Weak Association Between Genetic Markers of Hyperuricemia and Cardiorenal Outcomes: Insights From the STANISLAS Study Cohort With a 20-Year Follow-Up.
Background Hyperuricemia is associated with poor cardiovascular outcomes, although it is uncertain whether this relationship is causal in nature. This study aimed to: (1) assess the heritability of serum uric acid (SUA) levels, (2) conduct a genome-wide association study on SUA levels, and (3) investigate the association between certain single-nucleotide polymorphisms and target organ damage. Methods and Results The STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux) study cohort is a single-center longitudinal cohort recruited between 1993 and 1995 (visit 1), with a last visit (visit 4 [V4]) performed ≈20 years apart. Serum lipid profile, SUA, urinary albumin/creatinine ratio, estimated glomerular filtration rate, 24-hour ambulatory blood pressure monitoring, transthoracic echocardiography, pulse wave velocity, and genotyping for each participant were assessed at V4. A total of 1573 participants were included at V4, among whom 1417 had available SUA data at visit 1. Genome-wide association study results highlighted multiple single-nucleotide polymorphisms on the SLC2A9 gene linked to SUA levels. Carriers of the most associated mutated SLC2A9 allele (rs16890979) had significantly lower SUA levels. Although SUA level at V4 was highly associated with diabetes, prediabetes, higher body mass index, CRP (C-reactive protein) levels, estimated glomerular filtration rate variation (visit 1-V4), carotid intima-media thickness, and pulse wave velocity, rs16890979 was only associated with higher carotid intima-media thickness. Conclusions Our findings demonstrate that rs16890979, a genetic determinant of SUA levels located on the SLC2A9 gene, is associated with carotid intima-media thickness despite significant associations between SUA levels and several clinical outcomes, thereby lending support to the hypothesis of a link between SUA and cardiovascular disease.


Racial differences in temporal changes in newborn viability and survival by gestational age.
This study examines trends in the rates of very preterm, moderately preterm and gestational age-specific neonatal mortality, and in the gestational age limit of viability in South Carolina (SC) from 1975 to 1994. We also investigate whether trends were similar between African-Americans and Whites. We hypothesised that disproportionate reductions in gestational age-specific mortality, rather than any major changes in the gestational age distributions of either race group, underlie any increasing racial disparity in overall mortality rates. During 1975-94, single livebirths, who were born to mothers resident in SC and were either White or African-American based on recorded maternal race, were selected for the investigation. We define the gestational age limit of viability as the gestational age at which > or = 50% of infants in the population died within 28 days of life. Although preterm percentages have not improved, there was a marked decline in neonatal mortality. Gestational age-specific neonatal mortality decreased for both race groups, although there were greater reductions for White preterm infants. By the end of the study period, the African-American neonatal mortality rate was 2.3 times that of Whites and the gestational age at which 50% of newborns died within 28 days of life was 24.5 weeks for Whites and 23.9 weeks for African-Americans. The ongoing decline in neonatal mortality continues to be mainly due to reductions in gestational age-specific neonatal mortality, probably related to high-risk obstetric and neonatal care. Technological developments in these areas may have differentially benefited Whites, resulting in an increasing racial disparity in neonatal mortality rates. Preterm African-American infants no longer have a marked survival advantage over White infants, even at the gestational age limit of viability.


[The structure and polymorphism of the Pain-1 vacuolar invertase locus in Solanum species].
Nucleotide sequences of Solanum vacuolar invertase Pain-1 gene from 17 representatives of five subgenera Potatoe, Solanum, Leptostemonum, Minon, Brevantherum have been obtained. Structure and polymorphism of Pain-1 have been characterized. The length of analyzed DNA fragment from 3'-end of III exon to 5'-end of V exon, ranged from 603 to 977 bp, with a highly variable III intron, saturated numerous indels and SNPs. In the coding region for 27 Solanum accessions 80 SNPs have been detected. 34 SNPs caused amino acid changes. Several single SNPs and SNP sets are found to be specific for single species or taxonomic groups. Estimated genetic distances and reconstructed phylogenic trees showed concordance with previous classifications of the investigated species and showed the utility of the Pain-1 locus for taxonomic identification and Solanaceae phylogeny.


Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy (2)
This article has analyzed the pathogenesis of sodium and water retention in several circumstances. The initiator of retention has been proposed to be either a fall in cardiac output (e.g., low-output cardiac failure and vasoconstrictor hypovolemic nephrotic syndrome) or peripheral arterial vasodilatation (e.g., high-output cardiac failure, cirrhosis, arteriovenous fistula, and pregnancy). In the only state discussed, in which the kidney is diseased and not merely responding to extrarenal reflexes--i.e., nephrotic syndrome--intrarenal mechanisms may predominate and lead to expansion of the arterial vascular tree and suppression of the renin-angiotensin-aldosterone system (i.e., hypervolemic nephrotic syndrome). Otherwise, when kidneys are healthy, either a fall in cardiac output or peripheral arterial vasodilatation may diminish arterial vascular filling and thereby initiate a series of hemodynamic and hormonal events that result in renal sodium and water retention (Fig. 7). Finally, the approach presented in this article should be considered to be a vantage point from which to evaluate states of sodium and water retention, but not to be an exclusive position.


Comparison of keratometric changes after myopic ablation: ray tracing versus simulated keratometry.
To compare the changes in corneal power (ΔK) induced by myopic ablations estimated by Placido-disk and total corneal power (TCP) ray tracing methods to the refractive change (ΔSE). Manifest refraction, simulated keratometry from a Placido-disk based system, and TCP from a dual-Scheimpflug analyzer were obtained from 35 patients (58 eyes) before and 3 months after a myopic ablation. The change in the manifest refraction that occurred after surgery was then vertex distance corrected and compared to the changes observed in corneal power with the various systems analyzed. The Placido-based simulated keratometry overestimated the corneal power after the procedure by 0.50 ± 0.53 diopters (D) when compared to refractive change in the corneal plane induced by the laser surgery (ΔSE-ΔK). The ray tracing method showed the opposite trend, with the TCP simulated keratometry showing an underestimation of the corneal power of -0.25 ± 0.48 D. The Placido system showed a direct correlation between the overestimation of the corneal power and the level of myopia, whereas the ray tracing method showed an underestimation, which was more pronounced in higher levels of myopia. Ray tracing methods underestimate corneal power as opposed to the overestimation in corneal power after refractive surgery, directly related to the level of myopia, observed in Placido-based systems. They have the potential to overcome the errors in calculations based on anterior curvature alone. However, ray tracing methods need to be validated and optimized before it can be used routinely in IOL calculation.


Colonic varices. Three case reports and review of the literature.
Three cases of colonic varices are presented. An extensive review of the literature revealed 29 other cases, whose clinical summaries are included. The majority of patients had portal hypertension and almost always presented with hematochezia. The most fruitful diagnostic tests were sigmoidoscopy and SMA arteriogram. The best therapeutic regimen for the severe bleeder with colonic varices is portacaval shunt.


Heparanase Involvement in Exosome Formation.
Exosomes are secreted vesicles involved in signaling processes. The biogenesis of a class of these extracellular vesicles depends on syntenin, and on the interaction of this cytosolic protein with syndecans. Heparanase, largely an endosomal enzyme, acts as a regulator of the syndecan-syntenin-exosome biogenesis pathway. The upregulation of syntenin and heparanase in cancers may support the suspected roles of exosomes in tumor biology.


Family Influence on Children's Nutrition and Physical Activity Patterns in Oman.
The objective of this study is to expand the understanding of the family influence on children's nutrition and physical activity patterns in Oman. A cross-sectional research design was used in this study. We recruited 204 dyads (a mother with a child) conveniently. Research data were collected in public cycle one schools, nongovernmental community centers, and home visits from five provinces in Oman. Study measures included a general information survey, anthropometric measurements, electronic children and family nutrition and physical activity questionnaires, and a single-day dietary recall for children. Univariate, bivariate, and multivariate analyses were used. Children's nutrition intake was significantly associated with parental education level, family income, and family nutrition and physical activity patterns, while children's physical activity patterns were significantly associated with maternal BMI and parental education level. Children's nutrition and physical activity patterns are associated with maternal BMI, family's sociodemographic characteristics, and family's nutrition and physical activity pattern. Family is a key element in shaping and influencing children's lifestyle-related behaviors. School-health programs that actively involve the families hold promise in promoting children's nutrition and physical activity pattern. Future research should be directed toward understanding the moderating and mediating factors.


Rapid detection and typing of strains of Mycobacterium avium subsp. paratuberculosis from broth cultures.
A liquid culture followed by molecular confirmation was evaluated for potential to improve sensitivity and reduce time to diagnosis of Mycobacterium avium subsp. paratuberculosis infection. Fecal samples from 240 animals from Ohio farms were assessed for presence of M. avium subsp. paratuberculosis using four different protocols: (i) sedimentation processing followed by inoculation on Herrold's Egg Yolk media (HEYM) slants (monitored biweekly up to 16 weeks), (ii) double centrifugation processing followed by inoculation on HEYM slants (monitored biweekly up to 16 weeks), (iii) liquid-solid double culture method using modified 7H9 broth (8 weeks) followed by subculture on HEYM slants (monitored up to 8 weeks), and (iv) liquid culture using modified 7H9 broth (8 weeks) followed by molecular assays for the presence of two M. avium subsp. paratuberculosis-specific targets. The number of positive samples detected by each protocol was 37, 53, 65, and 76, respectively. Twenty-seven samples were positive by all four methods. Based on samples positive by at least one method (n = 81), the sensitivities for sedimentation processing, double centrifugation processing, liquid-solid double culture, and liquid culture followed by molecular confirmation were 46%, 65%, 80%, and 94%, respectively. Fingerprinting of the positive samples using two polymorphic (G and GGT) short sequence repeat regions identified varying levels of within-farm and between-farm diversity. Our data indicate that liquid culture followed by molecular confirmation can significantly improve sensitivity and reduce time-to-diagnosis (from 16 to 8 weeks) of M. avium subsp. paratuberculosis infection and can also be efficiently employed for the systematic differentiation of M. avium subsp. paratuberculosis strains to understand the epidemiology of Johne's disease.


ASVCP guidelines: allowable total error guidelines for biochemistry.
As all laboratory equipment ages and contains components that may degrade with time, initial and periodically scheduled performance assessment is required to verify accurate and precise results over the life of the instrument. As veterinary patients may present to general practitioners and then to referral hospitals (both of which may each perform in-clinic laboratory analyses using different instruments), and given that general practitioners may send samples to reference laboratories, there is a need for comparability of results across instruments and methods. Allowable total error (TEa ) is a simple comparative quality concept used to define acceptable analytical performance. These guidelines are recommendations for determination and interpretation of TEa for commonly measured biochemical analytes in cats, dogs, and horses for equipment commonly used in veterinary diagnostic medicine. TEa values recommended herein are aimed at all veterinary settings, both private in-clinic laboratories using point-of-care analyzers and larger reference laboratories using more complex equipment. They represent the largest TEa possible without generating laboratory variation that would impact clinical decision making. TEa can be used for (1) assessment of an individual instrument's analytical performance, which is of benefit if one uses this information during instrument selection or assessment of in-clinic instrument performance, (2) Quality Control validation, and (3) as a measure of agreement or comparability of results from different laboratories (eg, between the in-clinic analyzer and the reference laboratory). These guidelines define a straightforward approach to assessment of instrument analytical performance.


Characterisation of the vascular pathology in Sigmodon hispidus (Rodentia: Cricetidae) following experimental infection with Angiostrongylus costaricensis (Nematoda: Metastrongylidae).
Angiostrongylus costaricensis is a nematode that causes human abdominal angiostrongyliasis, a disease found mainly in Latin American countries and particularly in Brazil and Costa Rica. Its life cycle involves exploitation of both invertebrate and vertebrate hosts. Its natural reservoir is a vertebrate host, the cotton rat Sigmodon hispidus. The adult worms live in the ileo-colic branches of the upper mesenteric artery of S. hispidus, causing periarteritis. However, there is a lack of data on the development of vasculitis in the course of infection. To describe the histopathology of vascular lesions in S. hispidus following infection with A. costaricensis. Twenty-one S. hispidus were euthanised at 30, 50, 90 and 114 days post-infection (dpi), and guts and mesentery (including the cecal artery) were collected. Tissues were fixed in Carson's Millonig formalin, histologically processed for paraffin embedding, sectioned with a rotary microtome, and stained with hematoxylin-eosin, resorcin-fuchsin, Perls, Sirius Red (pH = 10.2), Congo Red, and Azan trichrome for brightfield microscopy analysis. At 30 and 50 dpi, live eggs and larvae were present inside the vasa vasorum of the cecal artery, leading to eosinophil infiltrates throughout the vessel adventitia and promoting centripetal vasculitis with disruption of the elastic layers. Disease severity increased at 90 and 114 dpi, when many worms had died and the intensity of the vascular lesions was greatest, with intimal alterations, thrombus formation, iron accumulation, and atherosclerosis. In addition to abdominal angiostrongyliasis, our data suggest that this model could be very useful for autoimune vasculitis and atherosclerosis studies.


On cats and the territorial imperative.
Of all the medical innovationes of our era, computed tomography is undoubtedly one of the most fascinating, and many nonradiologists are seeking entry into the field. If CT is to remain a radiological specialty, we must act to ensure that our training and experience are adequate to meet this new challenge.


A novel multiplex assay for simultaneous quantification of total and S129 phosphorylated human alpha-synuclein.
Alpha-synuclein (asyn) has been shown to play an important role in the neuropathology of Parkinson's disease (PD). In the diseased brain, classic intraneuronal inclusions called Lewy bodies contain abnormal formations of asyn protein which is mostly phosphorylated at serine 129 (pS129 asyn). This suggests that post-translational modifications may play a role in the pathogenic process. To date, several uniplex assays have been developed in order to quantify asyn not only in the brain but also in cerebrospinal fluid and blood samples in order to correlate asyn levels to disease severity and progression. Notably, only four assays have been established to measure pS129 asyn specifically and none provide simultaneous readout of the total and pS129 species. Therefore, we developed a sensitive high-throughput duplex assay quantifying total and pS129 human asyn (h-asyn) in the same well hence improving accuracy as well as saving time, consumables and samples. Using our newly established duplex assay we measured total and pS129 h-asyn in vitro showing that polo-like kinase 2 (PLK2) can phosphorylate asyn up to 41 % in HEK293 cells and in vivo the same kinase phosphorylated h-asyn up to 17 % in rat ventral midbrain neurons. Interestingly, no increase in phosphorylation was observed when PLK2 and h-asyn were co-expressed in rat striatal neurons. Furthermore, using this assay we investigated h-asyn levels in brain tissue samples from patients with PD as well as PD dementia and found significant differences in pS129 h-asyn levels not only between disease tissue and healthy control samples but also between the two distinct disease states especially in hippocampal tissue samples. These results demonstrate that our duplex assay for simultaneous quantification is a useful tool to study h-asyn phosphorylation events in biospecimens and will be helpful in studies investigating the precise causative link between post-translational modification of h-asyn and PD pathology.


Dimethyl fumarate treatment of relapsing-remitting multiple sclerosis influences B-cell subsets.
To test the hypothesis that dimethyl fumarate (Tecfidera, BG-12) affects B-cell subsets in patients with relapsing-remitting multiple sclerosis (RRMS). Peripheral blood B cells were compared for surface marker expression in patients with RRMS prior to initiation of treatment, after 4-6 months, and at more than 1 year of treatment with BG-12. Production of interleukin (IL)-10 by RRMS patient B cells was also analyzed. Total numbers of peripheral blood B lymphocytes declined after 4-6 months of BG-12 treatment, due to losses in both the CD27+ memory B cells and CD27(neg) B-cell subsets. Some interpatient variability was observed. In contrast, circulating CD24(high)CD38(high) (T2-MZP) B cells increased in percentage in the majority of patients with RRMS after 4-6 months and were present in higher numbers in all of the patients after 12 months of treatment. The CD43+CD27+ B-1 B cells also increased at the later time point in most patients but were unchanged at 4-6 months compared to pretreatment levels. Purified B cells from 7 of the 9 patients with RRMS tested after 4-6 months of treatment were able to produce IL-10 following CD40 ligand stimulation, and the amount corresponded with the combined levels of T2-MZP and B-1 B cells in the sample. None of the patients with RRMS in this study have had a relapse while taking BG-12. These data suggest that BG-12 differentially affects B-cell subsets in patients with RRMS, resulting in increased numbers of circulating B lymphocytes with regulatory capacity.


Calcium currents in hair cells isolated from the cochlea of the chick.
1. Calcium currents were characterized in tall hair cells isolated from the chick's cochlea to determine what types of Ca2+ channels existed and if these varied in cells with differing voltage responses to current injection. 2. Whole-cell, tight-seal recordings showed that the current-voltage relation of cochlear hair cells of the chick was dominated by K+ current. However, when outward K+ current was blocked it was found that all hair cells had a smaller, maintained inward current. 3. This inward current was a Ca2+ current since it required Ca2+ in the external medium, could also be carried by Ba2+, and was blocked reversibly by 5 mM-Co2+ and by Ni2+ and Cd2+ at micromolar concentrations. The Ca2+ channels were opened at membrane potentials positive to -50 mV, and the current was maximal near 0 mV. 4. The dihydropyridine BayK8644 (0.5 microM) produced a voltage-dependent increase of inward current. Ten micromolar nifedipine partially blocked the inward current. The outward Ca2(+)-activated K+ current was also reduced in the presence of 10 microM-nifedipine. These effects of dihydropyridines were completely reversible. 5. The Ca2+ current had rapid activation kinetics, reaching steady-state levels within 1 ms. If all outward currents were completely blocked the Ca2+ current showed no inactivation during depolarization lasting 200 ms. 6. No differences in voltage activation range, pharmacology, or kinetics of the Ca2+ current were found in tall hair cells from apical and basal regions of the cochlea. This is in contrast to the marked differences in K+ currents amongst cells from these two widely separated regions of the cochlea.


[Adiposity percentage relationship with hormone receptors immunoreactive score in breast cancer mexican women].
Adipose tissue is an important estrogen resource and they are involved in breast cancer development. To establish the relationship between adiposity percentage and the estrogen and progesterone receptors immunoreactive score in Mexican women with breast cancer. This is a transversal and analytical study. We identified breast cancer women with cancer histologic diagnosis. We calculated: adiposity percentage and immunoreactive score. We performed correlation analysis between adiposity percentage, body mass index, diabetes mellitus and arterial hypertension, with estrogen and progesterone receptors in breast cancer samples. We perform logistic regression and Odds Ratio estimations. We studied 43 patients with breast cancer and we observed association between adiposity percentage and estrogen and progesterone immnunoreactive score (rP 0.470; p 0.003 and rP 0.328; p 0.042, respectively). The most important risk factor in breast cancer positive to estrogen receptors was obesity (OR 19.1, IC95% 2.1 a 169.1, p 0.008), and previous obesity in breast cancer positive to progesterone receptors (OR 20.7, IC95% 2.3 a 185.9, p 0.007). Adiposity percentage is an important risk factor to develop breast cancer positive to hormone receptors related with the risk of breast cancer positive to hormonal receptors.


Biventricular Pacing Going Along with Acute Hemodynamic Response in a Patient with Huge Anterior Wall Aneurysm - Importance of Pacing Viable Myocardium.
BACKGROUND Response to cardiac resynchronization therapy (CRT) is variable among patients. Extensive scar tissue burden has been characterized as a negative predictor of significant response. Whereas mid-term and long-term response has been thoroughly investigated in randomized clinical trials; however, little is known about acute hemodynamic effects of biventricular pacing. CASE REPORT We report a case of an elderly female patient with severe ischemic cardiomyopathy and a large anterior wall aneurysm, who received right ventricular and biventricular pacing during ablation of incessant pleomorphic ventricular tachycardia. During the procedure, biventricular pacing was associated with a 20% acute increase in systolic blood pressure compared to right ventricular pacing, although there was no acute or long-term effect on left ventricular function. CONCLUSIONS The acute hemodynamic effect of CRT in our patient suggests an effect of CRT even in patients with negative predictors of CRT response such as severe ischemic cardiomyopathy with a large aneurysm. Although no marked increase in left ventricular function might be observed, the acute effect of CRT might contribute to stabilization of heart failure in these patients.


In vitro and in vivo evaluation of gastro-retentive carvedilol loaded chitosan beads using Gastroplus™.
The objective of present investigation was to develop gastro-retentive controlled release system of carvedilol using biological macromolecule, chitosan. 32 full factorial design was adopted for optimization of tripolyphosphate (X1) and curing time (X2). Bead stability in 0.1N HCl, buoyancy duration, density, drug loading, dissolution efficiency and cumulative percentage release at 8th hour were evaluated as dependent variables. The levels of X1 and X2 of optimized formulation having maximum desirability was found to 2.0% w/v and 62.66min, respectively. The in silico predicted responses and observed response were found to be in good agreement (percent bias error: -13.295 to +13.269). SEM images showed numerous pores in the cross sectional image that renders buoyancy. AUC0-∞ of optimized formulation was 1.47 times higher as compared to suspension corroborating enhanced extent of absorption. Tmax and mean residence time were significantly higher from optimized formulation vis a vis suspension. In silico study indicated maximum regional absorption from the duodenum (94.1%) followed by jejunum (5.6%). Wagner-Nelson and Loo-Reigelman method were the preferred deconvolution approach over numerical deconvolution to establish IVIVC. In conclusion, the study showed that gastro-retentive controlled release system prepared using chitosan could be a potential drug carrier of carvedilol with improved bioavailability.


[The Conn syndrome. The clinical and surgical aspects of 18 cases of adrenal adenoma].
Presentation of a series of 18 patients who underwent surgery of aldosterone-producing adrenal adenoma (Conn's syndrome) over the last 10 years. Assessment of the most significant clinical and pathological aspects from a surgical point of view. Retrospective study evaluating a broad range of features: clinical, analytical, hormonal, imaging, types of anaesthesia, approaches, technique used, intra and post-operative morbidity and mortality, evolution and pathoanatomical diagnosis. The most frequent clinical data of primary hyperaldosteronism were: 94.4% volume-dependent HBP, 50% headaches and dizziness, 27.8% epistasis and/or episodes of angor or acute myocardial infarction, and 22.2% heart failure. The biochemical study and hormonal testing evidenced: hypokalemia in 88.9%, metabolic alkalosis 66.7% and hypernatremia in 61.1%. Mean aldosterone levels were 517.5 pg/mL, and urinary levels 85.9 mcg/day. Resting plasma renin activity (PRA) < 0.2 ng/mL/h in 77.8% cases and positive aldosterone stimulation test in 61.1%: captopril test positive. Imaging diagnosis was based in CAT which was conclusive in 88.9% and ultrasound which was diagnostic in 27.8% cases. The surgical approach was: lumbotomy (over the 11th or 12th rib) in 14 patients and transpleurodiaphragmatic in all remaining patients. The intraoperative complications reported were placement of endothoracic tube due to iatrogenic pneumothorax in two occasions. Duration of the procedure (mean 136.1 min) and post-operative hospitalization (mean 7.76 days), as well as post-surgery follow-up for up to 96 months were also studied. At final time point there was 66.7 asymptomatic patients, 33.3% cases of HBP, and no deaths. Primary hyperaldosteronism due to adrenal adenoma is an uncommon reason for HBP, but in most cases can be cured with surgery. Biochemical and hormonal testing is determinant to research a diagnosis. Ultrasound and CAT are essential for imaging diagnosis, and occasionally NMR can be of help. Lumbotomy is considered the choice approach for these small tumours as it is a familial technique for urologists with a low complications rate.


[Influence of azosemide on renal metildigoxin excretion (author's transl)].
The influence of the diuretic azosemide on metildigoxin blood levels and on renal excretion was assessed in 20 patients with chronic cardiac failure. Two groups, each of 10 patients, were treated for 14 days with 0.1 and 0.2 mg metildigoxin, respectively. All patients received 2 tablets of azosemide, 80 mg each, from day 12 to 14 of treatment. There was no significant influence of the diuretic either on blood levels or renal excretion of metildigoxin.


Distribution and metabolism of intravenously administered choline[methyl- 3-H] and synthesis in vivo of acetylcholine in various tissues of guinea pigs.
The biosynthesis of acetylcholine and the fate of intravenously administered choline [methyl- 3-H] were studied in guinea pigs anesthetized with pentobarbital. Choline and acetylcholine were isolated by paper electrophoresis and estimated by use of a specific enzymatic (choline kinase) - radioisotopic assay. The concentration of acetylcholine ranged from 25.5 to 1.1 nmol/g in the following tissues (in order of decreasing concentration): duodenum, corpus striatum, stomach, cerebral cortex, spinal cord, abdominal fat, submaxillary gland, kidney, adrenal gland, spleen, liver, lung, heart and diaphragm. Choline [methyl- 3-H] was converted in the tissues to acetylcholine within 3 minutes after intravenous administration of the precursor. Virtually all the radioactivity in plasma at that time was present as free choline, suggesting that free choline from plasma is the immediate precursor for acetylcholine synthesized in the tissues cited. The concentration of free choline in tissues ranged from 344 nmol/g in adrenals to 40 nmol/g in heart, while that in plasma was 15 nmol/g. The initial half-life of choline in plasma, estimated from the rate of disappearance of choline after intravenous administration of either a tracer dose of choline [methyl- 3-H] (0.031 mumol/kg) or a high dose of choline chloride (200 mumol/kg), was less than 1 minute. This rapid removal of choline from plasma resulted from uptake (or binding) by tissues, with kidney and liver removing about 50% of the administered dose of choline [methyl- 3-H] within 3 minutes after its administration. Uptake of choline occurred in all tissues cited above, but there was a 20-fold difference in the uptake by the most active tissues (kidney and adrenals), as compared to that of the least active (central nervous system). Within 60 minutes after administration of choline [methyl- 3-H], most of the radioactive choline taken up by tissues had been converted to organic-soluble metabolites and to water-soluble metabolites that behaved like either phosphorylcholine or betaine during paper electrophoresis and chromatography. Betaine was the principal metabolite of choline in plasma. Radioactivity was excreted slowly into urine, which contained primarily free choline, betaine and a large amount of an unidentified metabolite. These findings indicate that the principal mechanism for the rapid removal of choline from plasma is uptake into tissues followed by metabolism.


Making osteoarthritis a public health priority: several initiatives are placing this chronic illness on the national agenda.
National, state, and local policymakers and society at large are paying growing attention to osteoarthritis. This movement is fueled by organizations and coalitions that are championing important initiatives. This article spotlights several initiatives sponsored by the Arthritis Foundation and other organizations.


Expression and function of blimp1/krox, an alternatively transcribed regulatory gene of the sea urchin endomesoderm network.
The blimp1/krox gene of Strongylocentrotus purpuratus, formerly krox1, encodes zinc finger transcription factors which play a central role in both early and late endomesoderm specification. Here we show that there are two alternative splice forms transcribed under the control of different regulatory regions. The blimp/krox1b form was previously unknown, and is the form expressed during cleavage, beginning 6-9 h postfertilization. This form is required for the early events of endomesoderm specification. A different splice variant, blimp1/krox1a, is expressed only from gastrula stage onward. During cleavage stages the blimp1/krox gene is expressed in the large micromeres and veg2 descendents. Soon after, it is expressed in the ring of specified mesoderm cells at the vegetal pole of the blastula. Its expression is later restricted to the blastopore region and the posterior of the invaginating archenteron, and finally to the midgut and hindgut of the pluteus larva. The expression of blimp1/krox is dynamic, and involves several distinct spatial territories. A GFP recombinant BAC was created by substituting the GFP coding sequence for that of the second exon (1b), in order to distinguish the expression pattern of the early form from that of the late form. This construct closely mimics blimp1/krox1b expression during early stages of sea urchin development. To expand our knowledge of the downstream linkages of this gene, additional experiments were carried out using antisense morpholino oligos (MASO). We confirmed previously published data that blimp1/krox autoregulates its own expression, but discovered, surprisingly, that this gene represses rather than activates itself. This negative autoregulation is restricted to the mesodermal and probably skeletogenic territories during the blastula stage, as shown by in situ hybridization analysis of MASO injected embryos. The MASO perturbation analysis also revealed blimp1/krox inputs into other genes of the endomesoderm regulatory network.


Comparison of the acute phase response of cultured Morris hepatoma 7777 cells and of rat hepatocytes.
Isolated Morris hepatoma cells (line 7777) or adult rat hepatocytes were cultured for 3 days and daily production of four plasma proteins was estimated in the cell media by rocket immunoelectrophoresis with monospecific antisera. Addition of cytokines from rat peritoneal macrophages to cultured hepatocytes or hepatoma cells augmented accumulation in the medium of two positive acute phase proteins: fibrinogen (FIB) and cysteine proteinase inhibitor (CPI). At the same time synthesis of alpha-fetoprotein (AFP) was inhibited in hepatoma cells but remained undetectable in hepatocytes. Rat macrophage cytokines typically depressed synthesis of albumin (ALB) in cultured rat hepatocytes but increased production of this protein by hepatoma cells.


Use of cardiovascular imaging in risk restratification of the diabetic patient.
Diabetes mellitus is no longer considered a cardiovascular disease (CVD) risk equivalent, but the optimal methods of risk stratification are a matter of debate. The coronary calcium score (CCS) is a measure of the burden of atherosclerosis and is widely used for CVD risk stratification in the general population. We review recently published data to describe the role of the CCS in people with diabetes mellitus. People with diabetes mellitus have 10-year event rates for CVD and CVD mortality that are considered high, at a much lower level of CCS than the general population. Different categories of CCS are pertinent to men and women with diabetes mellitus. CCS may be particularly useful in clinical settings when CVD risk is known to be increased but difficult to quantify, for example peri-menopausal women, young persons with diabetes, type 1 diabetic individuals and others. With modern techniques, the radiation dose of a CSS has fallen to levels wherein screening and surveillance could be considered. The CCS is able to quantify CVD risk in people with diabetes mellitus when there is clinical uncertainty and identifies those with very high event rates. Future research should aim to identify effective risk reduction strategies in this important group.


Effect of cell-free spent media prepared from Aggregatibacter actinomycetemcomitans on the growth of Candida albicans and Streptococcus mutans in co-species biofilms.
This study explored the influence of cell-free spent media prepared from Aggregatibacter actinomycetemcomitans LuxS mutant (Aa-LuxS), its wild type strain (Aa-WT), and the laboratory strain (Aa-Y4), on the interaction between Candida albicans and Streptococcus mutans while growing in co-species biofilm for 48 h. By analyzing the results of crystal violet staining, [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] (MTT) assays, and quantitative real-time polymerase chain reaction (qPCR), we found that the presence of Aa-LuxS in treated biofilms did not affect biofilm development, while added Aa-WT or Aa-Y4 resulted in a significant decrease in both biofilm mass and the number of cells. The inhibitory effect of Aa-WT or Aa-Y4 was not dependent on the protein concentration in the spent media tested (1 and 10%). Gene transcription analyses indicated that Aa-WT/Aa-Y4 exhibits comparable inhibitory effects on the expression of hyphal-associated genes (ALS3 and HWP1), but not on the expression of YWP1, which encodes a yeast form of C. albicans. In contrast, except for gtfD, the expression of S. mutans gtfB/C genes encoding glucosyltransferase was not affected in Aa-WT and Aa-Y4 treated biofilms compared to the levels found in Aa-LuxS treated biofilms. Our results indicate that AI-2-containing spent media derived from Aa can reduce biofilm biomass without significantly inhibiting the survival rate of S. mutans.


Structural and functional analyses of human cerebral cortex using a surface-based atlas.
We have analyzed the geometry, geography, and functional organization of human cerebral cortex using surface reconstructions and cortical flat maps of the left and right hemispheres generated from a digital atlas (the Visible Man). The total surface area of the reconstructed Visible Man neocortex is 1570 cm2 (both hemispheres), approximately 70% of which is buried in sulci. By linking the Visible Man cerebrum to the Talairach stereotaxic coordinate space, the locations of activation foci reported in neuroimaging studies can be readily visualized in relation to the cortical surface. The associated spatial uncertainty was empirically shown to have a radius in three dimensions of approximately 10 mm. Application of this approach to studies of visual cortex reveals the overall patterns of activation associated with different aspects of visual function and the relationship of these patterns to topographically organized visual areas. Our analysis supports a distinction between an anterior region in ventral occipito-temporal cortex that is selectively involved in form processing and a more posterior region (in or near areas VP and V4v) involved in both form and color processing. Foci associated with motion processing are mainly concentrated in a region along the occipito-temporal junction, the ventral portion of which overlaps with foci also implicated in form processing. Comparisons between flat maps of human and macaque monkey cerebral cortex indicate significant differences as well as many similarities in the relative sizes and positions of cortical regions known or suspected to be homologous in the two species.


mit-o-matic: a comprehensive computational pipeline for clinical evaluation of mitochondrial variations from next-generation sequencing datasets.
The human mitochondrial genome has been reported to have a very high mutation rate as compared with the nuclear genome. A large number of mitochondrial mutations show significant phenotypic association and are involved in a broad spectrum of diseases. In recent years, there has been a remarkable progress in the understanding of mitochondrial genetics. The availability of next-generation sequencing (NGS) technologies have not only reduced sequencing cost by orders of magnitude but has also provided us good quality mitochondrial genome sequences with high coverage, thereby enabling decoding of a number of human mitochondrial diseases. In this study, we report a computational and experimental pipeline to decipher the human mitochondrial DNA variations and examine them for their clinical correlation. As a proof of principle, we also present a clinical study of a patient with Leigh disease and confirmed maternal inheritance of the causative allele. The pipeline is made available as a user-friendly online tool to annotate variants and find haplogroup, disease association, and heteroplasmic sites. The "mit-o-matic" computational pipeline represents a comprehensive cloud-based tool for clinical evaluation of mitochondrial genomic variations from NGS datasets. The tool is freely available at http://genome.igib.res.in/mitomatic/.


Notes from the Field: Increase in Reported Adverse Health Effects Related to Synthetic Cannabinoid Use - United States, January-May 2015.
On April 6, 2015, CDC received notification of an increase in telephone calls to U.S. poison centers related to synthetic cannabinoid use. Monthly calls to all poison centers are tracked by the National Poison Data System, which reported that adverse health effects or concerns about possible adverse health effects related to synthetic cannabinoid use increased 330% from 349 in January 2015 to 1,501 in April 2015. Synthetic cannabinoids include various psychoactive chemicals or a mixture of such chemicals that are sprayed onto plant material, which is then often smoked or ingested to achieve a "high." These products are sold under a variety of names (e.g., synthetic marijuana, spice, K2, black mamba, and crazy clown) and can be sold in retail outlets as herbal products. Law enforcement agencies have regulated a number of these substances; however, manufacturers of synthetic cannabinoids frequently change the formulation to avoid detection and regulation. After the initial notification, CDC analyzed information from the National Poison Data System on reported adverse health effects related to synthetic cannabinoid use for the period January-May 2015.


Clinical characteristics and prognosis of patients with heart failure and high concentrations of interleukin-17D.
Heart failure (HF) is associated with cytokine activation and inflammation. Experimental evidence suggests that plasma interleukin-17 (IL-17) is associated with myocardial fibrosis and cardiac dysfunction in HF. IL-17D, a subtype of IL-17 originates from particular tissues such as the heart. However, there is very limited data on the IL-17 cytokine family in patients with HF. Therefore, we investigated the association between circulating IL-17D levels, clinical characteristics and outcome in a large cohort of patients with heart failure. Plasma IL-17D was measured in 2032 patients with HF from 11 European countries using a proximity extension assay. The primary outcome was a composite of HF hospitalization or all-cause mortality. Patients with higher plasma IL-17D concentrations were more likely to have atrial fibrillation (AF), renal dysfunction and heart failure with preserved ejection fraction (HFpEF) and had higher plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations (all p < 0.001). IL-17D was not associated with interleukin-6 (IL-6) or C-reactive protein (CRP) concentrations. After adjustment for confounders in a multivariable Cox regression analysis, patients in the highest quartile of plasma IL-17D had a significantly increased risk of the composite outcome of HF hospitalization or all-cause mortality compared to patients in the lowest quartile [Hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.05-1.57]. In patients with HF, elevated plasma IL-17D concentrations are associated with higher plasma NT-proBNP concentrations and a higher prevalence of AF and renal dysfunction. High IL-17D concentrations are independently associated with worse outcome.


Absence of UV-induced stress in Bragg gratings recorded by high-intensity 264 nm laser pulses in a hydrogenated standard telecom fiber.
We report on photochemical two-photon Bragg grating preparation in hydrogenated fiber without any UV-induced stress in the core or cladding, leaving only the color-center model responsible for refractive index changes for UV femtosecond irradiation. Without hydrogen loading strong stress changes are observed in the core and in the cladding indicating glass compaction. The irradiation does not change the inelastic strains, in contrast to H(2)-loading.


Synergistic Effect of Hyperactive Antifreeze Protein on Inhibition of Gas-Hydrate Growth by Hydrophobic and Hydrophilic Groups.
Antifreeze proteins (AFPs) are biodegradable inhibitors that effectively prevent the formation of natural gas hydrates that block pipelines. In this study, molecular dynamics simulations were employed to establish a kinetic model of the hyperactive insect antifreeze protein (Tenebrio molitor, TmAFP) and its mutants to inhibit the growth of sI natural methane hydrate. Simulations revealed that the hydrophobic and hydrophilic groups of threonine (Thr) residues at hydrate-binding sites played a synergistic role in binding hydrates. The hydrophobic groups anchored TmAFP to the hydrate surface through residues Thr39-Thr65 by migrating pendant hydrophobic methyl groups to the hydrate semicages. The hydrophilic groups stabilized TmAFP by hydrogen bonding with water molecules and integrating them into a quasi-hydrate structure, which more effectively inhibited hydrate growth. The results suggest that the hydrate growth inhibition is attributed to both the shape complementarity and the flexibility of binding residues. The synergy between hydrophobic and hydrophilic groups provides guidance for the design of more effective hydrate inhibitors.


Multifunctional Poly(2-ethyl-2-oxazoline) Copolymers Containing Dithiolane and Pentafluorophenyl Esters as Effective Reactive Linkers for Gold Surface Coatings.
Surface functionalization with biological macromolecules is an important task for the development of sensor materials, whereby the interaction with other biological materials should be suppressed. In this work, we developed a novel multifunctional poly(2-ethyl-2-oxazoline)-dithiolane conjugate as a versatile linker for gold surface immobilization of amine-containing biomolecules, containing poly(2-ethyl-2-oxazoline) as antifouling polymer, dithiolane for surface immobilization, and activated esters for protein conjugation. First, a well-defined carboxylic acid containing copoly(2-ethyl-2-oxazoline) was synthesized by cationic ring-opening copolymerization of 2-ethyl-2-oxazoline with a methyl ester-containing 2-oxazoline monomer, followed by postpolymerization modifications. The side-chain carboxylic groups were then converted to amine-reactive pentafluorophenyl (PFP) ester groups. Part of the PFP groups was used for the attachment of the dithiolane moiety, which can efficiently bind to gold surfaces. The final copolymer contained 1.4 mol% of dithiolane groups and 4.5 mol% of PFP groups. The copolymer structure was confirmed by several analytical techniques, including NMR spectroscopy and size-exclusion chromatography. The kinetics of the PFP ester aminolysis and hydrolysis demonstrated significantly faster amidation compared to hydrolysis, which is essential for subsequent protein conjugation. Successful coating of gold surfaces with the polymer was confirmed by spectroscopic ellipsometry, showing a polymer brush thickness of 4.77 nm. Subsequent modification of the coated surfaces was achieved using bovine serum albumin as a model protein. This study introduces a novel reactive polymer linker for gold surface functionalization and offers a versatile polymer platform for various applications including biosensing and surface functionalization.


Mitogen-activated protein kinases and retinal ischemia.
Mitogen-activated protein kinases (MAPKs), consisting of three major enzymes-extracellular signal-regulated kinase (ERK), p38, and c-jun N-terminal kinase (JNK)-couple cell-surface receptors to critical regulatory targets and gene transcription. We hypothesized that MAPKs are differentially expressed and have distinct functions after retinal ischemia. Rats were subjected to retinal ischemia by elevation of intraocular pressure. Changes in MAPK expression were examined by Western blot of whole retinal homogenates and by immunohistochemistry of retinal cryosections. Phosphorylated (activated) ERK, p38, and JNK proteins were localized by fluorescent double labeling. The functional significance of activated MAPKs was assessed using pharmacological antagonists. Specific MAPK blockade was documented by kinase assay and immunohistochemistry for phosphorylated target proteins. The outcome after ischemia was examined with electroretinography (ERG), by measuring retinal cell layer thickness in paraffin-embedded sections, and by TUNEL staining on retinal cryosections. Data were analyzed using ANOVA and post hoc t-test, with P < 0.05 considered significant. Expression of phosphorylated JNK and p38 increased significantly after ischemia and followed a specific time course, beginning at 1 hour, and persisting up to 1 week later. JNK and p38 were expressed in the nuclei of ganglion and amacrine cells, the outer plexiform layer, the nerve fiber layer, and the axonal terminals of bipolar cells. Phosphorylated ERK was expressed in Müller cells, peaking at 1 to 6 hours after ischemia. Blocking activation of p38 or ERK significantly improved recovery of the ERG b-wave after ischemia, dramatically decreased thinning of the inner nuclear layers, and decreased the percentage of TUNEL-positive cells. The MAPKs each demonstrate a specific cellular distribution after ischemia, and ERK and p38 are linked to apoptosis. Blockade of p38 or ERK provides significant protection from ischemic damage, suggesting a novel therapeutic role for MAPK inhibition in neuroprotection.


Sideroblastic anaemia with reactive thrombocytosis versus myelodysplastic/myeloproliferative disease.
The reported incidence of thrombocytosis among cases of refractory anaemia with ring sideroblasts (RARS) may be as high as 15%. We report four additional cases of this association, which appear to be hematologically heterogeneous. One patient clearly represents a case of RARS with reactive thrombocytosis. Two cases have features suggestive of the coincidental occurrence of essential thrombocythemia and RARS. The fourth case could be best classified as a subtype of myelodysplastic/myeloproliferative disease unclassifiable (MDS/MPD U). Only new biological or molecular markers will allow better differentiation between these disorders.


[Biomechanics of pelvic ring and its structural elements].
Calculations and diagrams of the force distribution in pelvic bones' zone are presented. In persons without injuries and skeletal abnormalities all forces functioning on the pelvic ring are shown to be in balance. Proposed method of calculations enables to detect the treatment tactics (either conservative or operative management) in patients with pelvic bone fractures as well as in congenital abnormalities.


Inhibiting effect of (RS)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine on varicella-zoster virus replication in cell culture.
The activity and mode of action of the new nucleoside analog (RS)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (2HM-HBG) against varicella-zoster virus (VZV) were determined. In cell culture, replication of different strains of VZV was inhibited to 50% by 0.4 to 0.7 microM 2HM-HBG, while 685 microM was required to inhibit 50% of the DNA synthesis in uninfected human lung fibroblasts. A thymidine kinase-negative VZV strain was not inhibited by 100 microM 2HM-HBG. Inhibition of VZV replication was not reversible after 7 to 14 days of incubation, depending on the multiplicity of VZV. 2HM-HBG was shown to be selectively phosphorylated by purified VZV thymidine kinase, with an inhibition constant of 32.5 microM. The antiviral activity of 2HM-HBG in cell culture was decreased by the addition of deoxythymidine and deoxycytidine but not by other ribo- or deoxyribonucleosides.


Why are patients still in hospital after fast-track, unilateral unicompartmental knee arthroplasty.
Background and purpose - Previous studies have investigated risk factors related to prolonged length of stay following total knee arthroplasty (TKA), but little is known about specific factors resulting in continued hospitalization within the 1st postoperative days after unicompartmental knee arthroplasty (UKA). We investigated what specific factors prevent patients from being discharged on the day of surgery (DOS) and the first postoperative day (POD-1) following primary UKA in a fast-track setting.Patients and methods - We prospectively collected data on 100 consecutive and unselected medial UKA patients operated from December 2017 to May 2019. All patients were operated in a standardized fast-track setup with functional discharge criteria continuously evaluated from DOS and until discharge.Results - Median length of stay for the entire cohort was 1 day. 22% and 78% of all patients were discharged on DOS and POD-1, respectively. Lack of mobilization and pain separately delayed discharge in respectively 78% and 24% of patients on DOS. The main reasons for lack of mobilization were motor blockade (37%) and logistical factors (26%). For patients placed 1st or 2nd on the operating list, we estimate that the same-day discharge rate would increase to 55% and 40% respectively, assuming that pain and mobilization were successfully managed.Interpretation - One-fifth of unselected UKA patients operated in a standardized fast-track setup were discharged on DOS. Pain and lack of mobilization were the major reasons for continued hospitalization within the initial postoperative 24-48 hours. Strategies aimed at decreasing length of stay after UKA should strive to improve analgesia and postoperative mobilization.


A person-centered approach to individualizing a school-based universal preventive intervention.
This manuscript focuses on how individualized components may be embedded within a universal preventive intervention (TimeWise: Taking Charge of Leisure Time) to make program delivery more effective. Leisure related variables (motivation, boredom/interest and peer and parental influence) were used to suggest ways to individualize the program. Latent Class Analysis was used to develop individualized risk and strength profiles of adolescents (N = 617). Comparisons were made between a treatment and control group. Four classes were identified: undifferentiated high, intrinsic motivation, extrinsic motivation/amotivation, undifferentiated low. These classes were related to substance use. Membership in the intrinsic class was associated with intervention group while the extrinsic class was related to the control group. Results were useful in suggesting ways to tailor a universal prevention program.


[Drainage for external draining of biliary tract].
A specially designed surgical drainage for biliary tracts provides safe fixation and easy and minimally traumatic removal. There are no conditions for internal rotation of the tube, and the presence of a few openings in an active part of the drainage in combination with two channels prevent disorders of the drainage function in case of clogging of some of the openings. An opportunity to control the working shape during the removal of the drainage is considered to be its important advantage. The drainage can be adyiested to the shape of hepaticocholedoch. Besides, there is an opportunity of unloading the terminal part of choledoch and evacuating the regurgitation of a pancreatic secret. The design of the drainage prevents narrowing of the choledoch in the region of choledochotomy opening. The proposed variant of the drainage can be easily created in any operating room.


Free centrosomes: where do they all come from?
Centrosomes act as major microtubule-organizing centers in most cell types. Their functions in interphase and mitosis are usually facilitated by their association with the nucleus. This may be particularly true in very large cells. Several papers report free centrosomes in syncytial Drosophila embryos. However, this phenotype often remains little explored. Yet, free centrosomes can occur by multiple mechanisms, including functional defects of the mitotic spindle, detachment of centrosomes from the nuclear envelope, centrosome inactivation upon DNA damage, and de novo centrosome genesis. Deciphering the cellular mechanism leading to free centrosomes upon a given perturbation such as a mutation or injection of a drug, can provide valuable clues regarding the nature of the molecular pathway affected. To this end, genetic and cytological tests, as well as time-lapse imaging are available. These studies can inform on the biology of centrosomes, cell cycle regulation and cytoskeletal dynamics. Here we briefly discuss what to make of free centrosomes in the fly embryo.


Anti-biofilm surfaces from mixed dopamine-modified polymer brushes: synergistic role of cationic and zwitterionic chains to resist staphyloccocus aureus.
Infections resulting from the attachment of bacteria and biofilm formation on the surface of medical implants give rise to a severe problem for medical device safety. Thus, the development of antibacterial materials that integrate bactericidal and antifouling properties is a promising approach to prevent biomaterial-associated infections. In this study, two types of dopamine-modified polymers, dopamine-terminated quaternary ammonium salt polymer (D-PQAs) with various lengths of N-alkyl chain (D-PQA4C, D-PQA8C, and D-PQA12C) and dopamine-terminated poly(sulfobetaine methacrylate) (D-PSBMA), were synthesized via atom transfer radical polymerization (ATRP). Mixed polymer brushes of D-PQAs and D-PSBMA with various ratios were well-integrated onto the surface of a silicon wafer via a facile mussel-inspired adhesion. We demonstrate that the synergistic antibacterial effect depends on both the ratio of the two components and the surface structures of the mixed polymer brushes, originating from the interactions between D-PQAs and D-PSBMA. The N-alkyl chain length of D-PQAs influenced the distribution and orientation of the alkyl chain on the mixed polymer brushes. A chart of the antibacterial efficiency of the mixed polymer brushes was obtained to reveal the synergistic role of their cationic and zwitterionic chains to resist S. aureus. The dominant amount of antifouling D-PSBMA with a minor amount of bactericidal D-PQAs with a short N-alkyl chain length facilitated the synergistic antibacterial effect. The selected polymer brushes (PSBMA/PQA4C-10%, PSBMA/PQA4C-30%, and PSBMA/PQA8C-10%) could effectively prevent biofilm formation by S. aureus for a long time, while having good biocompatibility. This work may provide a universal design strategy for the preparation of anti-biofilm and biocompatible surfaces for biomedical applications.


Oncoplastic breast reduction surgery decreases rates of reoperation with no increased medical risk.
The purpose of this study is to compare the oncologic, medical, and surgical outcomes of lumpectomy versus oncoplastic breast reduction surgery (OBRS) on a national scale. A national insurance-based database was queried for patients who had a lumpectomy with or without a same-day breast reduction by Current Procedural Terminology (CPT) codes. Patients were then matched by obesity, body mass index range, age, region, neoadjuvant chemotherapy, and outcomes were compared. There were 421,455 patients in the lumpectomy group and 15,909 patients in the OBRS group. After matching, 15,134 patients were identified in each group. Repeat lumpectomy or subsequent mastectomy was more common in the lumpectomy group (15.2% vs. 12.2%, p < 0.001). OBRS patients had higher rates of 90-day surgical complications including dehiscence, infection, fat necrosis, breast abscesses, and antibiotic prescription (p < 0.001). Meanwhile, any medical complication was less common in the OBRS group (3.7% vs. 4.5%, p = 0.001). Logistic regression revealed that OBRS was associated with decreased odds of repeat lumpectomy (OR = 0.71, 95% CI 0.66-0.77, p < 0.001) with no significant increased odds of subsequent mastectomy (OR = 1.01, 95% CI 0.91-1.11, p = 0.914). OBRS was found to be associated with decreased risk for reoperation in the form of lumpectomy without increased likelihood of subsequent mastectomy. Although OBRS was associated with increased wound complications, medical complications were found to occur less frequently. This study endorses increased consideration of OBRS when lumpectomy or OBRS is appropriate.


Identification of shared genes and pathways: a comparative study of multiple sclerosis susceptibility, severity and response to interferon beta treatment.
Recent genome-wide association studies (GWAS) have successfully identified several gene loci associated with multiple sclerosis (MS) susceptibility, severity or interferon-beta (IFN-ß) response. However, due to the nature of these studies, the functional relevance of these loci is not yet fully understood. We have utilized a systems biology based approach to explore the genetic interactomes of these MS related traits. We hypothesised that genes and pathways associated with the 3 MS related phenotypes might interact collectively to influence the heterogeneity and unpredictable clinical outcomes observed. Individual genetic interactomes for each trait were constructed and compared, followed by prioritization of common interactors based on their frequencies. Pathway enrichment analyses were performed to highlight shared functional pathways. Biologically relevant genes ABL1, GRB2, INPP5D, KIF1B, PIK3R1, PLCG1, PRKCD, SRC, TUBA1A and TUBA4A were identified as common to all 3 MS phenotypes. We observed that the highest number of first degree interactors were shared between MS susceptibility and MS severity (p = 1.34×10(-79)) with UBC as the most prominent first degree interactor for this phenotype pair from the prioritisation analysis. As expected, pairwise comparisons showed that MS susceptibility and severity interactomes shared the highest number of pathways. Pathways from signalling molecules and interaction, and signal transduction categories were found to be highest shared pathways between 3 phenotypes. Finally, FYN was the most common first degree interactor in the MS drugs-gene network. By applying the systems biology based approach, additional significant information can be extracted from GWAS. Results of our interactome analyses are complementary to what is already known in the literature and also highlight some novel interactions which await further experimental validation. Overall, this study illustrates the potential of using a systems biology based approach in an attempt to unravel the biological significance of gene loci identified in large GWAS.


On measuring the size of distortions in coordination polyhedra.
There is no unique index that measures the size of the distortion found in a coordination polyhedron because different indices can result in a different ordering depending on the mode of the distortion (i.e. the third and higher moments of the bond-length distribution). This paper proposes the increase in the average bond length as a suitable index as this is directly related to the increase in volume of the coordination polyhedron and hence of the unit cell. Some examples are discussed.


Age-dependent changes in affinity-labeled receptors for Escherichia coli heat-stable enterotoxin in the swine intestine.
Intestinal brush border membranes from 1-day-old and 4-week-old (day of weaning) pigs were affinity labeled with an Escherichia coli heat-stable enterotoxin (STa) by cross-linking 125I-STa to receptor proteins with disuccinimidyl suberate. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography revealed that a radioactive protein with a relative molecular weight of 137,000 to 145,000 was present in both age groups. A strongly radioactive protein with an apparent Mr of 90,000 was present in the 1-day-old animals but not in those that were 4 weeks old. The major radioactive protein present in the older pigs had an Mr of 64,000 to 67,000, but this protein was missing or very weakly radioactive in the younger pigs. There was no significant difference between the groups in receptor affinity for STa, although the receptor density in the older animals was marginally significantly greater. STa-stimulated guanylate cyclase activity in membranes from 1-day-old pigs was only one-sixth that in 4-week-old pigs, although the basal and Lubrol PX-stimulated activities were similar.


The HLA-DRB1 shared epitope is not associated with antibodies against cyclic citrullinated peptide in Chinese patients with rheumatoid arthritis.
Rheumatoid arthritis (RA) is a destructive autoimmune polyarthritis that has been associated with a group of human leucocyte antigen (HLA)-DRB1 alleles that share a common amino-acid sequence at residues 70-74 called the shared epitope (SE). Recently, anti-cyclic citrullinated peptide (CCP) antibodies have also been reported to be associated with HLA-DR4 and have gained wide acceptance as early diagnostic markers for RA in Caucasian patients. The current study was performed to investigate whether the association between the SE (HLA-DRB1 0401/04/05/10) and anti-CCP antibodies is also present in Chinese Han patients with RA. One hundred and four RA patients and 122 healthy controls were recruited. HLA-DR4 was detected by the sequence-specific primer polymerase chain reaction (SSP-PCR) phototyping method. Anti-CCP antibodies and immunoglobulin M rheumatoid factor (IgM-RF) were measured by enzyme-linked immunosorbent assay (ELISA) and laser nephelometry, respectively. Of the Chinese patients with RA, 76.5% exhibited anti-CCP antibodies compared with none of the controls (76.5% vs. 0%, p<0.001). The prevalence of the SE was significantly higher in patients with RA compared with controls [p = 0.010, odds ratio (OR) = 2.42, 95% confidence interval (CI) = 1.16-5.07]. Among the HLA-DR4 alleles, the presence of HLA-DRB1 0401 was significantly higher in RA patients than in controls (p = 0.0118, OR = 9.68, 95% CI = 1.13-448.8). In our study we found that the SE was not associated with production of anti-CCP antibodies (p = 0.2899, OR = 1.920, 95% CI = 0.52-8.89). The prevalence of the SE is significantly lower in Chinese RA patients, as compared with previous reports of a study using a Caucasian cohort, indicating that distinct genetic risk factors might be associated with anti-CCP antibody production. These data emphasized the complexity of the genetic effects of the major histocompatibility complex on the RA phenotype.


Cobalt Porphyrin-Polypyridyl Surface Coatings for Photoelectrosynthetic Hydrogen Production.
Hybrid materials that link light capture and conversion technologies with the ability to drive reductive chemical transformations are attractive as components in photoelectrosynthetic cells. We show that thin-film polypyridine surface coatings provide a molecular interface to assemble cobalt porphyrin catalysts for hydrogen evolution onto a visible-light-absorbing p-type gallium phosphide semiconductor. Spectroscopic techniques, including grazing angle attenuated total reflection Fourier transform infrared spectroscopy, confirm that the cobalt centers of the porphyrin macrocycles coordinate to pyridyl nitrogen sites of the organic surface coating. The cobalt porphyrin surface concentration and fraction of pyridyl sites coordinated to a cobalt center are quantified using complementary methods of ellipsometry, inductively coupled plasma mass spectrometry, and X-ray photoelectron spectroscopy. In aqueous solutions under simulated solar illumination the modified cathode is photochemically active for hydrogen production, generating the product gas with near-unity Faradaic efficiency at a rate of ≈10 μL min-1 cm-2 when studied in a three-electrode configuration and polarized at the equilibrium potential of the H+/H2 couple. This equates to a photoelectrochemical hydrogen evolution reaction activity of 17.6 H2 molecules s-1 Co-1, the highest value reported to date for a molecular-modified semiconductor. Key features of the functionalized photocathode include (1) the relative ease of synthetic preparation made possible by application of an organic surface coating that provides molecular recognition sites for immobilizing the cobalt porphyrin complexes at the semiconductor surface and (2) the use of visible light to drive cathodic fuel-forming reactions in aqueous solutions with no added organic acids or sacrificial chemical reductants.


Workplace discrimination: experiences of practicing physicians.
In response to a growing concern regarding physician discrimination in the workplace, this study was developed to: (1) describe the types of discrimination that exist for the practicing physician and (2) determine which groups of physicians are more likely to experience the various forms of discrimination. Surveys were mailed to 1930 practicing physicians in Massachusetts. Participants were asked if they had encountered discrimination, how significant the discrimination was against a specific group, the frequency of personal discrimination, and the type of discrimination. Factor analysis identified four types of discrimination: career advancement, punitive behaviors, practice barriers and hiring barriers. A total of 445 responses were received (a 24% response rate). Sixty-three percent of responding physicians had experienced some form of discrimination. Respondents were women (46%), racial/ethnic minorities (42%) and international medical graduates (IMGs) (40%). In addition, 26% of those classified as white were also IMGs. Over 60% of respondents believed discrimination against IMGs was very or somewhat significant. Almost 27% of males acknowledged that gender bias against females was very or somewhat significant. IMGs were more likely to indicate that discrimination against IMGs was significant in their current organization. Of U.S. medical graduates (USMGs) 44% reported that discrimination against IMGs in their current organization was significant. Nonwhites were more likely to report that discrimination based on race/ethnicity was significant. Nearly 29% of white respondents also believed that such discrimination was very or somewhat significant. Physicians practicing in academic, research, and private practice sectors experience discrimination based on gender, ethnic/racial, and IMG status.


Facilitation of dopamine and acetylcholine release by intermittent hypoxia in PC12 cells: involvement of calcium and reactive oxygen species.
We have investigated the effects of preconditioning pheochromocytoma (PC12) cells with intermittent hypoxia (IH) on transmitter release during acute hypoxia. Cell cultures were exposed to either alternating cycles of hypoxia (1% O(2) + 5% CO(2); 30 s/cycle) and normoxia (21% O(2) + 5% CO(2); 3 min/cycle) for 15 or 60 cycles or normoxia alone (control) for similar durations. Control and IH cells were challenged with either hyperoxia (basal release) or acute hypoxia (Po(2) of approximately 35 Torr) for 5 min, and the amounts of dopamine (DA) and acetylcholine (ACh) released in the medium were determined by HPLC combined with electrochemical detection. Hypoxia augmented DA (approximately 80%) but not ACh release in naive cells, whereas, in IH-conditioned cells, it further enhanced DA release (ranging from 120 to approximately 145%) and facilitated ACh release (approximately 30%). Hypoxia-evoked augmentation of transmitter release was not seen in cells conditioned with sustained hypoxia. IH-induced increase in DA but not IH-induced ACh release during hypoxia was partially inhibited by cadmium chloride (100 microM), a voltage-gated Ca(2+) channel blocker. By contrast, 2-aminoethoxydiphenylborate (75 microM), a blocker of inositol 1,4,5-trisphosphate (IP(3)) receptors, and N-acetyl-L-cysteine (300 microM), a potent scavenger of reactive oxygen species, either attenuated or abolished IH-evoked augmentation of transmitter release during hypoxia. Together, the above results demonstrate that IH conditioning increases hypoxia-evoked neurotransmitter release from PC12 cells via mechanisms involving mobilization of Ca(2+) from intracellular stores through activation of IP(3) receptors. Our findings also suggest that oxidative stress plays a central role in IH-induced augmentation of transmitter release from PC12 cells during acute hypoxia.


Genome wide interactions of wild-type and activator bypass forms of σ54.
Enhancer-dependent transcription involving the promoter specificity factor σ(54) is widely distributed amongst bacteria and commonly associated with cell envelope function. For transcription initiation, σ(54)-RNA polymerase yields open promoter complexes through its remodelling by cognate AAA+ ATPase activators. Since activators can be bypassed in vitro, bypass transcription in vivo could be a source of emergent gene expression along evolutionary pathways yielding new control networks and transcription patterns. At a single test promoter in vivo bypass transcription was not observed. We now use genome-wide transcription profiling, genome-wide mutagenesis and gene over-expression strategies in Escherichia coli, to (i) scope the range of bypass transcription in vivo and (ii) identify genes which might alter bypass transcription in vivo. We find little evidence for pervasive bypass transcription in vivo with only a small subset of σ(54) promoters functioning without activators. Results also suggest no one gene limits bypass transcription in vivo, arguing bypass transcription is strongly kept in check. Promoter sequences subject to repression by σ(54) were evident, indicating loss of rpoN (encoding σ(54)) rather than creating rpoN bypass alleles would be one evolutionary route for new gene expression patterns. Finally, cold-shock promoters showed unusual σ(54)-dependence in vivo not readily correlated with conventional σ(54) binding-sites.


Pathophysiology of language, speech and emotions in neurodegenerative disease.
Studying neurodegenerative diseases has greatly expanded our knowledge of language, speech and emotion as these diseases can affect areas not typically seen with stroke or tumor. Newer imaging techniques such as voxel based morphometry), fluorodeoxyglucose (F18) positron emission tomography and functional magnetic resonance imaging have allowed localization of these deficits and a greater understanding of the language network targeted by these progressive neurodegenerative illnesses. This review illustrates these important points by describing five syndromes, using clinical cases and then noting the anatomy, typical pathology, and proposed pathophysiology. The syndromes are Progressive Nonfluent Aphasia, Semantic Dementia, Logopenic Aphasia, Primary Progressive Apraxia of Speech and Dysprosody of Speech. Clinicians recognizing these syndromes using the associated clinico-anatomic patterns will lead to more accurate diagnosis and improved patient counseling and management. Further, patients may be included in appropriate clinical trials when their doctors are aware of the most likely pathology.


It's the thought that counts: The role of hostile cognition in shaping aggressive responses to social exclusion.
Prior research has confirmed a casual path between social rejection and aggression, but there has been no clear explanation of why social rejection causes aggression. A series of experiments tested the hypothesis that social exclusion increases the inclination to perceive neutral information as hostile, which has implications for aggression. Compared to accepted and control participants, socially excluded participants were more likely to rate aggressive and ambiguous words as similar (Experiment 1a), to complete word fragments with aggressive words (Experiment 1b), and to rate the ambiguous actions of another person as hostile (Experiments 2-4). This hostile cognitive bias among excluded people was related to their aggressive treatment of others who were not involved in the exclusion experience (Experiments 2 and 3) and others with whom participants had no previous contact (Experiment 4). These findings provide a first step in resolving the mystery of why social exclusion produces aggression.


Multimodal treatment strategy for locally advanced breast cancer.
Between 1990 and 1995, 87 patients with locally advanced breast cancer were treated with initial chemotherapy consisting of 3-4 cycles of epirubicin and then with surgery, radiotherapy and chemotherapy. All patients with positive or unknown estrogen receptor status were administered tamoxifen. A complete response was observed in 9 patients and a partial response in 64. At a mean follow-up of 29.22 months, 25 patients had died of metastatic disease, and 48 patients are disease-free. 54% patients are alive at 5 years. Statistical analysis confirmed that neither age, menopausal status, size of the primary tumor nor histology seemed to influence the Disease Free and Overall Survival. Improved survival was observed in patients with negative lymph nodes and positive receptor status. The presence of a positive receptor status may be correlated with conserved integrity of hormone sensitivity and with a good response to the hormone therapy.


The effect of coordinate system selection on wrist kinematics.
Three-dimensional motion analysis of the hand and wrist is common in in-vitro and in-vivo biomechanical research. However, all studies rely on post testing analysis, where anatomical joint coordinate systems (JCS) are created to generate clinically relevant data to describe wrist motion. The purpose of this study was to present a comparison of four JCS that have been previously described in literature. Five cadaveric upper limbs were passively cycled through a flexion-extension and radial-ulnar deviation motion pathways using a wrist motion simulator. During testing, clinical wrist angle was measured using a goniometer. Following testing, wrist angle was calculated using four previously described methods of generating wrist coordinate systems, to facilitate their comparison. For flexion-extension wrist motion, only subtle difference between JCSs were detected. When comparing the performance of each JCS to the measured wrist angle during flexion-extension wrist motion, the RMSE for all three analyzed axes were all within 6.6°. For radial-ulnar deviation wrist motion, again only subtle difference between JCSs were detected. When comparing the performance of each JCS to the measured wrist angle during radial-ulnar deviation wrist motion, the RMSE for all three analyzed axes were all within 7.1°. The results of this coordinate system comparison do not favor one JCS generation method over another, as all were found to be similar and the small differences that were found are likely not clinically significant. We support using any of the analyzed coordinate system generation methods; however, a practical advantage of using certain methods is that the required digitized points to form the coordinate systems are palpable on the skin's surface.


European suslik as a possible carrier of plague in natural foci in eastern Europe.
It is possible that the outbreaks of plague observed in Roumania and Bulgaria in the 19th century were of local origin because marmots and susliks--known as the main carriers of plague in nature--were widely spread on the territory of these countries. In the subsequent years, marmots died out in consequence of the economic activity of man and the habitats of susliks became sporadic and occurred in small foci. However, data obtained in the last few decades point out the possibility of long-term preservation of plague infection in the populations of rodents occupying small areas of land. The presence of the European suslik in the countries of Eastern Europe and the fleas parasitizing on the rodent, capable of transferring plague infection, permit the authors to raise the question of a possible occurrence of natural foci of plague in Roumania and Bulgaria. Data are given demonstrating the suitability of an extensive epidemiological reconnaissance in these countries.


Non-normal Screening Mammography Results, Lumpectomies, and Breast Cancer Reported by California Women, 2001-2009.
Although screening mammography may contribute to decreases in breast cancer mortality in a population, it may also increase the risk of false positives, anxiety, and unnecessary and costly medical procedures in individuals. We report trends in self-reported non-normal screening mammography results, lumpectomies, and breast cancer in a representative sample of California women. Data were obtained from the 2001, 2005, and 2009 cross-sectional California Health Interview Surveys (CHIS) and weighted to the California population. CHIS employed a multistage sampling design to administer telephone surveys in 6 languages. Our study sample was restricted to women 40 years and older who reported a screening mammogram in the past 2 years. Sample sizes were 13,974 in 2001, 12,069 in 2005, and 15,552 in 2009. Women reporting non-normal results were asked whether they had an operation to remove the lump and, if so, whether the lump was confirmed as malignant. Between 2001 and 2009, the percent of California women who reported having been diagnosed with breast cancer was relatively stable. For each of the three age groups studied, the percentage of non-normal mammography results increased and the percentages of lumpectomies decreased and, for every woman reporting a diagnosis of breast cancer, three women reported a lumpectomy that turned out not to be cancer. This ratio was greater for younger women and less for older women. Despite relatively constant rates of breast cancer diagnosis from 2001 to 2009, the percentage of non-normal mammography results increased and lumpectomies declined.


[The effect of early immunosuppressive therapy on the rate of resections performed in patients with Chron's disease, in Veszprém county, Hungary, a population-based cohort study].
Medical therapy for Crohn's disease has changed significantly over the past 20 years with the increasing use of immunosuppressants. In contrast, surgery rates are still high and evidence about the the changes in the outcome of Crohn's disease over the past decades is scarce. The objective of this study was to analyze the evolution of the surgical rates and medical therapy in the population-based Veszprém county database. Data of 506 Crohn's disease patients were analyzed (age at diagnosis: 31.5 years, SD: 13.8 years). Both hospital and outpatient records were collected and comprehensively reviewed. The study population was divided into three groups based on the year of diagnosis (cohort A: 1977-1989, cohort B: 1990-1998 and cohort C: 1999-2008). Overall azathioprine, systemic steroid, and biological (only available after 1998) exposure was 45.8, 68.6, and 9.5%, respectively. The 1 and 5-year probabilities of azathioprine use were 3.2 and 6.2% in cohort A, 11.4 and 29.9% in cohort B, and 34.8 and 46.2% in cohort C. In multivariate analysis, decade of diagnosis (P<0.001), age at onset (P = 0.008), disease behavior at diagnosis (P<0.001), and need for systemic steroids (P<0.001) were significantly associated with the time to initiation of azathioprine therapy. Early azathioprine use was significantly associated with the time to intestinal surgery in Crohn's disease patients; in a multivariate Cox analysis (HR: 0.43, 95% confidence interval (CI): 0.28-0.65) and after matching on propensity scores for azathioprine use (HR: 0.42,95% CI:0.26-0.67). This population-based inception cohort showed that reduction in surgical rates was independently associated with increased and earlier azathioprine use.


More time in a community setting: A service evaluation of the impact of intrathecal drug delivery systems on place of care of patients with cancer pain.
Intrathecal Drug Delivery Systems are underutilised in the management of refractory cancer pain despite evidence of their efficacy. Not all patients who are offered this treatment modality accept it. There is no current evidence that indicates if the use of intrathecal drug delivery systems impacts on place of care for patients with cancer related pain. This service evaluation compared place of care, place of death and morphine equivalent daily dose at end of life for patients in whom Intrathecal Drug Delivery was successfully established versus those who chose comprehensive medical management. A retrospective longitudinal cohort study of 45 patients with cancer pain comparing those who had ongoing analgesia successfully delivered via an implanted Intrathecal Drug Delivery System (n = 28) with those who continued to receive comprehensive medical management (n = 17). There was a markedly greater time spent in the community in the intrathecal group than the medical management group (median 126.5vs 25.5 days; p = 0.002) and a lower morphine equivalent daily dose at end of life (median 127.5vs 440.0 p = 0.022). In patients with advanced cancer, the successful establishment of intrathecal analgesia is associated with more time in the community and a lower morphine equivalent daily dose at end of life. The study has low numbers, and the sample was retrospectively selected. Nevertheless, these findings suggest the initial investment of time in an inpatient setting may be beneficial. Further research is required, using larger, prospective studies of patient outcomes in this setting.


Kinase domain insert containing receptor promotor controlled suicide gene system kills human umbilical vein endothelial cells.
To evaluate the killing effect of double suicide gene mediated by adenovirus and regulated under kinase domain insert containing receptor (KDR) promoter on human umbilical vein endothelial cells. By PCR technology, human KDR promoter gene, Escherichia coli (E. coli) cytosine deaminase (CD) gene and the herpes simple virus-thymidine kinase (TK) gene were cloned. Plasmid pKDR-CDglyTK was constructed with them. Then, a recombinant adenoviral plasmid pAdKDR-CDglyTK was constructed in a "two-step transformation protocol". The newly constructed plasmids were transfected to 293 packaging cells to grow adenoviruses, which were further propagated and purified. Human umbilical vein endothelial cells (HUVEC) were infected with a different multiplicity of infection (MOI) of resultant recombinant adenovirus, the infection rate was measured with the aid of (GFP) expression. Infected cells were cultured in culture media containing different concentrations of (GCV) and/or 5-(FC), and the killing effects were measured. Recombinant adenoviruses AdKDR-CDglyTK were successfully constructed, and they infected HUVEC cells efficiently. Our data indicated that the infection rate was relevant to MOI of recombinant adenoviruses. HUVEC cells infected with AdKDR-CDglyTK were highly sensitive to the prodrugs, their survival rate correlated to both the concentration of the prodrugs and the MOI of recombinant adenoviruses. Our data also indicated that the two prodrugs used in combination were much more effective on killing transgeneic cells than GCV or 5-FC used alone. Prodrug/KDR-CDglyTK system is effective on killing HUVEC cells, its killing effect correlates to the concentration of prodrugs and recombinant adenovirus' MOI. Combined use of the two prodrugs confers better killing effects on transgeneic cells.


Anacardic Acids from Knema hookeriana as Modulators of Bcl-xL/Bak and Mcl-1/Bid Interactions.
Proteins of the Bcl-2 family are key targets in anticancer drug discovery. Disrupting the interaction between anti- and pro-apoptotic members of this protein family was the approach chosen in this study to restore apoptosis. Thus, a biological screening on the modulation of the Bcl-xL/Bak and Mcl-1/Bid interactions permitted the selection of Knema hookeriana for further phytochemical investigations. The ethyl acetate extract from the stem bark led to the isolation of six new compounds, three acetophenone derivatives (1-3) and three anacardic acid derivatives (4-6), along with four known anacardic acids (7-10) and two cardanols (11, 12). Their structures were elucidated by 1D and 2D NMR analysis in combination with HRMS experiments. The ability of these compounds to antagonize Bcl-xL/Bak and Mcl-1/Bid association was determined, using a protein-protein interaction assay, but only anacardic acid derivatives (4-10) exhibited significant binding properties, with Ki values ranging from 0.2 to 18 μM. Protein-ligand NMR experiments further revealed that anacardic acid 9, the most active compound, does not interact with the anti-apoptotic proteins Bcl-xL and Mcl-1 but instead interacts with pro-apoptotic protein Bid.


Supracardiac atherosclerosis in embolic stroke of undetermined source: the underestimated source.
The term 'embolic stroke of undetermined source' (ESUS) is used to describe patients with a non-lacunar ischaemic stroke without any identified embolic source from the heart or the arteries supplying the ischaemic territory, or any other apparent cause. When the ESUS concept was introduced, covert atrial fibrillation was conceived to be the main underlying cause in the majority of ESUS patients. Another important embolic source in ESUS is the atherosclerotic plaque in the carotid, vertebrobasilar, and intracranial arteries, or the aortic arch-collectively described as supracardiac atherosclerosis. There is emerging evidence showing that the role of supracardiac atherosclerosis is larger than it was initially perceived. Advanced imaging methods are available to identify plaques which high embolic risk. The role of novel antithrombotic strategies in these patients needs to be assessed in randomized controlled trials. This review presents the evidence which points towards a major aetiological association between atherosclerotic plaques and ESUS, summarizes the imaging features which may aid to identify plaques more likely to be associated with ESUS, discusses strategies to reduce the associated stroke risk, and highlights the rationale for future research in this field.


Constraints and limitations on the transcriptional response downstream of the Bicoid morphogen gradient.
The regulation of the hunchback promoter expression by the maternal Bicoid gradient has been studied as a model system in development for many years. Yet, at the level of quantitative agreement between data and theoretical models, even the first step of this regulation, transcription, continues to be challenging. This situation is slowly progressing, thanks to quantitative live-imaging techniques coupled to advanced statistical data analysis and modeling. Here, we outline the current state of our knowledge of this apparently "simple" step, highlighting the newly appreciated role of bursty transcription dynamics and its regulation.


Lactate as a fuel for mitochondrial respiration.
Lactate production in skeletal muscle has now been studied for nearly two centuries and still its production and functional role at rest and during muscle contraction is a subject of debate. Historically, skeletal muscle was seen mainly as the site of lactate production during contraction and lactate production associated with a lack of muscle oxygenation and fatigue. Later, it was recognized that skeletal muscle not only plays an important role in lactate production but also in lactate clearance and this in turn has led to a renewed interest in the metabolic fate of lactate in skeletal muscle and also in other tissues. Studies using lactate isotopes have shown that skeletal muscle extracts lactate from the circulation despite a substantial net lactate release, and that skeletal muscle has a large capacity for lactate oxidation; these processes being enhanced with exercise. Lactate dehydrogenase (LDH) controls the formation of lactate and may regulate the turnover of lactate in the muscle cell. Skeletal muscle contains five LDH isoforms (LDH1-5). Of the five LDH isoforms, the heart-specific LDH1, 2 is generally suggested to favour the reaction of lactate to pyruvate whereas the muscle-specific LDH4,5 isoform favours lactate formation. However, in this paper, it is argued that compartmentalization of the muscle cell and LDH association with cell structures may play a more predominant role in whether the LDH reaction proceeds towards lactate or pyruvate formation. The model for skeletal muscle lactate metabolism presented is in essence based on a synthesis of old and more recent studies on skeletal muscle lactate transport, uptake, release, oxidation, and the role of LDH at rest and during exercise.


Prevalence, characteristics, and predictors of early termination of cardiovascular clinical trials due to low recruitment: insights from the ClinicalTrials.gov registry.
Early termination of clinical trials due to low recruitment represents an understudied challenge for clinical research. We aimed to describe characteristics of cardiovascular trials terminated because of low recruitment and identify the major predictors of such early termination. We reviewed all cardiovascular clinical trials (7,042 studies) registered in ClinicalTrials.gov from February 29, 2000, to January 17, 2013, and assessed information about trials that were completed and those that were terminated early. Logistic regression models were developed to identify independent predictors of early termination due to low recruitment. Our search strategy identified 6,279 cardiovascular clinical trials, of which 684 (10.9%) were terminated prematurely. Of these halted trials, the main reason for termination was lower than expected recruitment (278 trials; 53.6%). When comparing trials that terminated early because of low recruitment with those that were completed, we found that studies funded by the National Institutes of Health or other US federal agencies (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.14-0.89), studies of behavior/diet intervention (OR 0.35, 95% CI 0.19-0.65), and single-arm design studies (OR 0.57, 95% CI 0.42-0.78) were associated with a lower risk of early termination. University/hospital-funded (OR 1.52, 95% CI 1.10-2.10) and mixed-source-funded studies (OR 2.14, 95% CI 1.52-3.01) were associated with a higher likelihood of early termination due to lower than expected recruitment rates. Low recruitment represents the main cause of early termination of cardiovascular clinical trials. Funding source, type of intervention, and study design are factors associated with early termination due to low recruitment and might be good targets for improving enrollment into cardiovascular clinical trials.


COVID-19 Mortality Prediction From Deep Learning in a Large Multistate Electronic Health Record and Laboratory Information System Data Set: Algorithm Development and Validation.
COVID-19 is caused by the SARS-CoV-2 virus and has strikingly heterogeneous clinical manifestations, with most individuals contracting mild disease but a substantial minority experiencing fulminant cardiopulmonary symptoms or death. The clinical covariates and the laboratory tests performed on a patient provide robust statistics to guide clinical treatment. Deep learning approaches on a data set of this nature enable patient stratification and provide methods to guide clinical treatment. Here, we report on the development and prospective validation of a state-of-the-art machine learning model to provide mortality prediction shortly after confirmation of SARS-CoV-2 infection in the Mayo Clinic patient population. We retrospectively constructed one of the largest reported and most geographically diverse laboratory information system and electronic health record of COVID-19 data sets in the published literature, which included 11,807 patients residing in 41 states of the United States of America and treated at medical sites across 5 states in 3 time zones. Traditional machine learning models were evaluated independently as well as in a stacked learner approach by using AutoGluon, and various recurrent neural network architectures were considered. The traditional machine learning models were implemented using the AutoGluon-Tabular framework, whereas the recurrent neural networks utilized the TensorFlow Keras framework. We trained these models to operate solely using routine laboratory measurements and clinical covariates available within 72 hours of a patient's first positive COVID-19 nucleic acid test result. The GRU-D recurrent neural network achieved peak cross-validation performance with 0.938 (SE 0.004) as the area under the receiver operating characteristic (AUROC) curve. This model retained strong performance by reducing the follow-up time to 12 hours (0.916 [SE 0.005] AUROC), and the leave-one-out feature importance analysis indicated that the most independently valuable features were age, Charlson comorbidity index, minimum oxygen saturation, fibrinogen level, and serum iron level. In the prospective testing cohort, this model provided an AUROC of 0.901 and a statistically significant difference in survival (P<.001, hazard ratio for those predicted to survive, 95% CI 0.043-0.106). Our deep learning approach using GRU-D provides an alert system to flag mortality for COVID-19-positive patients by using clinical covariates and laboratory values within a 72-hour window after the first positive nucleic acid test result.