in 44.4%, 89.7% and 61.2% of patients, respectively. The V type showed a more rapid and steady improvement compared with the other types. Progression of alopecia after peak improvement was seen in 10.3% of cases of the V type, 16.2% of the F type and 0% of the basic type. In conclusion, finasteride 1 mg showed a sustainable effect for at least 5 years in Korean male AGA patients. The exact time points showing signs of first clinical improvement and sustainability were different depending on the type of alopecia.


Catalytic activity of novel thermoplastic/cellulose-Au nanocomposites prepared by cryomilling.
Due to environmental concerns, increasing attention has been focused on the application and preparation of biobased polymers and their blends. In this study, cellulose, the most spread biopolymer on Earth, was used in the preparation of novel cotton/polypropylene-Au and cotton/polyethylene-Au nanocomposites via a green mechanochemical approach. First, mechanoradicals were generated by ball milling of the cotton and thermoplastics under cryo conditions, and then, these radicals were used in the reduction of Au ions to Au nanoparticles (Au NPs). Nanocomposites were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). The application of mechanochemistry in obtaining the cotton/thermoplastic blends allowed homogenous and fine blending of the samples and in addition, excluded the usage of toxic solvents. Since Au NPs exhibit a wide range of applications, e.g., in catalysis, cotton/thermoplastic-Au nanocomposites were used to catalyze the reduction reaction of 4-nitrophenol to 4-aminophenol, followed by UV-Vis spectroscopy. Finally, the hydrophobicity of the nanocomposites was alternated by tuning the blend composition. In the prepared nanocomposites, cotton and thermoplastics acted as very good supporting matrices for the Au NPs and provided satisfactory access to the NPs.


IgG response to Mycobacterium tuberculosis non-polar lipids and sonicated extracts among tuberculous meningitis patients.
The diagnosis of tuberculous meningitis (TBM) is a major global health concern due to its protean nature. There is a need to identify better biomarkers for the rapid and definitive diagnosis of TBM. Lipids have been poorly explored as diagnostic markers in TBM. Non-polar lipids (NPL) and mycobacterial sonicate extract (MTSE) antigens were assessed for diagnosis of Mycobacterium tuberculosis . A total of 110 cerebrospinal fluid samples were categorized as confirmed, suspected and non-TBM cases according to clinical presentation and laboratory investigations, which were further analysed by NPL and MTSE ELISA. The sensitivity and specificity of the NPL ELISA were 39.6 and 96 %, respectively, whereas the MTSE ELISA was 17 % sensitive and 92 % specific. The combination of the NPL and MTSE ELISA test was superior to these tests alone, with sensitivity and specificity of 43 and 88 %, respectively. This combination may be useful as an adjunct in the laboratory diagnosis of TBM. However, future studies in different settings among different populations, such as those with human immunodeficiency virus co-infection, are desirable to explore the full potential of biomarkers.


fMRI reveals large-scale network activation in minimally conscious patients.
The minimally conscious state (MCS) resulting from severe brain damage refers to a subset of patients who demonstrate unequivocal, but intermittent, behavioral evidence of awareness of self or their environment. Although clinical examination may suggest residual cognitive function, neurobiological correlates of putative cognition in MCS have not been demonstrated. To test the hypothesis that MCS patients retain active cerebral networks that underlie cognitive function even though command following and communication abilities are inconsistent. fMRI was employed to investigate cortical responses to passive language and tactile stimulation in two male adults with severe brain injuries leading to MCS and in seven healthy volunteers. In the case of the patient language-related tasks, auditory stimulation with personalized narratives elicited cortical activity in the superior and middle temporal gyrus. The healthy volunteers imaged during comparable passive language stimulation demonstrated responses similar to the patients' responses. However, when the narratives were presented as a time-reversed signal, and therefore without linguistic content, the MCS patients demonstrated markedly reduced responses as compared with volunteer subjects, suggesting reduced engagement for "linguistically" meaningless stimuli. The first fMRI maps of cortical activity associated with language processing and tactile stimulation of patients in the minimally conscious state (MCS) are presented. These findings of active cortical networks that serve language functions suggest that some MCS patients may retain widely distributed cortical systems with potential for cognitive and sensory function despite their inability to follow simple instructions or communicate reliably.


A comparison of interferon alfa-2a and podophyllin in the treatment of primary condylomata acuminata. The Condylomata International Collaborative Study Group.
to compare the response to treatment and recurrence rate of condylomata accuminata using subcutaneous injection of interferon alfa 2a 1.5 million units three times weekly for four weeks, or podophyllin resin 25% applied to lesions twice weekly for up to six weeks. Randomised open study. Multicentre European study in genitourinary medicine, dermatovenereology, and gynaecology departments. 87 males and 67 females with condylomata acuminata for less than six months and no history of previous treatment. Complete clearance of lesions and evidence of recurrence at three months and nine months after treatment commenced. A complete response was achieved at three months in 15 of 64 (23%) in the interferon treated group, and 31 of 69 (45%) in the podophyllin treated group (p = 0.003). At nine months 10 of 13 patients in the interferon group and 22 of 30 patients in the podophyllin group remained completely clear of lesions.


[Haematoma of the floor of the mouth following implant surgery].
A patient experienced severe bleeding in the floor of the mouth as a consequence of the placement of 2 implants in the resorbed anterior segment of the mandible. The resulting swelling of the floor of the mouth caused a life-threatening obstruction of the trachea. The patient was urgently transferred to a hospital. Treatment there consisted of the administration of medication and intensive observation. In the literature an intubation or the carrying out of a tracheotomy with possible surgical interventions is also described. The cause lay in damage to the lingual cortical plate of the mandible and trauma of the underlying vascular structures. Especially the cuspid and bicuspid regions are vulnerable because of the often seen lingual concavity in the processus alveolaris. Serious atrophy of the processus alveolaris is also a predisposition. To reduce the probability of such complications knowledge of the local anatomy, good clinical inspection and various radiographic evaluations are important. In case of obstruction of the trachea it is of vital importance to immediately transport the patient to the nearest hospital for further treatment.


Influence of the treatment of developmental dysplasia of the hip by the abduction brace on locomotor development in children.
To assess the influence of treating developmental dysplasia of the hip (DDH) with the abduction brace on locomotor development in children. One hundred children treated for DDH served as the study group. There were 80 girls and 20 boys. The children's average age at the beginning of the treatment was 8 weeks. The control group consisted of 100 healthy children with normal hips and without any locomotor system disorders. We have evaluated factors such as the age at which the treatment started, the duration of the treatment, the birth weight of the child and the time when the children started sitting and walking independently. On average, treatment with the abduction brace lasted 13 weeks (ranging from 6 to 26 weeks). The mean age at which the patients began to sit was 7 months, which was one week later compared to children from the control group (P = 0.28). The age at which they started walking was 12 months and 2 weeks, which was 3 weeks later than in the control group (P = 0.002). For children with DDH, the abduction brace is a safe and effective method of treatment and, although the infants begin to walk about 3 weeks later compared to healthy children, this practice does not seriously affect the child's locomotor development.


Chemical and Sensory Evaluation of Silicone and Polylactic Acid-Based Remedial Treatments for Elevated Methoxypyrazine Levels in Wine.
Alkylmethoxypyrazines (MPs) are a class of compounds that can elicit undesirable aroma and flavor characteristics in wine, and resist remediation using traditional wine making approaches. MPs are grape-derived constituents as well as contaminants from Coccinellidae beetles present during wine processing; the latter eliciting an off-flavor referred to as 'ladybug taint'. In this study we investigated the capacity of two plastic polymers-one silicone-based, the other polylactic acid-based-applied with varying surface areas to reduce concentrations of isopropylmethoxypyrazine (IPMP), sec-butylmethoxypyrazine (SBMP) and isobutylmethoxypyrazine (IBMP) in a Merlot wine using multi-dimensional gas chromatography coupled with mass spectrometry and headspace solid phase microextraction (SPME-MDGCMS). The impact of treatments on the sensory characteristics of the wine (descriptive analysis) and volatile aroma compounds (VOCs) (SPME-MDGCMS) was also investigated. Results showed substantial reductions for all of the target odorants: up to 38%, 44% and 39% for IPMP, SBMP and IBMP, respectively, for the silicone polymer, and up to 75%, 78% and 77% for IPMP, SBMP and IBMP, respectively, for the polylactic acid polymer. These polymers had no or minimal effect on VOCs at applications of 200 cm²/L for silicone or for all polylactic acid treatments. Sensory impacts were less clear, but generally showed minimal effect from the treatments. Taken overall, the data confirm the utility of both polylactic acid and silicone polymers in reducing elevated levels of grape-derived MPs, as well as potentially improving wine contaminated by ladybug taint.


Structure and function of the antibiotic resistance-mediating methyltransferase AviRb from Streptomyces viridochromogenes.
The emergence of antibiotic-resistant bacterial strains is a widespread problem in medical practice and drug design, and each case requires the elucidation of the underlying mechanism. AviRb from Streptomyces viridochromogenes methylates the 2'-O atom of U2479 of the 23S ribosomal RNA in Gram-positive bacteria and thus mediates resistance to the oligosaccharide (orthosomycin) antibiotic avilamycin. The structure of AviRb with and without bound cofactor S-adenosyl-L-methionine (AdoMet) was determined, showing that it is a homodimer belonging to the SpoU family within the SPOUT class of methyltransferases. The relationships within this class were analyzed in detail and, in addition, a novel fourth SpoU sequence fingerprint is proposed. Each subunit of AviRb consists of two domains. The N-terminal domain, being related to the ribosomal proteins L30 and L7Ae, is likely to bind RNA. The C-terminal domain is related to all SPOUT methyltransferases, and is responsible for AdoMet-binding, catalysis and dimerization. The cofactor binds at the characteristic knot of the polypeptide in an unusually bent conformation. The transferred methyl group points to a broad cleft formed with the L30-type domain of the other subunit. Measurements of mutant activity revealed four important residues responsible for catalysis and allowed the modeling of a complex between AviRb and the RNA target. The model includes a specificity pocket for uracil but does not contain a base for deprotonating the 2'-O atom of U2479 on methylation.


High-frequency stable isotope signals in uneven-aged forests as proxy for physiological responses to climate in Central Europe.
Picea abies (L.) Karst. and Fagus sylvatica (L.) are important tree species in Europe, and the foreseen increase in temperature and vapour pressure deficit (VPD) could increase the vulnerability of these species. However, their physiological performance under climate change at temperate and productive sites is not yet fully understood, especially in uneven-aged stands. Therefore, we investigated tree-ring width and stable isotope chronologies (δ13C/δ18O) of these two species at 10 sites along a climate gradient in Central Europe. In these uneven-aged stands, we compared the year-to-year variability of dominant and suppressed trees for the last 80 years in relation to the sites' spatial distribution and climate. δ18O and δ13C were generally consistent across sites and species, showing high sensitivity to summer VPD, whereas climate correlations with radial growth varied much more and depended on mean local climate. We found no significant differences between dominant and suppressed trees in the response of stable isotope ratios to climate variability, especially within the annual high-frequency signals. In addition, we observed a strikingly high coherence of the high-frequency δ18O variations across long distances with significant correlations above 1500 km, whereas the spatial agreement of δ13C variations was weaker (~700 km). We applied a dual-isotope approach that is based on known theoretical understanding of isotope fractionations to translate the observed changes into physiological components, mainly photosynthetic assimilation rate and stomatal conductance. When separating the chronologies in two time windows and investigating the shifts in isotopes ratios, a significant enrichment of either or both isotope ratios over the last decades can be observed. These results, translated by the dual-isotope approach, indicate a general climate-driven decrease in stomatal conductance. This improved understanding of the physiological mechanisms controlling the short-term variation of the isotopic signature will help to define the performance of these tree species under future climate.


Characterization of rabbit lung lysosomes and their role in surfactant dipalmitoylphosphatidylcholine catabolism.
Although alveolar surfactant is rapidly catabolized in adult rabbit lungs, the pathways have not been characterized. Pathways of surfactant secretion and recycling involve lamellar bodies and multivesicular bodies, organelles shown to be related to lysosomes by cytochemistry and autoradiography. Since lysosomes are central to intracellular catabolic events, it is possible that lysosomes are involved in intrapulmonary surfactant catabolism. Lysosomes relatively free of contaminating organelles (as determined morphologically and by marker enzymes for mitochondria, endoplasmic reticulum, peroxisomes, and plasma membranes) were obtained from post-lavage lung homogenates of 1-kg rabbits by differential centrifugation in buffered sucrose and gradient separation in percoll (density, 1.075-1.165). The role of lung lysosomes in catabolism of dipalmitoylphosphatidylcholine (DPC) was then studied in rabbits killed 4, 12, and 24 h following intratracheal injection of [3H]DPC and [14C] dihexadecyl phosphatidylcholine (DPC-ether). While equal amounts of label were in the lamellar body containing fractions at 4 h, nearly 6-fold more DPC-ether label than DPC label was recovered in the lysosomal fractions. By 24 h, there was 15-fold more DPC-ether in the lysosomes. This is the first report of successful isolation of lysosomes relatively free of other organelles from rabbit lungs. The tracer studies indicate DPC and DPC-ether follow similar intracellular processing after alveolar uptake. The subsequent accumulation of the ether analog in the lysosomal fractions supports a role for these organelles in surfactant DPC catabolism.


Strategies for improving access to primary care services for homeless immigrants in England: a Delphi study.
The aim of the study was to identify the most prioritized strategies in improving access to primary care services (PCS) for homeless immigrants. The issue of improving access to PCS for homeless immigrants is a complex and multifaceted one, and yet there is limited research on the strategies aimed at improving these services. Hence, the need for more studies that directly engage homeless immigrants and service providers in understanding their barriers to accessing PCS and their preferences for improving access to these services. The study used a two round Delphi method to elicit the views of stakeholders. The Delphi process utilized a web-based questionnaire. The stakeholders included healthcare providers and voluntary sector providers. The first round had a total of 58 items belonging to 14 categories. The second round comprised a total of 25 items belonging to 12 categories which were preselected based on participants' ranking of their importance in the first round. Participants were required to rank the relative importance of all the items on a 5-point Likert scale. Data were analysed using the STATA-15 software package. A total of 12 stakeholders participated in both rounds of the Delphi survey. The top three strategies encompassed fighting against discrimination and prejudice, improving and promoting mental health services, and empowering homeless immigrants. These evidence-based strategies hold the potential to support the implementation of healthcare interventions aimed at improving access to PCS and healthcare outcomes for homeless immigrants. However, it is crucial to conduct further research that includes homeless immigrants in the Delphi study to gain insights into the strategies that are most important to them in enhancing access to PCS, as they are the primary target users. Such research will contribute to the development of comprehensive and effective interventions tailored to the specific needs of homeless.


The Impact of Obesity on the Association between Vitamin D Deficiency and Cardiovascular Disease.
The aim of this article is to review the literature regarding the relationship between vitamin D deficiency and cardiovascular disease (CVD) and its modification in the presence of obesity. Despite the strong association between vitamin D status and cardiovascular outcomes, vitamin D supplementation trials in the general population have failed to decrease the incidence of cardiovascular events and mortality. A comprehensive study of the published literature and a comparison with experimental data lead to the conclusion that obesity, due to its high prevalence and strong association with both vitamin D deficiency and CVD, may act as a critical confounder, which is responsible for the different results on this association. Adoption of a vitamin D preventive supplementation strategy for CVD is unlikely to yield any benefit to the general population. However, it might be particularly useful in obese adults with increased risk for CVD.


Dynamics of Mycobacterium and bovine tuberculosis in a human-buffalo population.
A new model for the transmission dynamics of Mycobacterium tuberculosis and bovine tuberculosis in a community, consisting of humans and African buffalos, is presented. The buffalo-only component of the model exhibits the phenomenon of backward bifurcation, which arises due to the reinfection of exposed and recovered buffalos, when the associated reproduction number is less than unity. This model has a unique endemic equilibrium, which is globally asymptotically stable for a special case, when the reproduction number exceeds unity. Uncertainty and sensitivity analyses, using data relevant to the dynamics of the two diseases in the Kruger National Park, show that the distribution of the associated reproduction number is less than unity (hence, the diseases would not persist in the community). Crucial parameters that influence the dynamics of the two diseases are also identified. Both the buffalo-only and the buffalo-human model exhibit the same qualitative dynamics with respect to the local and global asymptotic stability of their respective disease-free equilibrium, as well as with respect to the backward bifurcation phenomenon. Numerical simulations of the buffalo-human model show that the cumulative number of Mycobacterium tuberculosis cases in humans (buffalos) decreases with increasing number of bovine tuberculosis infections in humans (buffalo).


Improved scatter correction with factor analysis for planar and SPECT imaging.
Quantitative nuclear medicine imaging is an increasingly important frontier. In order to achieve quantitative imaging, various interactions of photons with matter have to be modeled and compensated. Although correction for photon attenuation has been addressed by including x-ray CT scans (accurate), correction for Compton scatter remains an open issue. The inclusion of scattered photons within the energy window used for planar or SPECT data acquisition decreases the contrast of the image. While a number of methods for scatter correction have been proposed in the past, in this work, we propose and assess a novel, user-independent framework applying factor analysis (FA). Extensive Monte Carlo simulations for planar and tomographic imaging were performed using the SIMIND software. Furthermore, planar acquisition of two Petri dishes filled with 99mTc solutions and a Jaszczak phantom study (Data Spectrum Corporation, Durham, NC, USA) using a dual head gamma camera were performed. In order to use FA for scatter correction, we subdivided the applied energy window into a number of sub-windows, serving as input data. FA results in two factor images (photo-peak, scatter) and two corresponding factor curves (energy spectra). Planar and tomographic Jaszczak phantom gamma camera measurements were recorded. The tomographic data (simulations and measurements) were processed for each angular position resulting in a photo-peak and a scatter data set. The reconstructed transaxial slices of the Jaszczak phantom were quantified using an ImageJ plugin. The data obtained by FA showed good agreement with the energy spectra, photo-peak, and scatter images obtained in all Monte Carlo simulated data sets. For comparison, the standard dual-energy window (DEW) approach was additionally applied for scatter correction. FA in comparison with the DEW method results in significant improvements in image accuracy for both planar and tomographic data sets. FA can be used as a user-independent approach for scatter correction in nuclear medicine.


Assessing the inclusion of primary school children in vision screening for refractive error program of India.
In India, teachers screen middle school children using the 6/9 Snellen's optotype. Recently, the National Program for Control of Blindness included primary school students also. The present cross-sectional study was planned to assess the inclusion of primary school students. Compliance to spectacles was ascertained after 6 months follow-up. Randomly selected 23 Government primary schools. A total of 30 teachers were nominated and given hands-on training in vision screening and recording formats. Teachers conducted vision screening of primary school students of their respective schools using the 6/12 Snellen's chart and referred students with subnormal vision to optometrist. Optometrist also validated the screening done by teachers. Optometrist screened the vision of 5% randomly selected children screened by teachers as having normal vision. Descriptive statistics used STATA version 13.0. A total of 6056 students screened by the teachers. Sensitivity and specificity of teacher screening were 92.3% (confidence interval [CI] 88.6-95.0) and 72.6% (CI 68.2-76.6)), respectively. About 277 students underwent refraction and 186 prescribed spectacles. The prevalence of myopia, hypermetropia, and astigmatism is 2.5% (2.1-2.9), 0.6% (0.4-0.8), and 1.3% (1.0-1.6), respectively. Compliance to spectacles usage is 36%. Burden of refractive error in primary school is very low. Trained teachers can identify children with subnormal vision, but the false-positive rate is very high. Compliance to spectacle use among primary school children is also less. Vision screening by teachers prioritized in secondary schools and preschool screening should be done by more skilled eye care workers preferably optometrist.


Apatinib for advanced nonsmall-cell lung cancer: A retrospective case series analysis.
Apatinib, a tyrosine kinase inhibitor which selectively inhibits vascular endothelial growth factor receptor-2, has been shown to be beneficial to patients with a variety of cancers, including advanced nonsmall-cell lung cancer (NSCLC). Thus, this study was aimed to retrospectively assess the efficacy and safety of apatinib in patients with advanced/metastatic NSCLC who failed more than two lines of treatment. Twenty-three NSCLC patients were involved in this study, who received oral apatinib at a daily dose of 250/500/750 mg, with the progression after the failure of second-line therapy. Treatment was continued until disease progression. The tumor assessments were determined according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Safety was evaluated with adverse reactions and toxicities based on the Common Terminology Criteria for Adverse Events (version 4.0). Response and safety for the included patients were evaluated every 8 weeks. In this study, 23 NSCLC patients were followed from January 2015 to December 2016. Available image efficacy was obtained in 22 patients, including 4 identified as partial responses, 17 stable disease, and 1 progressive disease; no complete responses was observed. The objective response rate was 18.2%, and the disease control rate was 95.5%. Median progression free survival and overall survival for apatinib were 203 days (95% CI, 120-269) and 227 days (95% CI, 146-294), respectively. The most frequent treatment-related adverse events were hypertension, gastrointestinal reactions, and hand-foot skin reaction. Apatinib exhibited modest activity and acceptable toxicity for advanced NSCLC after the failure of chemotherapy or other targeted therapy.


Bronchopulmonary carcinoid with a single lymph node metastasis causing ectopic Cushing's syndrome.
Bronchial carcinoid tumors (BCTs) represent a subgroup of bronchopulmonary neuroendocrine tumors which have the ability to produce neuropeptides. Merely 2% of BCTs secrete ACTH and less than 1% of patients with Cushing's syndrome (CS) have a BCT. Typical BCTs rarely metastasize. We here present a patient with ectopic CS caused by a typical BCT, which metastasized into a lymph node. This case suggests that the diagnostic work up of CS should be wide and include ectopic ACTH-secreting BCT, and that ACTH secretion can be correlated to a more aggressive type of typical BCTs.


Transforming growth factor beta1 and beta2 reduce the number of gonocytes by increasing apoptosis.
Transforming growth factors beta1 and beta2 (TGFbetas) have recently been detected by immunohistochemistry in the fetal and neonatal rat testis, and the aim of the present study was to determine whether these factors can act as local regulators to control the number of gonocytes. Testes were kept in organ culture, and TGFbeta1 was found to have dose-dependent inhibitory effect on the number of gonocytes in testes explanted on fetal day 13.5. Either TGFbeta1 or beta2 at 10 ng/ml reduced the number of gonocytes by half after 2 days culture. TGFbetas did not decrease the BrdU labeling index of gonocytes or Sertoli cells, whereas these factors significantly increased the DNA fragmentation in gonocytes (TUNEL method). The other testicular cell types showed no positive TUNEL reaction. TGFbeta1 did not reduce the number of gonocytes in testes explanted on fetal day 17.5 (i.e. during the quiescent phase), but it did so in testes explanted on postnatal day 3 (i.e. stage of resumption of mitosis). To determine the potential cell type targets for TGFbetas, type I and type II TGFbeta receptors were immunolocalized in developing testis from fetal day 13.5 to postnatal day 3. Both receptors were present in the gonocytes throughout the whole period studied, and in the Leydig cells from fetal day 16.5 onward, but they were not detected in the Sertoli cells. Taken together, these results suggest that TGFbetas directly increase apoptosis in gonocytes without changing their mitotic activity during the developmental phases of proliferation.


The production and generalization of large-magnitude heart rate deceleration by contingently faded biofeedback.
Eight subjects were taught to decrease their heart rates via biofeedback training. Four of these received contingently faded, beat-by-beat analogue feedback and contingent reinforcement each time their performance met a specified and adjusting criterion. The other four received continuous, beat-by-beat analogue feedback, but not the contingent reinforcement. Subjects in the two groups were yoked to ensure equal densities of reinforcement. Subjects in the first group were asked to decrease heart rates 15% from baseline and were then trained using only 75%, 50% and 25% of beat-by-beat feedback. It was hypothesized that the immediate reinforcement of appropriate behavior and the contingent fading (following mastery) of feedback would aid in the generalization of the response. Following completion of all criterion steps or 10 training sessions, whichever came first, all subjects were tested with no feedback and no contingent reinforcement. The group receiving contingently faded feedback training showed a significantly greater heart rate decrease in the training sessions and also the test session. These results were interpreted as indicating that biofeedback can be conceptualized as an operant conditioning paradigm, and that the use of operant techniques may help subjects produce clinically significant changes.


[Application of big data analyses for musculoskeletal cell differentiation].
Next generation sequencer has strongly progress big data analyses in life science. Among various kinds of sequencing data sets, epigenetic platform has just been important key to clarify the questions on broad and detail phenomenon in various forms of life. In this report, it is introduced that the research on identification of novel transcription factors in osteoclastogenesis using DNase-seq. Big data on musculoskeletal research will be organized by IFMRS and is getting more crucial.


Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function.
Deletion of phenylalanine-508 (Phe-508) from the N-terminal nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR), a member of the ATP-binding cassette (ABC) transporter family, disrupts both its folding and function and causes most cystic fibrosis. Most mutant nascent chains do not pass quality control in the ER, and those that do remain thermally unstable, only partially functional, and are rapidly endocytosed and degraded. Although the lack of the Phe-508 peptide backbone diminishes the NBD1 folding yield, the absence of the aromatic side chain is primarily responsible for defective CFTR assembly and channel gating. However, the site of interdomain contact by the side chain is unknown as is the high-resolution 3D structure of the complete protein. Here we present a 3D structure of CFTR, constructed by molecular modeling and supported biochemically, in which Phe-508 mediates a tertiary interaction between the surface of NBD1 and a cytoplasmic loop (CL4) in the C-terminal membrane-spanning domain (MSD2). This crucial cytoplasmic membrane interface, which is dynamically involved in regulation of channel gating, explains the known sensitivity of CFTR assembly to many disease-associated mutations in CL4 as well as NBD1 and provides a sharply focused target for small molecules to treat CF. In addition to identifying a key intramolecular site to be repaired therapeutically, our findings advance understanding of CFTR structure and function and provide a platform for focused biochemical studies of other features of this unique ABC ion channel.


Cervical Vagus Nerve Stimulation Disrupts Gastric Slow Wave Activity in Rats.
Cervical vagus nerve stimulation (cVNS) is a promising neuromodulation therapy for treating symptoms of disease in peripheral organs. The rat is a common animal model for studying and trialing new applications of cVNS therapy, but the stomach and its activity in rats is less well characterized than other animals, such as pigs. We sought to investigate the effects of acute, in vivo cVNS on gastric bioelectrical activity as an intermediate step to computational modeling of the effects of cVNS on gastric smooth muscle electromechanical coupling. Here we show a method of detecting bioelectrical gastric slow wave events using a non-linear energy operator. The marked events are compared to the underlying bioelectrical slow wave activity.The mean propagation velocity before stimulation was 0.79 ± 0.31 mm s-1, and the mean interval was 17.4 ± 1.4 s. During cVNS, there was a significant increase in velocity (1.02 ± 0.69 mm s-1; p < 0.001), and decrease in interval (15.4 ± 2.9 s; p = 0.0196). At stimulation onset, premature slow waves were induced at an ectopic pacemaker location and waves originating at the ectopic and initial pacemaker sites continued to collide following the cessation of cVNS.This work forms the basis for more thorough investigation of the effects of cVNS on gastric bioelectrical slow wave activity and consequential smooth muscle contractions in rats. A better understanding of the effects of cVNS on gastric function will allow the refinement of cVNS therapy to target the stomach, and avoid off-target effects on the stomach.Clinical relevance- This work presents a signal processing and analysis approach for the investigation of cervical vagus nerve stimulation on gastric bioelectrical activity in rats. Vagus nerve stimulation may enable the control and amelioration of hunger, gastric emptying, or functional gastric disorders.


Ocular haemodynamics and colour contrast sensitivity in patients with type 1 diabetes.
There is evidence that altered ocular blood flow is involved in the development and progression of diabetic retinopathy. However, the nature of these perfusion abnormalities is still a matter of controversy. Ocular haemodynamics were characterised with two recently introduced methods. The cross sectional study was performed in 59 patients with type 1 diabetes with a diabetes duration between 12 and 17 years and an age less than 32 years and a group of 25 age matched healthy controls. Scanning laser Doppler flowmetry and laser interferometric measurement of fundus pulsation amplitude were used to assess retinal and pulsatile choroidal blood flow, respectively. In addition, colour contrast sensitivity along the tritan axis was determined. Fundus pulsation amplitude, but not retinal blood flow, increased with the progression of diabetic retinopathy. Retinal blood flow was influenced by plasma glucose levels (r = 0.32), whereas fundus pulsation amplitude was associated with HbA(1c) (r = 0.30). In addition, a negative correlation between the colour contrast sensitivity along the tritan axis and retinal blood flow was observed. The present study indicates that pulsatile choroidal blood flow increases with the progression of diabetic retinopathy. Increased retinal blood flow appears to be related to loss of colour sensitivity in patents with type 1 diabetes.


NSAIDs and cardiovascular risk.
NSAIDs are the most largely used class of drugs in the world, due to their large use in many diseases, in particular for the systemic inflammatory diseases. Nevertheless, today NSAIDs are less used for some of these diseases, due to several side-effects correlated to these drugs. The antiinflammatory mechanism of NSAIDs consist in the inibhition of two forms of cyclooxygenase, namely COX-1 (its block contributes to an antiplatelet effect) and COX-2 (its block has a greater antiinflammatory, antipyretic and analgesic effect). The COX-2 inhibition might reduce the risk of gastrointestinal toxicity, but several studies have shown the cardiovascular side effects of this inhibition. Mechanisms of the cardiovascular side effects are controversial yet, so the aim of this document is to review side-effects profile of NSAIDs and, specifically, to investigate cardiovascular consequences of NSAIDs use in clinical practice.


ADRIS--The Adverse Drug Reactions Information Scheme.
Under the Adverse Drug Reactions Information Scheme (ADRIS) data and knowledge relevant to the etiology of adverse drug reactions (ADRs) such as chemical structure of parent compounds, metabolites, covalent adducts, nucleic acid and protein sequences, protein structures, pharmaco-, toxico- and enzyme kinetics, pharmaco- and toxicodynamics, protein interactions, molecular pathways and complexes, as well as toxicological and clinical outcomes, are collected and logically and semantically related. ADRIS reflects the ontological prerequisite for the creation of databases and knowledge discovery systems for the abstraction and visualization of theragenomic concepts. A final outcome is the prediction of ADRs based on a profound knowledge of drug function and the molecular basics for personalized drug safety and eventually, personalized medicine.


Fine structure of progenitor cells in early ectopic human embryos.
This study has documented the major types of lineage progenitor cells at the second level of cell differentiation after the establishment of the primary germ layers in ectopic human embryos in vivo. These correspond to stages 8 and 9 of embryogenesis (weeks 3-4) in the Carnegie collection. The aim of this study was to provide images of fine structure of tissue progenitor cells to compare them with current imaging of their equivalent stem cells identified using fluorescent stem cell markers. These include neural, mesenchymal, endodermal, ectodermal (epidermal) and haematopoietic progenitor cells, including those for amniotic, yolk sac and chorionic tissues that are used in current stem cell research. Neural induction by the notochord has been imaged. This study should give valuable clues to understand the pattern of cell differentiation of embryonic stem cells (ESC) in vitro, which are more or less mimicked in ESC colonies, embryoid bodies and neurospheres as documented in the literature. The fine structure of week-3 and week-4 human ectopic embryos is presented to demonstrate progenitor tissue cells that will eventually form the brain, spinal cord, skin, gut, heart, blood, muscle, bone and other tissues of the human body later on in development. These images should help stem cell researchers using fluorescent markers and other techniques to identify embryonic and adult stem cells in culture.


Enhancement of pain inhibition by working memory with anodal transcranial direct current stimulation of the left dorsolateral prefrontal cortex.
The aim of this study was to examine whether transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) enhances pain inhibition by improving working memory (WM). Forty healthy volunteers participated in two tDCS sessions. Pain was evoked by electrical stimulation at the ankle. Participants performed an n-back task (0-back and 2-back). The experimental protocol comprised five counterbalanced conditions (0-back, 2-back, pain, 0-back with pain and 2-back with pain) that were performed twice (pre-tDCS baseline and during tDCS). Compared with the pre-tDCS baseline values, anodal tDCS decreased response times for the 2-back condition (p < 0.01) but not for the 0-back condition (p > 0.5). Anodal tDCS also decreased pain ratings marginally in the 2-back with pain condition, but not the 0-back with pain condition (p = 0.052 and p > 0.2, respectively). No effect was produced by sham tDCS for any condition (p > 0.2). These results indicate that tDCS of the left DLPFC may enhance pain inhibition by improving WM.


Direct visualization of the phosphorylated epidermal growth factor receptor during its internalization in A-431 cells.
Epidermal growth factor (EGF) rapidly stimulates receptor autophosphorylation in A-431 cells. After 1 min the phosphorylated receptor can be identified at the plasma membrane using an anti-phosphotyrosine antibody. With further incubation at 37 degrees C, approximately 50% of the phosphorylated EGF receptor was internalized (t1/2 = 5 min) and associated with the tubulovesicular system and later with multivesicular bodies, but not the nucleus. During this period, there was no change in the extent or sites of phosphorylation. At all times the phosphotyrosine remained on the cytoplasmic side of the membrane, opposite to the EGF ligand identified by anti-EGF antibody. These data indicate that (a) the tyrosine-phosphorylated EGF receptor is internalized in its activated form providing a mechanism for translocation of the receptor kinase to substrates in the cell interior; (b) the internalized receptor remains intact for at least 60 min, does not associate with the nucleus, and does not generate any tyrosine-phosphorylated fragments; and (c) tyrosine phosphorylation alone is not the signal for receptor internalization.


Different effects of ageing on elastic and muscular arterial bifurcations in men.
In a previous study we have shown that the wall of the elastic carotid artery bifurcation (CAB) stiffens inhomogeneously with increasing age, the carotid artery bulb being most affected. In the present study the effect of ageing on the elastic properties of the wall and the strain the wall is exposed to along the muscular femoral artery bifurcation (FAB) was investigated using the CAB for comparison. The study was performed with 10 young (aged 20-30 years) and 10 old (50-60 years) presumed healthy volunteers. Distensibility along the bifurcation was determined by measuring noninvasively the maximum relative diameter changes of the artery during systole (peak delta d/d.100%), which is also a measure of strain, at various sites along both bifurcations by means of a vessel wall moving detector system. This system also makes the assessment of (end-diastolic) diameter possible. At all levels along the CAB, the diameter was significantly larger in the old than in the young. In the FAB, the diameter was only significantly larger in the old than in the young in the common and superficial femoral arteries. At all levels in the CAB, peak delta d/d.100% was significantly lower in the old than in the young, the carotid artery bulb being more affected than the common carotid artery (CCA), while in the FAB this parameter was lower in the old than in the young only in the common femoral artery (CFA). Peak delta d/d.100% was similar in the CCA and in the bulb in the young, but significantly higher in the CCA than at all levels in the bulb in the old. In the FAB, in the young peak delta d/d 100% was significantly higher in the CFA than at both levels in the deep and superficial femoral arteries, while in the old no significant differences in peak delta d/d.100% along the FAB could be detected. These findings indicate that the loss of wall elasticity with increasing age is different in the muscular and elastic arterial bifurcations investigated. The homogeneous distribution of wall elasticity in the elastic CAB at a younger age becomes inhomogeneous at an older age, while the opposite is observed in the muscular FAB. The changes in strain the different parts of the bifurcations are exposed to with increasing age are different in the CAB and the FAB. Differences in distensibility along bifurcations will make them deform inhomogeneously during the cardiac cycle.


In Silico Profiling of Clinical Phenotypes for Human Targets Using Adverse Event Data.
We present a novel approach for the molecular transformation and analysis of patient clinical phenotypes. Building on the fact that drugs perturb the function of targets/genes, we integrated data from 8.2 million clinical reports detailing drug-induced side effects with the molecular world of drug-target information. Using this dataset, we extracted 1.8 million associations of clinical phenotypes to 770 human drug-targets. This collection is perhaps the largest phenotypic profiling reference of human targets to-date, and unique in that it enables rapid development of testable molecular hypotheses directly from human-specific information. We also present validation results demonstrating analytical utilities of the approach, including drug safety prediction, and the design of novel combination therapies. Challenging the long-standing notion that molecular perturbation studies cannot be performed in humans, our data allows researchers to capitalize on the vast tomes of clinical information available throughout the healthcare system.


Nonpathogenic isolates of Yersinia enterocolitica do not contain functional inv-homologous sequences.
Previous studies have demonstrated a correlation between the ability of isolates of Yersinia enterocolitica to cause disease and to invade tissue culture cells in vitro. Two genes, inv and ail, isolated from a pathogenic strain of Y. enterocolitica have each been shown to confer this invasive phenotype upon Escherichia coli. Eighty pathogenic, invasive isolates studied by Miller et al. (Infect. Immun. 57:121-131, 1989) contained sequences homologous to both of these genes. Thirty-five nonpathogenic, noninvasive isolates similarly studied had no ail homology but carried inv-homologous sequences. We investigated inv-homologous sequences from four nonpathogenic isolates. Recombinant clones of these inv-homologous sequences did not confer the invasive phenotype upon E. coli. No RNA transcripts capable of encoding a full-length Inv protein were detected in the four noninvasive Yersinia strains. When the inv gene from a pathogenic isolate was introduced into two of these strains, the resulting transformants invaded tissue culture cells in vitro. The inv gene was transcribed in a pathogenic Yersinia isolate grown at 30 degrees C but not at all in these cells grown at 37 degrees C. The production of RNA transcripts homologous to inv in transformants was not regulated by temperature to the same degree as was seen for pathogenic isolates. We conclude that the inv gene in nonpathogenic strains of Y. enterocolitica is nonfunctional. Y. enterocolitica isolates epidemiologically linked to disease contain both a functional inv gene and a functional ail gene. Environmental isolates not associated with disease have a nonfunctional inv gene and no ail gene.


Selective genetic analysis of p53 immunostain positive cells.
The isolation of p53 immunostain positive cells from histological sections for molecular genetic studies is a difficult task, especially if there are few positive cells. To eliminate contaminating DNA from p53 negative cells, which can obscure the results of molecular assays, a variation on the technique of immunohistoselective sequencing was developed. This is a highly selective approach, whereby immunostained sections of formalin fixed, paraffin wax embedded tissue are exposed to ultraviolet irradiation to damage the DNA in p53 negative cells. The DNA in positive cells remains unaffected because the dark immunostain protects their nuclei from ultraviolet light. Polymerase chain reaction single strand conformation polymorphism of samples enriched with p53 immunostain positive cells has shown that this method can produce pure samples of mutated DNA. The isolation of DNA from minority immunostain positive cells allows a wide range of molecular analyses to be carried out on these samples, which would otherwise be hampered by the problem of contaminating background cells.


Contralateral pneumonectomy after single-lung transplantation for emphysema.
An intractable contralateral air leak developed in a 46-year-old woman after right single-lung transplantation for emphysema. A left pneumonectomy was performed on postoperative day 17, leaving the patient with only one transplanted lung. Fifteen months postoperatively the patient is well and has satisfactory pulmonary function. Survival with a good quality of life is possible after single-lung transplantation and bilateral sequential pneumonectomies.


HIV-associated anal cancer: has highly active antiretroviral therapy reduced the incidence or improved the outcome?
Highly active antiretroviral therapy (HAART) has reduced the incidence and improved the survival of patients with Kaposi sarcoma and AIDS-related non-Hodgkin lymphoma. We wished to evaluate its effects on incidence and survival in HIV-associated anal cancer. We measured the incidence and survival of patients with invasive anal cancer from our prospective cohort of 8640 HIV-seropositive individuals. In our cohort of 8640 HIV-seropositive individuals, the incidence of invasive anal cancer (diagnosed in 26 patients) is 60 per 100,000 patient-years. This is 120 times higher than in the age- and gender-matched general population. The incidence of invasive anal cancer in the HIV cohort was 35 (95% confidence interval CI: 15-72) per 100,000 patient-years of follow-up in the pre-HAARTera (1984-1995) and 92 (95% CI: 52-149) per 100,000 patient-years of follow-up in the post-HAARTera (1996-2003) (P > 0.05). These figures are significantly higher than those for the general population (P < 0.001 for both) and give a relative risk of 67 and 176 in the pre- and post-HAART eras, respectively, compared with the general population. The 5-year overall survival is 47% (95% CI: 24%-70%), and the 5-year disease-free survival is 66% (95% CI: 45%-87%). There is no difference in overall survival between the pre- and post-HAART eras (log rank P = 0.19). Unlike other HIV-associated cancers, there has been no significant change in the incidence, clinical features, or overall survival since the introduction of HAART.


Cold adaptation in DEAD-box proteins.
Spontaneous rearrangements of RNA structures are usually characterized by large activation energies and thus become very slow at low temperatures, yet RNA structure must remain dynamic even in cold-adapted (psychrophilic) organisms. DEAD-box proteins constitute a ubiquitous family of RNA-dependent ATPases that can often unwind short RNA duplexes in vitro (helicase activity), hence the belief that one of their major (though not exclusive) roles in vivo is to assist in RNA rearrangements. Here, we compare two Escherichia coli DEAD-box proteins and their orthologs from the psychrophilic bacteria Pseudoalteromonas haloplanktis and Colwellia psychrerythraea from the point of view of enzymatic properties. One of these proteins (SrmB) is involved in ribosome assembly, whereas the other (RhlE) presumably participates in both mRNA degradation and ribosome assembly; in vitro, RhlE is far more active as a helicase than SrmB. The activation energy associated with the ATPase activity of the psychrophilic SrmB is lower than for its mesophilic counterpart, making it more active at low temperatures. In contrast, in the case of psychrophilic RhlE, it is the RNA unwinding activity, not the ATPase activity, that has a reduced activation energy and is therefore cold-adapted. We argue that these different modes of cold adaptation reflect the likely function of these proteins in vivo: RNA helicase for RhlE and ATP-dependent RNA binding for SrmB. The cold adaptation of helicases like RhlE presumably facilitates RNA metabolism in psychrophilic bacteria.


Measles resurgence in France in 2008, a preliminary report.
Since the beginning of 2008, France is experiencing a resurgence of measles. It started in a religious traditionalist group with low coverage and secondarily spread to the general population. This situation is the consequence of the insufficient vaccine coverage (less than 90 % at 24 months of age) which had led to the accumulation of susceptibles over the last years. More than 550 cases have been notified in 2008, the vast majority being unvaccinated. One measles-related death has occurred early 2009. Efforts to enhance communication to the general public and the health professionals on measles vaccination and control measures around cases are ongoing.


TBCRC 002: a phase II, randomized, open-label trial of preoperative letrozole with or without bevacizumab in postmenopausal women with newly diagnosed stage 2/3 hormone receptor-positive and HER2-negative breast cancer.
In preclinical studies, the expression of vascular endothelial growth factor (VEGF) in hormone receptor-positive breast cancer is associated with estrogen-independent tumor growth and resistance to endocrine therapies. This study investigated whether the addition of bevacizumab, a monoclonal antibody against VEGF, to letrozole enhanced the antitumor activity of the letrozole in the preoperative setting. Postmenopausal women with newly diagnosed stage 2 or 3 estrogen and/or progesterone receptor-positive, HER2-negative breast cancer were randomly assigned (2:1) between letrozole 2.5 mg PO daily plus bevacizumab 15 mg/kg IV every 3 weeks (Let/Bev) and letrozole 2.5 mg PO daily (Let) for 24 weeks prior to definitive surgery. Primary objective was within-arm pathologic complete remission (pCR) rate. Secondary objectives were safety, objective response, and downstaging rate. Seventy-five patients were randomized (Let/Bev n = 50, Let n = 25). Of the 45 patients evaluable for pathological response in the Let/Bev arm, 5 (11%; 95% CI, 3.7-24.1%) achieved pCR and 4 (9%; 95% CI, 2.5-21.2%) had microscopic residual disease; no pCRs or microscopic residual disease was seen in the Let arm (0%; 95% CI, 0-14.2%). The rates of downstaging were 44.4% (95% CI, 29.6-60.0%) and 37.5% (95% CI, 18.8-59.4%) in the Let/Bev and Let arms, respectively. Adverse events typically associated with letrozole (hot flashes, arthralgias, fatigue, myalgias) occurred in similar frequencies in the two arms. Hypertension, headache, and proteinuria were seen exclusively in the Let/Bev arm. The rates of grade 3 and 4 adverse events and discontinuation due to adverse events were 18% vs 8% and 16% vs none in the Let/Bev and Let arms, respectively. A small RNA-based classifier predictive of response to preoperative Let/Bev was developed and confirmed on an independent cohort. In the preoperative setting, the addition of bevacizumab to letrozole was associated with a pCR rate of 11%; no pCR was seen with letrozole alone. There was additive toxicity with the incorporation of bevacizumab. Responses to Let/Bev can be predicted from the levels of 5 small RNAs in a pretreatment biopsy. This trial is registered with ClinicalTrials.gov (Identifier: NCT00161291), first posted on September 12, 2005, and is completed.


Whole genome sequencing of Crassostrea ariakensis (Mollusca: Ostreidae) and C. hongkongensis expands understandings of stress resistance in sessile oysters.
To understand the environmental adaptations among sessile bivalves lacking adaptive immunity, a series of analyses were conducted, with special emphasis on the widely distributed C. ariakensis. Employing Pacbio sequencing and Hi-C technologies, whole genome for each of a C. ariakensis (southern China) and C. hongkongensis individual was generated, with the contig N50 reaching 6.2 and 13.0 Mb, respectively. Each genome harbored over 30,000 protein-coding genes, with approximately half of each genome consisting of repeats. Genome alignment suggested possible introgression between C. gigas and C. ariakensis (northern China), and re-sequencing data corroborated this result and indicated significant gene flow between C. gigas and C. ariakensis. These introgressed candidates, well-represented by genes related to immunity and osmotic pressure, may be associated with environmental stresses. Gene family dynamics modeling suggested immune-related genes were well represented among the expanded genes in C. ariakensis. These outcomes could be attributed to the spread of C. ariakensis.


Local induction of the alc gene switch in transgenic tobacco plants by acetaldehyde.
The alc promoter system, derived from the filamentous fungi Aspergillus nidulans, allows chemically regulated gene expression in plants and thereby the study of gene function as well as metabolic and developmental processes. In addition to ethanol, this system can be activated by acetaldehyde, described as the physiological inducer in A. nidulans. Here, we show that in contrast to ethanol, acetaldehyde allows tissue-specific activation of the alc promoter in transgenic tobacco plants. Soil drenching with aqueous acetaldehyde solutions at a concentration of 0.05% (v/v) resulted in the rapid and temporary induction of the alc gene expression system exclusively in roots. In addition, the split root system allows activation to be restricted to the treated part of the root. The temporary activation of the alc system by soil drenching with acetaldehyde could be prolonged over several weeks by subsequent applications at intervals of 7 d. This effect was demonstrated for the root-specific induction of a yeast-derived apoplast-located invertase under the control of the alcohol-inducible promoter system. In leaves, which exhibit a lower responsiveness to acetaldehyde than roots, the alc system was induced in the directly treated tissue only. Thus, acetaldehyde can be used as a local inducer of the alc gene expression system in tobacco plants.


Minimal clinically important difference for asthma endpoints: an expert consensus report.
Minimal clinically important difference (MCID) can be defined as the smallest change or difference in an outcome measure that is perceived as beneficial and would lead to a change in the patient's medical management.The aim of the current expert consensus report is to provide a "state-of-the-art" review of the currently available literature evidence about MCID for end-points to monitor asthma control, in order to facilitate optimal disease management and identify unmet needs in the field to guide future research.A series of MCID cut-offs are currently available in literature and validated among populations of asthmatic patients, with most of the evidence focusing on outcomes as patient reported outcomes, lung function and exercise tolerance. On the contrary, only scant and partial data are available for inflammatory biomarkers. These clearly represent the most interesting target for future development in diagnosis and clinical management of asthma, particularly in view of the several biologic drugs in the pipeline, for which regulatory agencies will soon require personalised proof of efficacy and treatment response predictors.


Undetected, uncontrolled blood pressure in type 2 diabetes: self-monitored blood pressure profiles.
To construct a novel and clinically relevant means of representing self-monitored blood pressure (SMBP). Patients treated to an office blood pressure (BP) < 130/80 mmHg measured their BP at home for 14 days using an Omron IC semi-automatic portable monitor with memory. SMBP data were transferred from the monitor to a computer to produce graphic profiles (SMBPp) that depict the hourly variation in BP throughout a "typical" or modal day. Office BP and SMBP data from 66 subjects with type 2 diabetes and hypertension (HTN), who completed a previous study of intensified management, were analyzed based on European Society of Hypertension-European Society of Cardiology (ESH-ESC) classifications. Patients were classified as Optimal (6), Normal (12), High Normal (15), Isolated systolic HTN (29) and Grades 1, 2 or 3 HTN (4). SMBP disagreed in 32 cases, placing 29 patients in higher risk categories. Analysis by SMBPp of the 33 patients originally classified as Optimal, Normal or High Normal showed that on average 50 +/- 31% of their systolic SMBP values exceeded ESH-ESC thresholds for HTN (135 mmHg). It also revealed that 74 +/- 21% of their SMBP values exceeded the treatment goal (< 25 mmHg) for high-risk patients with type 2 diabetes. SMBPp allowed for a definitive measurement of the dynamic daily BP changes. It produced compelling evidence of persistent patterns of BP fluctuations among patients with normal office BP whose uncontrolled HTN would have remained undetected.


The assessment and the farmers' perceived ranking of feed resources and coping strategies with feed scarcity in smallholder dairy farming in selected district towns of Jimma Zone, Ethiopia.
Inadequate quantity and quality of feed resources are major constraints limiting milk production and reproductive performance of dairy cattle in Ethiopia. The aim of this study was to assess dairy cattle feed resources, feeding practices, the farmers' perceived ranking of feed resources, causes of feed shortage, and coping strategies to feed scarcity in smallholder dairy system in selected district towns of Jimma Zone, Ethiopia. Data were obtained by interviewing 52 randomly selected smallholder dairy farmers using structured questionnaires and through direct observations. Results showed that 20 main feed types used by dairy farmers were identified and categorized into natural pastures, crop residues, green feeds, hay, agro-industrial by-products, concentrate mix, and non-conventional feeds. Overall, natural pasture (mean rank = 0.453), non-conventional feeds (0.307), cut green feeds (0.086), conserved hay (0.076), crop residues (0.049), and concentrate feeds (0.029) were ranked as the main feed resources in decreasing order of importance. Natural pasture grazing (92.2% of the respondents), hay (35.6%), and green feeds (29.4%) were the most important conventional basal feeds used. Wheat bran (11.7% of the respondents) followed by commercial concentrate mix (9.4%), Noug seedcake (8.3%), grain (7.8%), and molasses (6.1%) were the concentrate supplements used. Overall, bulule-flour mill leftovers (67.2% of the farmers), bean and pea hulls (57.2%) and atella-local brew by-product (37.2%), enset (Ensete ventricosum, 34.4%), and sugarcane top (32.2%) were the non-conventional feeds available and used during feed scarcity. Barley and teff (Eragrostis teff) straws and maize and sorghum stovers were the main crop residues used in the dry seasons. Overall, 73.9, 12.2, 12.2, and 1.7% of the respondents practiced free grazing, zero grazing, semi-zero, and a combination of zero- and free-grazing systems, respectively. Over 84% of the respondents in the dry season and 50% in the wet season reported experiencing a shortage of feeds. Poor feed availability (73.9% of the respondents) was reported as the main causes of feed shortage followed by shortage of pastureland (7.8%). Increased use of bulule (55.6% of the respondents), crop residues (16.1%), non-conventional feed resources (14.4%), conserved hay (11.1%), purchased green feeds and concentrates (1.1%), and reducing herd size (1.1%) were the farmers' adopted coping strategies to mitigate feed shortage. It is suggested that technical intervention to improve the quality and efficient utilization of the existing feed resources is crucial to enable sustainable feed supply and boost milk production. Technologies that are easy to adopt, feasible, and low cost are also needed to be developed in participatory manner.


ER sliding dynamics and ER-mitochondrial contacts occur on acetylated microtubules.
The endoplasmic reticulum (ER) network is extremely dynamic in animal cells, yet little is known about the mechanism and function of its movements. The most common ER dynamic, termed ER sliding, involves ER tubule extension along stable microtubules (MTs). In this study, we show that ER sliding occurs on nocodazole-resistant MTs that are posttranslationally modified by acetylation. We demonstrate that high MT curvature is a good indicator of MT acetylation and show in live cells that ER sliding occurs predominantly on these curved, acetylated MTs. Furthermore, increasing MT acetylation by drug treatment increases the frequency of ER sliding. One purpose of the ER sliding on modified MT tracts could be to regulate its interorganelle contacts. We find that all mitochondria and many endosomes maintain contact with the ER despite the movements of each. However, mitochondria, but not endosomes, preferentially localize to acetylated MTs. Thus, different ER dynamics may occur on distinct MT populations to establish or maintain contacts with different organelles.


Social determinants of breast cancer screening in urban primary care practices: a community-engaged formative study.
The recent decline in the breast cancer mortality rate can be attributed to intensive screening and early detection efforts. However, studies have documented a decline in self-reported recent mammography use and interventions to enhance mammography utilization have yielded modest improvements. To address the root causes of breast cancer disparities and improve mammography use, interventions need to address multiple layers of patient, provider, and health system factors. Using community-based participatory research principles, we sought to learn from women receiving care through urban primary care practices about issues surrounding mammography screening and strategies to increase screening. We conducted five focus groups among 41 eligible women who were predominantly African American, recruited using nonprobability purposive sampling methods from urban community health centers in Baltimore, Maryland. Data are reported from three focus groups (n = 28) that provided usable data. We used the social determinants of health perspective to conduct a qualitative content analysis and interpretation of the data. Major obstacles to obtaining a screening mammogram were individual-level (i.e., pain from the procedure) and structural-level factors (i.e., cost, geography, convenience). Strategies to overcome obstacles could include the creation of structural mechanisms whereby women can receive a host of services during one visit to a healthcare professional's office. Important promoters of screening behavior included social-level factors such as social support, hope, and positive treatment outcomes. The social determinants of health perspective provided a unique perspective to frame barriers and promoters of mammography utilization and insights to develop interventions aimed at improving cancer control among women receiving care at urban primary care health centers.


Clinical and Histopathologic Features of Immune Checkpoint Inhibitor-related Pneumonitis.
Immune checkpoint inhibitors (ICIs) have revolutionized oncology, but are associated with immune-related adverse events. Clinically, pneumonitis is a well-recognized complication, but its histopathologic features are poorly understood. Institutional archives were searched for patients having ICI therapy and subsequent lung tissue sampling. After excluding infectious cases, 9 patients (5 women, median: 59 y) were identified with clinically suspected ICI-related pneumonitis. Clinical history, imaging, and pathology slides were reviewed. Patients received pembrolizumab (6 cases), nivolumab (1), ipilimumab followed by pembrolizumab (1), or pembrolizumab followed by nivolumab (1); the latter experienced pneumonitis with both agents. Treatment duration ranged from 1 to 33 cycles (median: 8). Three patients received concurrent chemotherapy and 1 received radiation; the remainder received ICI monotherapy. Symptoms were nonspecific; 2 patients were asymptomatic. Thoracic imaging showed bilateral ground glass or nodular opacities in all cases, often with pleural effusion. Histologically, organizing pneumonia was seen in 7 patients, all with subclinical or mild disease, admixed with vague non-necrotizing airspace granulomas in 3 cases; all 6 patients with follow-up did well. One patient had acute fibrinous pneumonitis and 1 had diffuse alveolar damage; both died. All 9 cases showed foamy macrophages and pneumocyte vacuolization; 6 had rare eosinophils. ICI-related pneumonitis presents as bilateral ground-glass opacities or nodules, and usually manifests as organizing pneumonia histopathologically, often with vague non-necrotizing airspace granulomas. Foamy macrophages and pneumocyte vacuolization are characteristic and rare eosinophils are often seen. Less commonly, acute fibrinous pneumonitis or diffuse alveolar damage can occur, which may be fatal.


Contribution of capecitabine for therapy of patients with gastroesophageal cancer: an update of recent phase III results.
Capecitabine, an orally administered fluoropyrimidines, is widely used in the treatment of multiple malignancies. It has been extensively evaluated in patients with gastroesophageal carcinoma. Since recent reviews have discussed phase I/II trials (Cancer 107:221-231, 2006; Drugs 67:601-610, 2007), we focus on the impact of the results of the most current phase III trials using capectiabine in the treatment of advanced gastroesophageal cancers, primarily in the first-line setting. To find published phase III trials, Medline was searched for English-language clinical trials published from 1996 through June 2007 along with relevant abstracts presented at the American Society of Clinical Oncology, and meetings of the European Cancer Conference and European Society of Medical Oncology. Only representative trials were chosen for this manuscript. The most frequently investigated combinations are capecitabine with taxanes, platinols, and camptothecins. Recent results of a large phase III trial (REAL-2) in untreated patients with gastroesophageal cancer suggest that capecitabine is a non-inferior substitute for intravenous 5-fluorouracil. These results of REAL-2 trial are substantiated by a smaller phase III trial. Previous analysis of multiple trials had suggested that capecitabine, when combined in doses lower than 1250 mg/m(2) twice daily, consistently resulted in lower frequency of Grade 3 or 4 toxic effects. Capecitabine provides much needed convenience to patients with gastroesophageal cancer. The recent data derived from two phase III trials confirm that capecitabine is a suitable substitute for intravenous 5-fluorouracil in patients whose swallowing is not greatly affected. Capecitabine remains a subject of further investigations in this group of patients with interest.


A nationwide population-based study of tension-type headache in Brazil.
To estimate the 1-year prevalence of tension-type headache (TTH) and the degree of the association of TTH with some sociodemographic characteristics of a representative sample of the adult population of Brazil. This was an observational, cross-sectional, population-based study. We conducted telephone interviews on 3848 people, aged 18-79 years, randomly selected from the 27 states of Brazil. Trained lay interviewers administered the structured questionnaire. It included questions about the sociodemographic characteristics of the population, as well as questions about headache. The degree of the association was calculated through prevalence ratios, adjusted with Poisson regression by gender, age, years of education, marital status, household income, job status, body mass index (BMI), and physical exercise. The estimated 1-year gender- and-age-adjusted prevalence of TTH was 13.0% (95% CI: 11.8-14.2%); 15.4% in males and 9.5% in females. The prevalence of probable TTH was 22.6% (95% CI: 21.1-24.1%). Most (86.2%) subjects reported episodic TTH; 6.4% had chronic TTH. The prevalence was higher at 18-29 years of age (16.2%). TTH was 1.6 times more prevalent in men, and 1.54 times more in subjects with more than 11 years of education. There was no significant association of TTH with marital or job status, household income, BMI, and physical activity. This is the first nationwide epidemiological study of TTH in Brazil. The overall prevalence of TTH in Brazil is low, at 13%. TTH is significantly more prevalent in males and subjects with higher education level.


The role of purinergic P2Y12 and P2Y13 receptors in ADPβS-induced inhibition of the cardioaccelerator sympathetic drive in pithed rats.
ATP is a cotransmitter released with other neurotransmitters from sympathetic nerves, where it stimulates purinergic receptors. Purinergic adenosine P1 receptors (coupled to Gi/o proteins) produce sympatho-inhibition in several autonomic effectors by prejunctional inhibition of neurotransmitter release. Similarly, signalling through P2Y12 and P2Y13 receptors coupled to Gi/o proteins is initiated by the ATP breakdown product ADP. Hence, this study has pharmacologically investigated a possible role of ADP-induced inhibition of the cardioaccelerator sympathetic drive in pithed rats, using a stable ADP analogue (ADPβS) and selective antagonists for the purinergic P2Y1, P2Y12 and P2Y13 receptors. Accordingly, male Wistar rats were pithed and: (i) pretreated i.v. with gallamine (25 mg/kg) and desipramine (50 μg/kg) for preganglionic spinal (C7-T1) stimulation of the cardioaccelerator sympathetic drive (n = 78); or (ii) prepared for receiving i.v. injections of exogenous noradrenaline (n = 12). The i.v. continuous infusions of ADPβS (10 and 30 μg/kg/min) dose-dependently inhibited the tachycardic responses to electrical sympathetic stimulation, but not those to exogenous noradrenaline. The cardiac sympatho-inhibition produced by 30 μg/kg/min ADPβS was (after i.v. administration of compounds) (i) unchanged by 1-ml/kg bidistilled water or 300-μg/kg MRS 2500 (P2Y1 receptor antagonist), (ii) abolished by 300-μg/kg PSB 0739 (P2Y12 receptor antagonist) and (iii) partially blocked by 3000-μg/kg MRS 2211 (P2Y13 receptor antagonist). Our results suggest that ADPβS induces a cardiac sympatho-inhibition that mainly involves the P2Y12 receptor subtype and, probably to a lesser extent, the P2Y13 receptor subtype. These receptors may represent therapeutic targets for treating cardiovascular pathologies, including stroke and myocardial infarctions.


The second rheumatic heart disease forum report.
The second rheumatic heart disease (RHD) forum was held on February 18, 2013, at the Sixth World Congress of Pediatric Cardiology and Cardiac Surgery in Cape Town, South Africa, to focus attention on key areas in global RHD control, management, and prevention. Building on the foundation of the first RHD forum, over 150 interested participants met to discuss critical issues on the RHD landscape. Unique to this meeting was a mixture of diverse backgrounds and disciplines, all crucially important to the conversation around RHD control and prevention. Some clear priorities have emerged for RHD activities in the next era: the necessity for political intervention and policy change; increasing the health workforce by incorporating teaching, training, and task-shifting; revitalizing the research agenda by merging basic, clinical, and translational research; and obtaining universal access to high-quality penicillin. There was also an urgent request for new resources; for existing resources to be further developed, improved, and shared across platforms; and for resources to be supported in the nonmedical arena. Finally, the necessity of involving the patient community in the ongoing discussion was highlighted. The participants of both the first and second RHD forum represent a new, thriving, and growing community of RHD activists who should usher in a new era of significant improvements in RHD control and prevention.


Effects of task-specific augmented feedback on deficit modification during performance of the tuck-jump exercise.
Anterior cruciate ligament (ACL) injuries are prevalent in female athletes. Specific factors have possible links to increasing a female athlete's chances of suffering an ACL injury. However, it is unclear if augmented feedback may be able to decrease possible risk factors. To compare the effects of task-specific feedback on a repeated tuck-jump maneuver. Double-blind randomized controlled trial. Sports-medicine biodynamics center. 37 female subjects (14.7 ± 1.5 y, 160.9 ± 6.8 cm, 54.5 ± 7.2 kg). All athletes received standard off-season training consisting of strength training, plyometrics, and conditioning. They were also videotaped during each session while running on a treadmill at a standardized speed (8 miles/h) and while performing a repeated tuck-jump maneuver for 10 s. The augmented feedback group (AF) received feedback on deficiencies present in a 10-s tuck jump, while the control group (CTRL) received feedback on 10-s treadmill running. Outcome measurements of tuck-jump deficits were scored by a blinded rater to determine the effects of group (CTRL vs AF) and time (pre- vs posttesting) on changes in measured deficits. A significant interaction of time by group was noted with the task-specific feedback training (P = .03). The AF group reduced deficits measured during the tuck-jump assessment by 23.6%, while the CTRL training reduced deficits by 10.6%. The results of the current study indicate that task-specific feedback is effective for reducing biomechanical risk factors associated with ACL injury. The data also indicate that specific components of the tuck-jump assessment are potentially more modifiable than others.


[Endogenous peptides as a single system of regulatory substances].
Endogenous peptides of the whole organism, irrespective of the place of their synthesis, mostly play the role of the elements constituting a code for triggering the integrative mechanisms of regulation of the functions of organs' systems or the whole organism. The data is presented on the results of radio-immunological assessment of concentration changes in the regulatory peptides in response to effect of the substances introduced into the vascular bed of animals.


Heat stress and age induced maternal effects on wing size and shape in parthenogenetic Drosophila mercatorum.
Maternal effects on progeny wing size and shape in a homozygous parthenogenetic strain of Drosophila mercatorum were investigated. The impact of external maternal factors (heat stress) and the impact of internal maternal factors (different maternal and grand maternal age) were studied. The offspring developed under identical environmental conditions, and due to lack of genetic variation any phenotypic difference among offspring could be ascribed to maternal effects. Wing size was estimated by centroid size, shape was analysed with the Procrustes geometric morphometric method and variation in landmark displacement was visualized by principal component analysis. Both kinds of maternal effects had a significant impact on progeny wing size and shape. Maternal heat stress led to the same pattern of response in size and shape among the progeny, with increased difference between the control group and progeny from heat stressed flies in both size and shape with increased maternal heat stress temperature. The effects of maternal age, however, led to different responses in size and shape between the different progeny groups. The observed variation in landmark displacements was similar, and in both cases mainly associated with shape differences of the posterior part of the wing. Finally, our results suggest that maternal effect has some evolutionary implications by altering the genetic correlations among traits, which can affect the response to selective pressures.


Hypertrophic cardiomyopathy in three generations of a large Norwegian family. A clinical, echocardiographic, and genetic study.
Hypertrophic cardiomyopathy is a heart muscle disease with an obscure aetiology. Data from four generations of a large family (71 members) are presented. The occurrence of hypertrophic cardiomyopathy among members of the two oldest generations was compatible with a pattern of autosomal dominant inheritance. Seven out of 14 siblings in the second generation had definite signs of or were clinically suspected of having hypertrophic cardiomyopathy. The severity and distribution of left ventricular hypertrophy varied, but three (21%) brothers in generation II showed the classic picture of left ventricular outflow obstruction. Four siblings (29%) died suddenly aged 11, 22, 38, and 40 years. A high incidence of the disease would have been expected in the two younger generations (41 members, aged 1-31 years), but only two, a 16 year old boy and a 17 year old girl had signs of asymmetric septal hypertrophy. Current diagnostic procedures, including M mode and cross sectional echocardiography, are not sufficiently sensitive to identify young family members who may have preclinical hypertrophic cardiomyopathy. No evidence for close genetic linkage between a postulated locus for hypertrophic cardiomyopathy and the major histocompatibility complex (antigens HLA-A, HLA-B, and HLA-DR) was found.