Asymptomatic or "silent" atrial fibrillation: frequency in untreated patients and patients receiving azimilide.
Asymptomatic, or "silent" atrial fibrillation could increase the risk of stroke. Little is known about the frequency of asymptomatic atrial fibrillation in patients who also have symptomatic atrial fibrillation; similarly, little is known about the effect of antiarrhythmic drug therapy on asymptomatic atrial fibrillation. Patients in sinus rhythm with a history of symptomatic atrial fibrillation or atrial flutter received placebo or azimilide (35 to 125 mg) once daily for 6 or 9 months in 4 similar double-blind trials. The end point was the first recurrence of a symptomatic ECG-documented supraventricular arrhythmia. Routine transtelephonic electrocardiograms, in the absence of symptoms, were recorded for 30 seconds every 2 weeks until patients completed follow-up or documented a symptomatic supraventricular arrhythmia. Of the 1380 patients, 489 received placebo. Among these patients receiving placebo, 303 transmitted at least one routine ECG while asymptomatic. Asymptomatic atrial fibrillation was recorded in 50 (17%) within 6 months and before recurrence of symptomatic supraventricular arrhythmia. In the 3 trials evaluating azimilide in therapeutic doses (100 and 125 mg), asymptomatic atrial fibrillation occurred in 49 of 382 (13%) receiving azimilide and 43 of 233 (18%) receiving placebo. Although drug effect on time to first asymptomatic event was not statistically significant (hazard ratio, 0.70; P=0.09), there was a 40% reduction in asymptomatic atrial fibrillation on azimilide compared with placebo (P=0.03) when repeated observations were considered. Asymptomatic atrial fibrillation is common in untreated patients with a history of symptomatic atrial fibrillation (and is likely underestimated by this analysis). Azimilide may reduce the occurrence of this silent arrhythmia.


Neural-network-based adaptive UPFC for improving transient stability performance of power system.
This paper uses the recently proposed H(infinity)-learning method, for updating the parameter of the radial basis function neural network (RBFNN) used as a control scheme for the unified power flow controller (UPFC) to improve the transient stability performance of a multimachine power system. The RBFNN uses a single neuron architecture whose input is proportional to the difference in error and the updating of its parameters is carried via a proportional value of the error. Also, the coefficients of the difference of error, error, and auxiliary signal used for improving damping performance are depicted by a genetic algorithm. The performance of the newly designed controller is evaluated in a four-machine power system subjected to different types of disturbances. The newly designed single-neuron RBFNN-based UPFC exhibits better damping performance compared to the conventional PID as well as the extended Kalman filter (EKF) updating-based RBFNN scheme, making the unstable cases stable. Its simple architecture reduces the computational burden, thereby making it attractive for real-time implementation. Also, all the machines are being equipped with the conventional power system stabilizer (PSS) to study the coordinated effect of UPFC and PSS in the system.


Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen.
The present clinical trial was undertaken to assess the clinical safety and possible efficacy of administering tamoxifen to patients with recurrent malignant glial tumors at dosages calculated to achieve levels sufficient to inhibit protein kinase C within the tumor cells. Chronic p.o. tamoxifen was administered in very high dosages to 32 patients (20 males and 12 females; age range, 26-75 years; mean, 49 years) with histologically verified malignant glioma [anaplastic astrocytoma (12 patients) or glioblastoma multiforme (20 patients)] who had demonstrated clinical and radiographical progression or recurrence following external beam radiation therapy (and additional chemotherapy in 11; immunotherapy in 2). The dosage of tamoxifen administered was 200 mg/day to males and 160 mg/day to females given in a twice daily schedule. Clinical and radiographical (defined as a greater than 50% decrease in volume of the enhancing lesion volume on magnetic resonance imaging and a decrease in metabolic activity on serial positron emission tomographic scans) response was noted in 8 patients (25%; 4/12 with anaplastic astrocytoma and 4/20 glioblastoma multiforme), with an additional 6 patients (19%) exhibiting stabilization of disease with minimal side effects. Median survival from the time of diagnosis for the entire cohort was 24 months (104 weeks), for the anaplastic astrocytoma group 42.5 months (185 weeks), and for the glioblastoma group 17.4 months (75.5 weeks). From the initiation of tamoxifen, median survival for the entire cohort was 10.1 months (44 weeks), for the anaplastic astrocytoma group 16 months (69 weeks), and for the glioblastoma group 7.2 months (31 weeks). The mean length of follow-up of all patients after initiating tamoxifen was 16 months (69 weeks), while the mean length of follow-up of alive patients is 22.6 months (98 weeks) (range up to 51 months). These data suggest that a subgroup of patients with malignant gliomas respond or stabilize with chronic high-dose tamoxifen therapy. This therapy may represent an alternative or adjuvant to existing chemotherapies for these tumors; further clinical trials are warranted.


Genetic characterization of human populations: from ABO to a genetic map of the British people.
From 1900, when Landsteiner first described the ABO blood groups, to the present, the methods used to characterize the genetics of human populations have undergone a remarkable development. Concomitantly, our understanding of the history and spread of human populations across the earth has become much more detailed. As has often been said, a better understanding of the genetic relationships among the peoples of the world is one of the best antidotes to racial prejudices. Such an understanding provides us with a fascinating, improved insight into our origins as well as with valuable information about population differences that are of medical relevance. The study of genetic polymorphisms has been essential to the analysis of the relationships between human populations. The evolution of methods used to study human polymorphisms and the resulting contributions to our understanding of human health and history is the subject of this Perspectives.


Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis.
Lowering blood pressure (BP) is widely used to reduce vascular risk in individuals with diabetes. To determine the associations between BP-lowering treatment and vascular disease in type 2 diabetes. We searched MEDLINE for large-scale randomized controlled trials of BP-lowering treatment including patients with diabetes, published between January 1966 and October 2014. Two reviewers independently extracted study characteristics and vascular outcome data. Estimates were stratified by baseline BP and achieved BP, and pooled using fixed-effects meta-analysis. All-cause mortality, cardiovascular events, coronary heart disease events, stroke, heart failure, retinopathy, new or worsening albuminuria, and renal failure. Forty trials judged to be of low risk of bias (100,354 participants) were included. Each 10-mm Hg lower systolic BP was associated with a significantly lower risk of mortality (relative risk [RR], 0.87; 95% CI, 0.78-0.96); absolute risk reduction (ARR) in events per 1000 patient-years (3.16; 95% CI, 0.90-5.22), cardiovascular events (RR, 0.89 [95% CI, 0.83-0.95]; ARR, 3.90 [95% CI, 1.57-6.06]), coronary heart disease (RR, 0.88 [95% CI, 0.80-0.98]; ARR, 1.81 [95% CI, 0.35-3.11]), stroke (RR, 0.73 [95% CI, 0.64-0.83]; ARR, 4.06 [95% CI, 2.53-5.40]), albuminuria (RR, 0.83 [95% CI, 0.79-0.87]; ARR, 9.33 [95% CI, 7.13-11.37]), and retinopathy (RR, 0.87 [95% CI, 0.76-0.99]; ARR, 2.23 [95% CI, 0.15-4.04]). When trials were stratified by mean baseline systolic BP at greater than or less than 140 mm Hg, RRs for outcomes other than stroke, retinopathy, and renal failure were lower in studies with greater baseline systolic BP (P interaction <0.1). The associations between BP-lowering treatments and outcomes were not significantly different, irrespective of drug class, except for stroke and heart failure. Estimates were similar when all trials, regardless of risk of bias, were included. Among patients with type 2 diabetes, BP lowering was associated with improved mortality and other clinical outcomes with lower RRs observed among those with baseline BP of 140 mm Hg and greater. These findings support the use of medications for BP lowering in these patients.


Short- and long-term results of open heart surgery in patients with abdominal solid organ transplant.
Cardiac disease is a common cause of mortality and morbidity in patients with abdominal solid organ transplant. Improvement of the results of abdominal organ transplantation has contributed to an increasing pool of patients who require open heart surgery. We investigated short- and long-term results of open heart surgery in patients with functioning abdominal solid organ transplants. We retrospectively examined 60 patients (52.5 years in average) undergoing coronary artery bypass grafting and/or valve surgery since July 1988 after abdominal organ transplantation. There were 22 females (37%). They consisted of 46 kidney, nine kidney-pancreas and five liver recipients. Cardiac surgery was performed 68.9 months after transplantation. Preoperative serum creatinine level was 2.1 mg/dl, and 11 patients (18%) had creatinine level more than 3.0 mg/dl. Eleven patients (18%) were operated upon on non-elective basis. Twelve patients (20%) were not given stress-dose steroids postoperatively. Three patients died early after surgery (5.0%). Twenty-six major complications were seen in 17 patients (28%), including deterioration of renal function in seven (three patients required temporary hemodialysis), three major infections, two bleeding complications, and two strokes. No graft loss was encountered. No differences were seen in mortality and morbidity between patients with or without stress-dose steroids. Multivariate analysis identified cardiopulmonary bypass time (P<0.05) as a risk factor for operative death, preoperative creatinine level (P<0.05), cardiopulmonary bypass time (P<0.05) and the amount of fresh frozen plasma used (P<0.05) for major complication, non-elective surgery (P<0.01) for deterioration of renal function. Thirteen patients died and five kidney allografts failed late after surgery. Three- and 5-year patient and graft survivals were 70.8 and 66.8, 84.5 and 84.5%, respectively. Multivariate regression analysis identified female gender (P<0.05), body mass index (P<0.001) and non-elective surgery (P<0.001) as risk factors for late death, and preoperative creatinine level (P<0.05) for late graft loss. Open heart surgery can be performed with acceptable short- and long-term results in patients with functioning abdominal transplants. Stress-dose steroid may be unnecessary in selected patients. Aggressive use of open heart surgery in this patient population to avoid non-elective surgery may further improve early and late surgical outcomes.


Clinical staging in psychiatry: a cross-cutting model of diagnosis with heuristic and practical value.
Staging models are used routinely in general medicine for potentially serious or chronic physical disorders such as diabetes, arthritis and cancers, describing the links between biomarkers, clinical phenotypes and disease extension, and promoting a personalised or stratified medicine approach to treatment planning. Clinical staging involves a detailed description of where an individual exists on a continuum of disorder progression from stage 0 (an at-risk or latency stage) through to stage IV (late or end-stage disease). The approach is popular owing to its clinical utility and is increasingly being applied in psychiatry. The concept offers an informed approach to research and the active promotion of indicated prevention and early intervention strategies. We suggest that for young persons with emerging bipolar disorder, such transdiagnostic staging models could provide a framework that better reflects the developmental psychopathology and matches the complex longitudinal inter-relationships between subsyndromal and syndromal mood, psychotic and other disorders.


Synergistic dual automaticity in sinoatrial node cell and tissue models.
The mechanism of sinoatrial node (SAN) automaticity is traditionally attributed to membrane ion currents. Recent evidence indicates spontaneous sarcoplasmic reticulum (SR) Ca(2+) cycling also plays an important role. A computer simulation on SAN cell and 1D tissue model was performed. In the SAN cells, SR Ca(2+) cycling broadly modulated the sinus rate from 1.74 Hz to 3.87 Hz. Shortening of the junctional SR refilling time and increase of SR Ca(2+) release were responsible for sinus rate acceleration. However, under the fast SR Ca(2+) cycling, decreased L-type Ca(2+) current (I(CaL)) resulted in irregular firing. When Ca(2+) cycling was suppressed, I(f) and I(CaT) both acted to stabilize the pacemaker rhythm, but I(CaT) had less effect than I(f). At the 1D level, the electrical coupling between neighboring cells had little effect on the earliest pacemaker location. The leading pacemaking site always colocalized with the site with the highest SR Ca(2+) cycling rate, but shifted to the site with less inhibited I(CaL). The rate of SR Ca(2+) cycling can effectively and broadly modulate the sinus rate. I(f), I(CaL) and I(CaT) play integral roles to guarantee SAN cell rhythmic firing. The leading pacemaker site is determined by intracellular Ca(2+) dynamics and membrane currents, indicating the synergistic dual automaticity not only exists in single SAN cells, but also at the tissue level.


The effect of the inhibitor diphenylene iodonium on the superoxide-generating system of neutrophils. Specific labelling of a component polypeptide of the oxidase.
NADPH-dependent superoxide production by the solubilized oxidase of neutrophils was inhibited 36% by diphenylene iodonium at a 1:1 stoichiometry with the enzyme flavoprotein content. Addition of diphenylene iodonium strongly inhibited the NADPH-dependent reduction of both FAD and cytochrome b-245 in steady-state kinetic experiments. Incubation of solubilized enzyme with diphenylene [125I]iodonium resulted in the specific labelling of a polypeptide of Mr 45,000. In the presence of NADPH the amount of label incorporated into the polypeptide was reduced. There was no difference in labelling between enzyme prepared from stimulated or unstimulated cells.


A lateral wavefront shearing interferometer with variable shear.
A lateral wavefront shearing interferometer is presented. Two diffraction gratings are used as beam splitters in the Fraunhofer planes of two successive image forming systems. Each diffraction order of the first grating forms an image of the object in an intermediate image plane. These are completely separated from each other, so that all but two can be blocked out. Then the second grating, together with the second image forming system, creates two partially overlapping sets of images of the two passing intermediate images. A variable lateral shear between these two sets is achieved by rotation of the gratings in opposite senses. The principle of this shearing interferometer has been experimentally verified. It can be simplified by folding so that only one grating and one image forming system are needed. Furthermore, a sine wave generator using an generator using an extended, polychromatic source is presented which is built on this principle.


Cool tadpoles from Arctic environments waste fewer nutrients - high gross growth efficiencies lead to low consumer-mediated nutrient recycling in the North.
Endothermic organisms can adapt to short growing seasons, low temperatures and nutrient limitation by developing high growth rates and high gross growth efficiencies (GGEs). Animals with high GGEs are better at assimilating limiting nutrients and thus should recycle (or lose) fewer nutrients. Longer guts in relation to body mass may facilitate higher GGE under resource limitation. Within the context of ecological stoichiometry theory, this study combines ecology with evolution by relating latitudinal life-history adaptations in GGE, mediated by gut length, to its ecosystem consequences, such as consumer-mediated nutrient recycling. In common garden experiments, we raised Rana temporaria tadpoles from two regions (Arctic/Boreal) under two temperature regimes (18/23 °C) crossed with two food quality treatments (high/low-nitrogen content). We measured tadpole GGEs, total nutrient loss (excretion + egestion) rates and gut length during ontogeny. In order to maintain their elemental balance, tadpoles fed low-nitrogen (N) food had lower N excretion rates and higher total phosphorous (P) loss rates than tadpoles fed high-quality food. In accordance with expectations, Arctic tadpoles had higher GGEs and lower N loss rates than their low-latitude conspecifics, especially when fed low-N food, but only in ambient temperature treatments. Arctic tadpoles also had relatively longer guts than Boreal tadpoles during early development. That temperature and food quality interacted with tadpole region of origin in affecting tadpole GGEs, nutrient loss rates and relative gut length, suggests evolved adaptation to temperature and resource differences. With future climate change, mean annual temperatures will increase. Additionally, species and genotypes will migrate north. This will change the functioning of Boreal and Arctic ecosystems by affecting consumer-mediated nutrient recycling and thus affect nutrient dynamics in general. Our study shows that evolved latitudinal adaption can change key ecosystem functions.


Circadian rhythms of saliva melatonin in ADHD, anxious and normal children.
Attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders are the most frequent psychiatric disorders in children. Changes in rhythms of symptoms during the day may be influenced by genetic, biological and psychological factors. Some changes of melatonin rhythm may hypothetically change the activity of ADHD by changing arousal or in anxiety children by changing their emotional state. In our present study we identify one group of ADHD children combine type without comorbids, one group of anxiety children and a control group. Most changes of melatonin daily rhythm are supposed in the anxiety group, especially in sleeping time, and more prominent change in the ADHD group with prominent hyperactivity and conduct disorder symptoms. Thirty-four ADHD and forty-three control children and eleven anxiety children, all 6-12 years old, participated in the study. The saliva specimens were collected in four different sessions during the school year, around the time of the spring and autumn equinox, when the natural light lasted 11.2 h ± 0.9 h. In our study more symptoms of conduct disorder elevated positive or negative correlations between psychopathology and saliva level of melatonin in ADHD and anxiety samples. We hypothesize that co-morbidity of ADHD or anxiety with impulsivity and conduct disorders might have elevated correlations between psychopathology of ADHD or anxiety and plasma melatonin level.


In vivo molecular imaging of atherosclerotic lesions in ApoE-/- mice using VCAM-1-specific, 99mTc-labeled peptidic sequences.
Vascular cell adhesion molecule 1 (VCAM-1) plays a major role in the chronic inflammatory processes involved in vulnerable atherosclerotic plaque development. We previously showed that the (99m)Tc-labeled major histocompatibility complex 1-derived peptide B2702p bound specifically to VCAM-1 and allowed the ex vivo imaging of atherosclerotic lesions in Watanabe heritable hyperlipidemic rabbits. However, B2702p target-to-background ratio was suboptimal for the in vivo imaging of VCAM-1 expression in atherosclerotic lesions. To improve the target-to-background ratio, 20 derivatives of B2702p (B2702p1-B2702p20) were synthesized using the alanine scan methodology. We hypothesized that (99m)Tc-radiolabeled B2702p derivatives might allow the molecular imaging of VCAM-1 expression in an experimental model of atherosclerosis. A mouse model of focal atherosclerotic plaque development induced by left carotid artery ligation in apolipoprotein E double-knockout (ApoE(-/-)) mice was used (n = 82). (99m)Tc-B2702p and (99m)Tc-B2702p1-(99m)Tc-B2702p20 were injected intravenously in anesthetized animals 3 wk after the ligation. Whole-body planar imaging was performed for 3 h. SPECT imaging of 6 additional ligated ApoE(-/-) mice was also performed with (99m)Tc-B2702p1. The animals were then euthanized, and the biodistribution of (99m)Tc-labeled peptides was evaluated by γ-well counting of excised organs. Expression of VCAM-1 in the ligated and contralateral carotid arteries was evaluated by immunohistology. Robust VCAM-1 immunostaining was observed in the left carotid atherosclerotic lesions as a consequence of artery ligation, whereas no VCAM-1 expression was detected in the contralateral carotid artery. Among all evaluated peptides, (99m)Tc-B2702p1 exhibited the most favorable properties. By γ-well counting, there was a significant 2.0-fold increase in the (99m)Tc-B2702p1 left-to-right carotid artery activity ratio (2.6 ± 0.6) and a 3.4-fold increase in the left carotid-to-blood activity ratio (1.4 ± 0.4) in comparison to (99m)Tc-B2702p (1.3 ± 0.2 and 0.4 ± 0.1, respectively, P < 0.05 for both comparisons). Similarly, planar image quantification indicated a higher left-to-right carotid activity ratio in (99m)Tc-B2702p1- than in (99m)Tc-B2702p-injected mice (1.2 ± 0.1 vs. 1.0 ± 0.0, respectively, P < 0.05). Finally, a significantly higher (99m)Tc-B2702p1 activity in the left than in the right carotid artery was observed by SPECT imaging (2.2 ± 0.4 vs. 1.4 ± 0.3 cpm/mm(2)/injected dose, respectively, P < 0.05). (99m)Tc-B2702p1 is a potentially useful radiotracer for the in vivo molecular imaging of VCAM-1 expression in atherosclerotic plaques.


Discovery of a non-peptidic inhibitor of west nile virus NS3 protease by high-throughput docking.
The non-structural 3 protease (NS3pro) is an essential flaviviral enzyme and therefore one of the most promising targets for drug development against West Nile virus (WNV) and dengue infections. In this work, a small-molecule inhibitor of the WNV NS3pro has been identified by automatic fragment-based docking of about 12000 compounds and testing by nuclear magnetic resonance (NMR) spectroscopy of only 22 molecules. Specific binding of the inhibitor into the active site of NS3pro and its binding mode are confirmed by 15N-HSQC NMR spectra. The inhibitory activity is further validated by an enzymatic assay and a tryptophan fluorescence quenching assay. The inhibitor [4-(carbamimidoylsulfanylmethyl)-2,5-dimethylphenyl]-methylsulfanylmethanimidamide has a good ratio of binding affinity versus molecular weight (ligand efficiency of 0.33 kcal/mol per non-hydrogen atom), and thus has good potential as lead compound for further development to combat West Nile virus infections.


Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.
Detection of low-affinity or transient interactions can be a bottleneck in our understanding of signaling networks. To address this problem, we developed an arrayed screening strategy based on protein complementation to systematically investigate protein-protein interactions in live human cells, and performed a large-scale screen for regulators of telomeres. Maintenance of vertebrate telomeres requires the concerted action of members of the Telomere Interactome, built upon the six core telomeric proteins TRF1, TRF2, RAP1, TIN2, TPP1, and POT1. Of the ∼12,000 human proteins examined, we identified over 300 proteins that associated with the six core telomeric proteins. The majority of the identified proteins have not been previously linked to telomere biology, including regulators of post-translational modifications such as protein kinases and ubiquitin E3 ligases. Results from this study shed light on the molecular niche that is fundamental to telomere regulation in humans, and provide a valuable tool to investigate signaling pathways in mammalian cells.


Effect of tidal volume and frequency on the temporal fall in lung compliance.
In this study we have investigated how changes in respiratory frequency and tidal volume in anesthetized dogs affect the fall in dynamic compliance (Cdyn) that occurs with time after a hyperinflation. Results showed that increasing frequency [at controlled arterial (PaCO2)] PCO2 from 16 to 32 breaths/min had no effect on either the rate of fall or the magnitude of the fall up to 1 h after the hyperinflation. However, increasing the tidal volume from 300 to 750 ml abolished the fall in Cdyn from 10 to 50 min after the hyperinflation; the fall within the first 10 min remained unchanged. We also examined the effect of a simulated "hyperinflation" on the compliance of strips of parenchymal tissue in vitro. This result indicated that in the absence of surface forces, parenchymal tissue demonstrates a fall in compliance, which is complete within 10 min. Overall our findings are consistent with the hypothesis that the fall in Cdyn after hyperinflation is a two-phase process. The initial rapid fall in Cdyn (i.e., within 10 min) may simply represent a passive recovery process from the hyperinflation stress on the parenchymal tissue. The slower fall occurring after 10 min likely results from progressive increases in surface tension, and this increase can apparently be blocked by increases in tidal volume.


Altered actin centripetal retrograde flow in physically restricted immunological synapses.
Antigen recognition by T cells involves large scale spatial reorganization of numerous receptor, adhesion, and costimulatory proteins within the T cell-antigen presenting cell (APC) junction. The resulting patterns can be distinctive, and are collectively known as the immunological synapse. Dynamical assembly of cytoskeletal network is believed to play an important role in driving these assembly processes. In one experimental strategy, the APC is replaced with a synthetic supported membrane. An advantage of this configuration is that solid structures patterned onto the underlying substrate can guide immunological synapse assembly into altered patterns. Here, we use mobile anti-CD3epsilon on the spatial-partitioned supported bilayer to ligate and trigger T cell receptor (TCR) in live Jurkat T cells. Simultaneous tracking of both TCR clusters and GFP-actin speckles reveals their dynamic association and individual flow patterns. Actin retrograde flow directs the inward transport of TCR clusters. Flow-based particle tracking algorithms allow us to investigate the velocity distribution of actin flow field across the whole synapse, and centripetal velocity of actin flow decreases as it moves toward the center of synapse. Localized actin flow analysis reveals that, while there is no influence on actin motion from substrate patterns directly, velocity differences of actin are observed over physically trapped TCR clusters. Actin flow regains its velocity immediately after passing through confined TCR clusters. These observations are consistent with a dynamic and dissipative coupling between TCR clusters and viscoelastic actin network.


The clinical effectiveness of transcanalicular diode laser-assisted revision surgery for failed endoscopic endonasal dacryocystorhinostomy.
We report the results and clinical effectiveness of transcanalicular diode laser-assisted revision surgery for failed endoscopic endonasal dacryocystorhinostomy (EDCR). We reviewed electronic charts of 53 eyes in 51 revision surgery patients, with anatomical failure after primary EDCR. The major cause of failed EDCR was membranous obstruction of the rhinostomy site (36/53 eyes, 67.9%). The second most common cause of failure was granulomatous obstruction (13/53 eyes, 24.5%). The overall success rate of the first revision surgery was 83.0% (44/53 eyes). Revision surgery for membranous obstruction (36 eyes) showed a 100% success rate, while a 50% success rate was achieved in granulomatous obstruction (13 eyes). 2 patients with synechial obstruction also showed good results (100%). Sump syndrome (two eyes) showed a 100% failure rate after revision surgery. When granuloma was the main cause of obstruction (13 eyes), the size of the granuloma was correlated with the success of revision surgery. Granuloma size was larger in failed revision surgery (p=0.002). A diode laser can achieve effective tissue dissection with minimal damage and is a good alternative technique for patients with membranous obstruction who had a failed EDCR. However, it may not be appropriate for large granulomatous obstruction and sump syndrome.


Ambivalent messages: adolescents' perspectives on pregnancy and birth.
To examine, from a youth's perspective, adolescent pregnancy and parenting in Baltimore, Maryland, a city with high rates of adolescent pregnancy. Six gender-stratified focus groups with 13- to 19-year-olds (4 female and 2 male groups; n = 47). We recorded focus groups, transcribed them verbatim, and analyzed them using the constant comparison method. Participants completed questionnaires to collect demographic and behavioral information. Results fit into a social-ecological framework. Individual (e.g., contraceptive use behaviors, religion), interpersonal (e.g., peer norms, maintaining male partners), and community (e.g., clinic factors, perceptions of community) level influences on adolescent pregnancy emerged. Participants discussed contradictory messages that were often gendered in their expectations; for instance, women were responsible for not getting pregnant and raising children. Adolescents expressed beliefs both against (e.g., challenging to complete school) and supporting early childrearing (e.g., religion). Recommendations for addressing the different influences included mentors, education, and community resources. Adolescents' perspectives and values regarding pregnancy and parenting may not mirror traditional and expected norms for pregnancy and requirements for raising a child. These findings challenge the framing of existing interventions as they may not accurately reflect adolescents' values regarding pregnancy and parenting, and thus may need to be modified to highlight positive attitudes toward contraception and postponing pregnancy.


Estimating the Global Demand and Delivery of Cancer Surgery.
Cancer is a leading cause of death and disability globally. While surgery remains a vital part of cancer management, access to surgical care remains inconsistent. Our objective was to estimate the global need for cancer-related surgery and to identify disparities in the surgeon workforce. The World Health Organization International Agency for Research on Cancer and the Global Cancer Observatory were queried for estimates on national incidences of 35 different malignancies. The proportion of patients requiring surgery for each of these cancers was extrapolated from the United States Surveillance, Epidemiology and End-Result database. The number of people requiring cancer surgery in each country was calculated and compared with the surgical workforce. Estimates were presented as choropleth maps. Associations were tested with country development indicators. An estimated 9,464,214 (95% CI 4,364,196-14,564,230) patients required cancer-related surgical care in 2018. An overall 1.24 people needed cancer surgery per 1000 population. This was related to income status (p < 0.01) and Human Development Index (r = 0.86, p < 0.001), with the largest need being in high-income countries. The number of people requiring cancer surgery per surgeon (CP-S ratio) ranged from 7.3 in the European region to 80 in the African regions. The CP-S ratio was 10 times higher for low- versus high-income countries (p < 0.001) and was inversely related to healthcare expenditure (r = -0.59, p < 0.001). An estimated 9.5 million people required cancer surgery globally. Low- and middle-income countries experience a severe and acute shortage of surgeons to provide for the cancer surgery needs of the population.


Temperature Investigation on 3C-SiC Homo-Epitaxy on Four-Inch Wafers.
In this work, results related to the temperature influence on the homo-epitaxial growth process of 3C-SiC is presented. The seed for the epitaxial layer was obtained by an innovative technique based on silicon melting: after the first step of the hetero-epitaxial growth process of 3C-SiC on a Si substrate, Si melts, and the remaining freestanding SiC layer was used as a seed layer for the homo-epitaxial growth. Different morphological analyses indicate that the growth temperature and the growth rate play a fundamental role in the stacking faults density. In details, X-ray diffraction and micro-Raman analysis show the strict relationship between growth temperature, crystal quality, and doping incorporation in the homo-epitaxial chemical vapor deposition CVD growth process of a 3C-SiC wafer. Furthermore, photoluminescence spectra show a considerable reduction of point defects during homo-epitaxy at high temperatures.


Where in the world is interprofessional education? A global environmental scan.
Despite increasing recognition for the importance of interprofessional education (IPE), little is known about where in the world it occurs, how it is conducted and why it is offered. This international environmental scan was commissioned by the World Health Organization (WHO) to answer these questions and inform efforts to support IPE on a global scale. An internet-based survey targeting educators and researchers in WHO's 193 Member States was conducted between February and April 2008. Participants were recruited by WHO staff through a range of country focal points, collaborating centres, regional networks and partner organizations. The scan garnered 396 responses representing 41 countries from WHO's six regions, various income-economies and many health professions. IPE was often (i) voluntary (22%); (ii) not based on explicit learning outcomes (34%); (iii) not assessed for what was learned (63%); (iv) not offered by trained facilitators (69%); and (v) not formally evaluated (30%). Participants reported many benefits of IPE for education, practice and policy. Results are limited primarily by reliance on self-reports and an English-only, internet-based questionnaire. Significant efforts are required to ensure that IPE is designed, delivered and evaluated in keeping with internationally recognized best practice.


Induced chromosome deletions cause hypersociability and other features of Williams-Beuren syndrome in mice.
The neurodevelopmental disorder Williams-Beuren syndrome is caused by spontaneous approximately 1.5 Mb deletions comprising 25 genes on human chromosome 7q11.23. To functionally dissect the deletion and identify dosage-sensitive genes, we created two half-deletions of the conserved syntenic region on mouse chromosome 5G2. Proximal deletion (PD) mice lack Gtf2i to Limk1, distal deletion (DD) mice lack Limk1 to Fkbp6, and the double heterozygotes (D/P) model the complete human deletion. Gene transcript levels in brain are generally consistent with gene dosage. Increased sociability and acoustic startle response are associated with PD, and cognitive defects with DD. Both PD and D/P males are growth-retarded, while skulls are shortened and brains are smaller in DD and D/P. Lateral ventricle (LV) volumes are reduced, and neuronal cell density in the somatosensory cortex is increased, in PD and D/P. Motor skills are most impaired in D/P. Together, these partial deletion mice replicate crucial aspects of the human disorder and serve to identify genes and gene networks contributing to the neural substrates of complex behaviours and behavioural disorders.


Receptor-interacting Ser/Thr kinase 1 (RIPK1) and myosin IIA-dependent ceramidosomes form membrane pores that mediate blebbing and necroptosis.
Formation of membrane pores/channels regulates various cellular processes, such as necroptosis or stem cell niche signaling. However, the roles of membrane lipids in the formation of pores and their biological functions are largely unknown. Here, using the cellular stress model evoked by the sphingolipid analog drug FTY720, we show that formation of ceramide-enriched membrane pores, referred to here as ceramidosomes, is initiated by a receptor-interacting Ser/Thr kinase 1 (RIPK1)-ceramide complex transported to the plasma membrane by nonmuscle myosin IIA-dependent trafficking in human lung cancer cells. Molecular modeling/simulation coupled with site-directed mutagenesis revealed that Asp147 or Asn169 of RIPK1 are key for ceramide binding and that Arg258 or Leu293 residues are involved in the myosin IIA interaction, leading to ceramidosome formation and necroptosis. Moreover, generation of ceramidosomes independently of any external drug/stress stimuli was also detected in the plasma membrane of germ line stem cells in ovaries during the early stages of oogenesis in Drosophila melanogaster Inhibition of ceramidosome formation via myosin IIA silencing limited germ line stem cell signaling and abrogated oogenesis. In conclusion, our findings indicate that the RIPK1-ceramide complex forms large membrane pores we named ceramidosomes. They further suggest that, in addition to their roles in stress-mediated necroptosis, these ceramide-enriched pores also regulate membrane integrity and signaling and might also play a role in D. melanogaster ovary development.


Time Evolution of Correlation Functions in Quantum Many-Body Systems.
We give rigorous analytical results on the temporal behavior of two-point correlation functions-also known as dynamical response functions or Green's functions-in closed many-body quantum systems. We show that in a large class of translation-invariant models the correlation functions factorize at late times ⟨A(t)B⟩_{β}→⟨A⟩_{β}⟨B⟩_{β}, thus proving that dissipation emerges out of the unitary dynamics of the system. We also show that for systems with a generic spectrum the fluctuations around this late-time value are bounded by the purity of the thermal ensemble, which generally decays exponentially with system size. For autocorrelation functions we provide an upper bound on the timescale at which they reach the factorized late time value. Remarkably, this bound is only a function of local expectation values and does not increase with system size. We give numerical examples that show that this bound is a good estimate in nonintegrable models, and argue that the timescale that appears can be understood in terms of an emergent fluctuation-dissipation theorem. Our study extends to further classes of two point functions such as the symmetrized ones and the Kubo function that appears in linear response theory, for which we give analogous results.


Production of thermotolerant, detergent stable alkaline protease using the gut waste of Sardinella longiceps as a substrate: Optimization and characterization.
The gut wastes of Sardinella longiceps were used as substrate for protease production. The gut waste has 61.6% proteins, 21.8% lipids, 8.5% carbohydrates on dry weight basis and trace elements. The significant factors of protease fermentation were screened by Plackett-Burman design. A protease activity of 68.56 U/ml was predicted at 46.31 °C, incubation time 71.11 h, inoculum 4.86% (v/v) and substrate concentration 2.66% (w/v), using response surface methodology. However, the validation experiment showed 73.52 U/ml activity. The artificial neural network was found as a better tool to predict the experimental results. The partially purified protease showed higher activity at pH 9 and 10 and retained 90% activity after 120 h at pH 9. It showed maximum activity at 50 °C and retained 88% residual activity until 90 min at 50 °C. Zn++ enhanced the protease activity by 40%. The protease retained an activity of 93, 103, 90 and 98% against urea, β-mercaptoethanol, SDS and tween 80 respectively. The alkaline protease was compatible with all the commercial detergents tested with the residual activity above 90%. The alkaline protease exhibited 22% higher activity on the tryptone soya substrate. The gut waste of S. longiceps is a worthy low cost substrate for the production of industrially important alkaline protease.


Influence of Radiation Dose to Reconstructed Breast Following Mastectomy on Complication in Breast Cancer Patients Undergoing Two-Stage Prosthetic Breast Reconstruction.
Purpose: This study investigated the association between radiation dose and complication rate in patients who underwent breast reconstruction to understand the role of radiation hypofractionated regimen, boost radiation therapy (RT), and RT techniques. Methods: We retrospectively evaluated 75 patients treated with post-mastectomy adjuvant RT for breast cancer in the setting of two-stage prosthetic breast reconstruction. Near maximum radiation dose (Dmax) in the 2 or 0.03 cc of reconstructed breast or overlying breast skin was obtained from dose-volume histograms. Results: Post-RT complications occurred in 22.7% of patients. Receiver operating characteristic analysis showed that all near Dmax parameters were able to predict complication risk, which retained statistical significance after adjusting other variables (odds ratio 1.12 per Gy, 95% confidence interval 1.02-1.23) with positive dose-response relationship. In multiple linear regression model (R 2 = 0.92), conventional fractionation (β = 11.7) and 16 fractions in 2.66 Gy regimen (β = 3.9) were the major determinants of near Dmax compared with 15 fractions in 2.66 Gy regimen, followed by utilization of boost RT (β = 3.2). The effect of bolus and dose inhomogeneity seemed minor (P > 0.05). The location of hot spot was not close to the high density metal area of the expander, but close to the surrounding areas of partially deflated expander bag. Conclusions: This study is the first to demonstrate a dose-response relationship between risk of complications and near Dmax, where hypofractionated regimen or boost RT can play an important role. Rigorous RT-quality assurance program and modification of dose constraints could be considered as a critically important component for ongoing trials of hypofractionation. Based on our findings, we initiated a multi-center retrospective study (KROG 18-04) and a prospective study (NCT03523078) to validate our findings.


Measuring Patient Adherence to Malaria Treatment: A Comparison of Results from Self-Report and a Customised Electronic Monitoring Device.
Self-report is the most common and feasible method for assessing patient adherence to medication, but can be prone to recall bias and social desirability bias. Most studies assessing adherence to artemisinin-based combination therapies (ACTs) have relied on self-report. In this study, we use a novel customised electronic monitoring device--termed smart blister packs--to examine the validity of self-reported adherence to artemether-lumefantrine (AL) in southern Tanzania. Smart blister packs were designed to look identical to locally available AL blister packs and to record the date and time each tablet was removed from packaging. Patients obtaining AL at randomly selected health facilities and drug stores were followed up at home three days later and interviewed about each dose of AL taken. Blister packs were requested for pill count and extraction of smart blister pack data. Data on adherence from both self-report verified by pill count and smart blister packs were available for 696 of 1,204 patients. There was no difference between methods in the proportion of patients assessed to have completed treatment (64% and 67%, respectively). However, the percentage taking the correct number of pills for each dose at the correct times (timely completion) was higher by self-report than smart blister packs (37% vs. 24%; p<0.0001). By smart blister packs, 64% of patients completing treatment did not take the correct number of pills per dose or did not take each dose at the correct time interval. Smart blister packs resulted in lower estimates of timely completion of AL and may be less prone to recall and social desirability bias. They may be useful when data on patterns of adherence are desirable to evaluate treatment outcomes. Improved methods of collecting self-reported data are needed to minimise bias and maximise comparability between studies.


Mitochondrial genome primers for Lake Malawi cichlids.
Resolving the evolutionary history of rapidly diversifying lineages like the Lake Malawi Cichlid Flock demands powerful phylogenetic tools. Although this clade of over 500 species of fish likely diversified in less than two million years, the availability of extensive sequence data sets, such as complete mitochondrial genomes, could help resolve evolutionary patterns in this group. Using a large number of newly developed primers, we generated whole mitochondrial genome sequences for 14 Lake Malawi cichlids. We compared sequence divergence across protein-coding regions of the mitochondrial genome and also compared divergence in the mitochondrial loci to divergence at two nuclear protein-coding loci, Mitfb and Dlx2. Despite the widespread sharing of haplotypes of identical sequences at individual loci, the combined use of all protein-coding mitochondrial loci provided a bifurcating phylogenetic hypothesis for the exemplars of major lineages within the Lake Malawi cichlid radiation. The primers presented here could have substantial utility for evolutionary analyses of mitochondrial evolution and hybridization within this diverse clade.


First Report of Soybean dwarf virus on Soybean in Wisconsin.
Soybean dwarf virus (SbDV) causes widespread economic losses on soybean (Glycine max (L.) Merr.) in Japan (4), and has been reported on soybean in Virginia (2), in various legumes in the southeastern United States (1), and in peas in California (3). During late July and early August of 2003, soybean plants in Wisconsin were surveyed for SbDV. In 286 soybean fields at the R2-R4 growth stage, the uppermost fully unfurled leaf was collected from 10 plants at each of five sites. Samples were collected at random without regard to symptoms. SbDV symptom information was not recorded. Samples were stored on ice until frozen at -80°C. Five fields in four Wisconsin counties (Columbia, Lafayette, Sauk, and Waushara) tested positive for SbDV using double antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA). DAS-ELISA testing was conducted with reagents from Agdia, Inc (Elkhart, IN) following the manufacturer's protocol. Absorbance was read at 405 nm with a Stat Fax 2100 microplate reader (Awareness Technology, Inc., Palm City, FL) or visually evaluated. DAS-ELISA did not discriminate between strains of SbDV. The presence of SbDV was confirmed, and strain identity was inferred as dwarfing strain using reverse transcription-polymerase chain reaction (RT-PCR). Total RNA was extracted from homogenized leaf tissue, reverse transcribed, and amplified with the SuperScript One Step RT-PCR System (Invitrogen, Carlsbad, CA) and SbDV-specific primers (5'-CTGCTTCTGGTGATTACACTGCCG-3' and 5'-CGCTTTCATTTAACGYCATCAAAGGG-3'). Size of the RT-PCR products (110 bp) was consistent with the dwarfing strain, SbDV-D. All locations that tested positive for SbDV showed soybean aphids, Aphis glycines Matsumura (Homoptera: Aphididae), on 100% of soybean plants. Several aphid species have been reported to vector SbDV, but at this time, vector relations in the Wisconsin infections are unknown. To our knowledge, this is the first report of SbDV infecting soybean in Wisconsin. References: (1) V. D. Damsteegt et al. Plant Dis. 79:48, 1995. (2) A. Fayad et al. Phytopathology (Abstr.) 90(Suppl.):S132, 2000. (3) G. R. Johnstone et al. Phytopathology (Abstr.) 74:795(A43), 1984. (4) T. Tamada et al. Ann. Phytopathol. Soc. Jpn. 35:282, 1969.


Semi-automated literature mining to identify putative biomarkers of disease from multiple biofluids.
Computational methods for mining of biomedical literature can be useful in augmenting manual searches of the literature using keywords for disease-specific biomarker discovery from biofluids. In this work, we develop and apply a semi-automated literature mining method to mine abstracts obtained from PubMed to discover putative biomarkers of breast and lung cancers in specific biofluids. A positive set of abstracts was defined by the terms 'breast cancer' and 'lung cancer' in conjunction with 14 separate 'biofluids' (bile, blood, breastmilk, cerebrospinal fluid, mucus, plasma, saliva, semen, serum, synovial fluid, stool, sweat, tears, and urine), while a negative set of abstracts was defined by the terms '(biofluid) NOT breast cancer' or '(biofluid) NOT lung cancer.' More than 5.3 million total abstracts were obtained from PubMed and examined for biomarker-disease-biofluid associations (34,296 positive and 2,653,396 negative for breast cancer; 28,355 positive and 2,595,034 negative for lung cancer). Biological entities such as genes and proteins were tagged using ABNER, and processed using Python scripts to produce a list of putative biomarkers. Z-scores were calculated, ranked, and used to determine significance of putative biomarkers found. Manual verification of relevant abstracts was performed to assess our method's performance. Biofluid-specific markers were identified from the literature, assigned relevance scores based on frequency of occurrence, and validated using known biomarker lists and/or databases for lung and breast cancer [NCBI's On-line Mendelian Inheritance in Man (OMIM), Cancer Gene annotation server for cancer genomics (CAGE), NCBI's Genes & Disease, NCI's Early Detection Research Network (EDRN), and others]. The specificity of each marker for a given biofluid was calculated, and the performance of our semi-automated literature mining method assessed for breast and lung cancer. We developed a semi-automated process for determining a list of putative biomarkers for breast and lung cancer. New knowledge is presented in the form of biomarker lists; ranked, newly discovered biomarker-disease-biofluid relationships; and biomarker specificity across biofluids.


Predictors of non-pulmonary vein ectopic beats initiating paroxysmal atrial fibrillation: implication for catheter ablation.
The purpose of this study was to investigate the predictor of non-pulmonary vein (PV) ectopic beats initiating paroxysmal atrial fibrillation (PAF). Non-PV ectopic beats can initiate PAF in some patients and play an important role in the recurrence of PAF after PV isolation. Information on the predictors of non-PV ectopic beats initiating PAF is unknown. This study included 293 patients (215 men and 78 women, age 60 +/- 14 years) with clinically documented drug-refractory PAF. Of the 94 patients with non-PV ectopic beats initiating PAF, 38 (40%) patients had superior vena cava (SVC) ectopic beats and 32 (34%) had left atrial posterior free wall (LAPFW) ectopic beats. In a univariate analysis, only female gender was related to the presence of non-PV (p = 0.016) and SVC ectopic beats (p = 0.012). Right atrial enlargement (p = 0.005) and left atrial enlargement (p < 0.001) were related to the presence of LAPFW ectopic beats. In a multivariate analysis, female gender (p = 0.043; odds ratio 2.00, 95% confidence interval [CI] 1.02 to 3.92) and left atrial enlargement (p = 0.007; odds ratio 2.34, 95% CI 1.27 to 4.32) could predict the presence of non-PV ectopic beats. Subgroup analysis showed that female gender could predict the presence of SVC ectopic beats (p = 0.039; odds ratio 2.14, 95% CI 1.04 to 4.43). In contrast, left atrial enlargement could predict the presence of LAPFW ectopic beats (p = 0.002; odds ratio 3.89, 95% CI 1.62 to 9.38). The location of non-PV ectopic beats initiating PAF can be predicted by both gender and left atrial enlargement.


Perfusion magnetic resonance imaging correlates of neuropsychological impairment in multiple sclerosis.
Although cognitive impairment is common in multiple sclerosis (MS), its pathophysiology is still poorly understood. Abnormalities of cerebral blood flow (CBF) have long been acknowledged in MS and advances in perfusion magnetic resonance imaging (MRI) allow for their assessment in vivo. We investigated the relationship between regional perfusion changes and neuropsychological (NP) dysfunctions in patients with relapsing-remitting and primary-progressive MS. Absolute CBF, cerebral blood volume (CBV) and mean transit time were measured in 32 MS patients and 11 healthy controls using dynamic susceptibility contrast-enhanced T2(*)-weighted MRI. A comprehensive NP test battery was administered to all patients. A mixed model analysis of covariance was performed for group comparisons in terms of perfusion measures in normal-appearing white matter (NAWM) and deep gray matter (GM). Pearson's correlations were used to describe the association of perfusion metrics with NP Z-scores. CBF and CBV values were significantly decreased in both NAWM and deep GM in MS patients compared with controls (P=0.01). In all patients, deep GM CBF was significantly associated with Rey Complex Figure Test (RCFT)-Copy (r=0.5; P=0.001) and deep GM CBV and NAWM CBV were significantly associated with Color-Word Interference Inhibition Switching test (D-KEFSIS) (r=0.4; P=0.008 and r=0.4; P=0.02). However, the only associations that remained significant after Bonferroni correction were between deep GM CBF and RCFT-Copy (P=0.006), and deep GM CBV and D-KEFSIS (P=0.04). Our results suggest a role for tissue perfusion impairment in NP dysfunction in MS. Large-scale studies are needed to characterize better this association.


A crystallographic study of bright far-red fluorescent protein mKate reveals pH-induced cis-trans isomerization of the chromophore.
The far-red fluorescent protein mKate (lambda(ex), 588 nm; lambda(em), 635 nm; chromophore-forming triad Met(63)-Tyr(64)-Gly(65)), originating from wild-type red fluorescent progenitor eqFP578 (sea anemone Entacmaea quadricolor), is monomeric and characterized by the pronounced pH dependence of fluorescence, relatively high brightness, and high photostability. The protein has been crystallized at a pH ranging from 2 to 9 in three space groups, and four structures have been determined by x-ray crystallography at the resolution of 1.75-2.6 A. The pH-dependent fluorescence of mKate has been shown to be due to reversible cis-trans isomerization of the chromophore phenolic ring. In the non-fluorescent state at pH 2.0, the chromophore of mKate is in the trans-isomeric form. The weakly fluorescent state of the protein at pH 4.2 is characterized by a mixture of trans and cis isomers. The chromophore in a highly fluorescent state at pH 7.0/9.0 adopts the cis form. Three key residues, Ser(143), Leu(174), and Arg(197) residing in the vicinity of the chromophore, have been identified as being primarily responsible for the far-red shift in the spectra. A group of residues consisting of Val(93), Arg(122), Glu(155), Arg(157), Asp(159), His(169), Ile(171), Asn(173), Val(192), Tyr(194), and Val(216), are most likely responsible for the observed monomeric state of the protein in solution.


Leukotriene D4 receptor-mediated synthesis and release of arachidonic acid metabolites in guinea pig lung: induction of thromboxane and prostacyclin biosynthesis by leukotriene D4.
The effects of the peptidoleukotrienes C4 (LTC4), D4 (LTD4), E4 (LTE4) and a series agonists and antagonists on arachidonic acid metabolism were characterized in minced guinea pig lung. In response to LTD4, guinea pig lung utilized and converted the endogenous arachidonic acid into a variety of cyclooxygenase metabolites [prostaglandins (PGs) E2, F2 alpha, 6-keto-F1 alpha and thromboxane (Tx) B2] and lipoxygenase metabolites (5,12-dihydroxy-6,8,11,14-eicosatetraneoic acid and 5,15-dihydroxy-5,9,11,13-eicosatetraneoic acid). Using radioimmunoassays, the stable, pharmacologically important metabolites of the cyclooxygenase pathway, 6-keto-PGF1 alpha and TxB2, were quantitated. LTD4, LTE4 and several synthetic agonists induced dose-dependent synthesis and release of TxB2 and 6-keto-PGF1 alpha. Agonist-induced synthesis and release of 6-keto-PGF1 alpha and TxB2 was time-dependent and was maximal after 10 to 12 min of incubation. The slow-reacting substance of anaphylaxis antagonist, FPL 55712, and the newly reported dithioacetal LTD4 receptor antagonists (SKF 102922 and SKF 102081) did not induce synthesis and release of TxB2 and 6-keto-PGF1 alpha in concentrations that blocked the agonist-induced smooth muscle contraction. Preincubation with these antagonists inhibited the synthesis and release of prostanoids induced by LTD4 in the guinea pig lung. Islet activating protein, which inactivates the inhibitory guanine nucleotide binding protein (Gi protein), partially inhibited the agonist-induced synthesis and release of prostanoids. Furthermore, the receptor binding affinities and/or the myotonic activities of the LTD4 agonists correlated linearly with the agonist-induced prostanoid synthesis and release effect.(ABSTRACT TRUNCATED AT 250 WORDS)


NR2B-deficient mice are more sensitive to the locomotor stimulant and depressant effects of ethanol.
The NR2B subunit of N-methyl d-aspartate glutamate receptors influences pharmacological properties and confers greater sensitivity to the modulatory effects of ethanol. This study examined behavioral responses to acute ethanol in a conditional knockout mouse model that allowed for a delayed genetic deletion of the NR2B subunit to avoid mouse lethality. Mice lacking the NR2B gene (knockout) were produced by mating NR2B[f/f] mice with CAMKIIa-driven tTA transgenic mice and the tetO-CRE transgenic mice. Adult male and female offspring representing each of the resultant genotypes (knockout, CAM, CRE and wildtype mice) were tested for open-field locomotor activity following acute low- and high-dose ethanol challenge as well as loss of righting reflex. Findings indicate that male and female mice lacking the NR2B subunit exhibited greater overall activity in comparison to other genotypes during the baseline locomotor activity test. NR2B knockout mice exhibited an exaggerated stimulant response to 1.5 g/kg (i.p.) and an exaggerated depressant response to 3.0 g/kg (i.p.) ethanol challenge. In addition, NR2B knockout mice slept longer following a high dose of ethanol (4.0 g/kg, i.p.). To evaluate pharmacokinetics, clearance rates of ethanol (1.5, 4.0 g/kg, i.p.) were measured and showed that female NR2B knockouts had a faster rate of metabolism only at the higher ethanol dose. Western blot analyses confirmed significant reduction in NR2B expression in the forebrain of knockout mice. Collectively, these data indicate that the NR2B subunit of the N-methyl d-aspartate glutamate receptor is involved in regulating low-dose stimulant effects of ethanol and the depressant/hypnotic effects of ethanol.


A home-based walking study to ameliorate perceived stress and depressive symptoms in people with a traumatic brain injury.
Abstract Objective: To determine whether a 12-week home-based walking programme can decrease perceived stress and depressive symptoms in persons with a traumatic brain injury (TBI). Community- and home-based. Sixty-nine participants with a TBI. Comparative effectiveness cross-over design with random assignment to treatment sequence and blinded post-hoc assessment of outcome where participants completed a 12-week walking intervention and a nutrition education module. The walking intervention utilized pedometers to track the amount of steps each participant walked daily. With the assistance of an assigned coach, weekly goals were given with the intent of increasing the amount of walking that the participant was initially completing. The nutrition control group was created to offset the impact of the coaching calls. Measurement of perceived stress and depressive symptoms was completed through the use of the Perceived Stress Scale (PSS) and Center for Epidemiological Studies-Depression (CES-D). These measures were collected at three time points: baseline and following each 12-week intervention. RESULTS indicated that both perceived stress and depression symptoms significantly improved following the walking intervention. While limitations existed with the study, it is evident that walking can be used as an efficient and cost-effective tool to manage perceived stress and depressive symptoms in persons who have sustained a TBI.


Caffeine intake and Menière's disease: Is there relationship?
Although it is commonly recognized that dietary restrictions may improve the clinical course of Menière's disease, their effectiveness has not been definitely demonstrated. The aim of this study was to examine whether caffeine consumption could be involved in Menière's disease. Cross-sectional, observational, case-control study, comparing caffeine consumption (intake of coffee, tea, kola-type beverages, energy drinks, and chocolate-containing beverages or foods) between patients with Menière's disease (group A) and patients affected by vertigo with other origins (group B) and/or control subjects (group C). 180 subjects (72 in group A, 72 in group B, and 36 in group C). Caffeine intake was categorized in four levels: very low (0-25 mg/day), low (26-100 mg/day), moderate (101-300 mg/day), and high (≥301 mg/day). Very low and low intake were considered light consumption, and moderate and high intake, heavy consumption. Mean daily caffeine intake was 175.8 mg. Menière's disease patients showed a daily caffeine intake (222 mg) greater than those not affected by this disease (145 mg). Excluding in group B migraine patients, differences in caffeine intake are significant among the three groups (P = 0.021). There were significantly more heavy-consumers in group A than in other two groups jointed (P = 0.024; OR = 1.301, IC95% (1.015;1.668)). In group A, the age at onset of symptoms in caffeine consumers (49.7 years) was lower than in non-consumers (55.9 years). It should be recommended to reduce caffeine intake in those population groups with higher risk of Menière's disease (e.g. subjects with family members suffering from this disease).


Increased Risk of Postthoracotomy Pain Syndrome in Patients with Prolonged Hospitalization and Increased Postoperative Opioid Use.
Background. Postthoracotomy pain syndrome (PTPS) is unfortunately very common following thoracotomy and results in decreased quality of life. The purpose of this retrospective study was to determine perioperative patient, surgical, and analgesic characteristics associated with the development of PTPS. Methods. Sixty-six patients who presented to the Mayo Clinic Rochester Pain Clinic were diagnosed with PTPS 2 months or more after thoracotomy with postoperative epidural analgesia. These patients were matched with sixty-six control patients who underwent thoracotomy with postoperative epidural analgesia and were never diagnosed with PTPS. Results. Median (IQR) hospital stay was significantly different between control patients (5 days (4, 6)) compared with PTPS patients (6 days (5, 8)), P < 0.02. The total opioid equivalent utilized in oral morphine equivalents in milligrams for the first three days postoperatively was significantly different between control patients and PTPS patients. The median (IQR) total opioid equivalent utilized was 237 (73, 508) for controls and 366 (116, 874) for PTPS patients (P < 0.005). Conclusion. Patients with a prolonged hospital stay after thoracotomy were at an increased risk of developing PTPS, and this is a novel finding. Patients who utilize higher oral morphine equivalents for the first 3 days were also at increased risk for PTPS.


Assessment of six commercial plasma small RNA isolation kits using qRT-PCR and electrophoretic separation: higher recovery of microRNA following ultracentrifugation.
Growing interest in blood-borne microRNAs (miRNAs) as biomarkers has led to the introduction of a number of commercial kits for isolating small RNAs from plasma/serum. We sought to compare the efficacy of six such kits in isolating miRNAs from either whole plasma or a plasma-derived ultracentrifugation (UC) fraction from 2 healthy volunteers with some of the results being validated in 10 additional subjects. To assess the overall yield and concentration of isolated small RNAs, we measured the levels of one spiked-in and four endogenous miRNAs by quantitative reverse transcription and polymerase chain reaction (qRT-PCR). We also tested the performance of the Agilent Bioanalyzer small RNA assay with these RNA samples. Additionally, we tested the effects of hemolysis on measured miRNA levels in whole plasma and in the UC fraction. Both the efficiency of RNA isolation and the relative levels of specific miRNAs in different samples varied considerably between the tested extraction methods. Of all kits tested, the QIAGEN miRNeasy kits (Mini and Serum/Plasma kits) and the Macherey-Nagel NucleoSpin kit produced the highest RNA yields. The QIAGEN Exo kit produced lesser yields than what could be extracted from the UC fraction using the QIAGEN miRNeasy kits and the Macherey-Nagel NucleoSpin kit. Bioanalyzer results showed an average correlation of R 2 = 0.8 with endogenous miRNA qRT-PCR results, for sample concentrations >40 pg/µl. The levels of the endogenous miRNAs measured in the two volunteer samples were compared with those in a larger group of subjects (n = 10) and found to be typical. Our comparison favors the use of the QIAGEN Serum/Plasma kit and the Macherey-Nagel NucleoSpin kit for plasma miRNA applications. Furthermore, extraction of miRNAs from the UC fraction results in higher yield than extraction from whole plasma.


Health care access and use among the rural uninsured.
The uninsured have poorer access to care and obtain care at greater acuity than those with health insurance; however, the differential impact of being uninsured in rural versus urban areas is largely unknown. Using data from the 2002-2007 Medical Expenditure Panel Survey, we examine whether uninsured rural residents have different patterns of health care use than their urban counterparts, and the factors associated with any differences. We find that being uninsured leads to poorer access in both rural and urban areas, yet the rural uninsured are more likely to have a usual source of care and use services than their urban counterparts. Further, controlling for demographic and health characteristics, the access and use differences between the uninsured and insured in rural areas are smaller than those observed in urban areas. This suggests that rural providers may impose fewer barriers on the uninsured who seek care than providers in urban areas.


Accuracy of the Kato-Katz, adhesive tape and FLOTAC techniques for helminth diagnosis among children in Kyrgyzstan.
The purpose of this study was to assess the accuracy of three copro-microscopic techniques for helminth diagnosis: Kato-Katz, adhesive tape and FLOTAC. A total of 163 children from a peri-urban municipality near Bishkek, Kyrgyzstan, participated and submitted multiple stool samples and adhesive tapes. Ninety children supplied at least two stool samples and two adhesive tapes. Three stool samples and three adhesive tapes were available from 71 and 64 children, respectively. From each stool sample, a single Kato-Katz thick smear was prepared and examined quantitatively. Additionally, the first stool sample was subjected to the FLOTAC technique and helminth eggs were counted. Adhesive tapes were checked for the presence of Enterobius vermicularis eggs. Using pooled results as a diagnostic 'gold' standard, the prevalence of Ascaris lumbricoides, E. vermicularis, Hymenolepis nana and Dicrocoelium dendriticum were 54.4%, 13.3%, 11.1% and 11.1%, respectively. Infection intensities were low. When compared to triplicate Kato-Katz, a single FLOTAC was more sensitive for the diagnosis of A. lumbricoides (89.5% versus 39.5%) and D. dendriticum (88.9% versus 33.3%), but less sensitive for H. nana (66.7% versus 88.9%). For E. vermicularis, three adhesive tapes showed much higher sensitivity than a single FLOTAC (92.9% versus 14.3%). FLOTAC yielded significantly higher faecal egg counts than Kato-Katz for A. lumbricoides and D. dendriticum. Overall results suggest that, although FLOTAC represents a promising technique for helminth diagnosis in Kyrgyzstan, the repeated adhesive tape test remains so far the method of choice for diagnosing E. vermicularis.


Routine procedures for isolation and identification of enterococci and fecal streptococci.
Over the past 6 years, a revised classification of the streptococci and enterococci, based primarily on molecular techniques such as 16S rRNA sequencing and DNA-DNA hybridization, emerged. However, little attention was placed on routine physiological tests that could be used in food and clinical laboratories to differentiate between species of a new genus, Enterococcus, and fecal Streptococcus spp. The purpose of this study was to devise a convenient and reliable system to identify enterococci and fecal streptococci by using conventional procedures. Fifty-nine strains of 13 Enterococcus spp., including the type strains and many strains used by previous investigators, were characterized by using conventional tube tests, the API Rapid Strep system, and MicroScan Pos ID panels. Results were compared with each other and with previously published results. A comparison of conventional tube tests versus published tube test results yielded 17 discrepancies. Although not all tests were done with each of the three systems, 28 discrepancies between results obtained with the API system and those obtained with conventional tube tests were found. There were 24 discrepancies between results obtained with the MicroScan Pos ID panel and those obtained with conventional tube tests. There were 12 discrepancies between the results with the API Rapid Strep system and those with the MicroScan Pos ID panels. We devised flow charts of key tests that might be used to identify cultures without resorting to nucleic acid analysis and other labor- and equipment-intensive analyses.


Rationale for the ASSAIL-MI-trial: a randomised controlled trial designed to assess the effect of tocilizumab on myocardial salvage in patients with acute ST-elevation myocardial infarction (STEMI).
Interleukin-6 (IL-6) may be involved in ischaemia-reperfusion injury and myocardial remodelling after myocardial infarction (MI). We have recently shown that IL-6 inhibition by tocilizumab attenuates systemic inflammation and troponin T-release in patients with acute non-ST elevation MI (NSTEMI). Experimental studies suggest that IL-6 inhibition can limit infarct size through anti-inflammatory mechanisms, but this has not been tested in clinical studies. With the ASSessing the effect of Anti-IL-6 treatment in MI (ASSAIL-MI) trial, we aim to examine whether a single administration of the IL-6 receptor antagonist tocilizumab can increase myocardial salvage in patients with acute ST-elevation MI (STEMI). The ASSAIL-MI trial is a randomised, double blind, placebo-controlled trial, conducted at three high-volume percutaneous coronary intervention (PCI) centres in Norway. 200 patients with first-time STEMI presenting within 6 hours of the onset of chest pain will be randomised to receive tocilizumab or matching placebo prior to PCI. The patients are followed-up for 6 months. The primary endpoint is the myocardial salvage index measured by cardiac MRI (CMR) 3-7 days after the intervention. Secondary endpoints include final infarct size measured by CMR and plasma markers of myocardial necrosis. Efficacy and safety assessments during follow-up include blood sampling, echocardiography and CMR. Based on previous experience the study is considered feasible and safe. If tocilizumab increases myocardial salvage, further endpoint-driven multicentre trials may be initiated. The ASSAIL-MI trial has the potential to change clinical practice in patients with STEMI. Clinicaltrials.gov, identifier NCT03004703.


Effect of blocking layer to boost photoconversion efficiency in ZnO dye-sensitized solar cells.
The effect of a ZnO compact blocking layer (BL) in dye-sensitized solar cells (DSSCs) based on ZnO photoanodes is investigated. BL is generated through spray deposition onto fluorine-doped tin oxide (FTO) conducting glass before the deposition of a ZnO active layer. The functional properties of dye-sensitized solar cells (DSSCs) are then investigated as a function of the thickness of the BL for two different kinds of ZnO active layer, i.e., hierarchically self-assembled nanoparticles and microcubes composed of closely packed ZnO sheets. Presence of BL leads to the improvement of photoconversion efficiency (PCE), by physically insulating the electrolyte and the FTO. This effect increases at increasing BL thickness up to around 800 nm, while thicker BL results in reduced cell performance. Remarkable increase in Jsc is recorded, which doubles as compared to cells without blocking layer, leading to PCE as high as 5.6% in the best cell under one sun irradiation (AM 1.5 G, 100 mW cm(-2)). Electrochemical impedance spectroscopy (EIS) elucidates the mechanism boosting the functional features of the cells with BL, which relies with enhanced chemical capacitance together with an almost unchanged recombination resistance, which are reflected in an increased electron lifetime. The results foresee a straightforward way to significantly improve the performance of ZnO-based DSSCs.


Interface reactions and stability of a hydride composite (NaBH4 + MgH2).
The use of the interaction of two hydrides is a well-known concept used to increase the hydrogen equilibrium pressure of composite mixtures in comparison to that of pure systems. The thermodynamics and reaction kinetics of such hydride composites are reviewed and experimentally verified using the example NaBH(4) + MgH(2). Particular emphasis is placed on the measurement of the kinetics and stability using thermodesorption experiments and measurements of pressure-composition isotherms, respectively. The interface reactions in the composite reaction were analysed by in situ X-ray photoelectron spectroscopy and by simultaneously probing D(2) desorption from NaBD(4) and H(2) desorption from MgH(2). The observed destabilisation is in quantitative agreement with the calculated thermodynamic properties, including enthalpy and entropy. The results are discussed with respect to kinetic limitations of the hydrogen desorption mechanism at interfaces. General aspects of modifying hydrogen sorption properties via hydride composites are given.


Risk-adjusted survival after coronary artery bypass grafting: implications for quality improvement.
Mortality represents an important outcome measure following coronary artery bypass grafting. Shorter survival times may reflect poor surgical quality and an increased number of costly postoperative complications. Quality control efforts aimed at increasing survival times may be misleading if not properly adjusted for case-mix severity. This paper demonstrates how to construct and cross-validate efficiency-outcome plots for a specified time (e.g., 6-month and 1-year survival) after coronary artery bypass grafting, accounting for baseline cardiovascular risk factors. The application of this approach to regional centers allows for the localization of risk stratification rather than applying overly broad and non-specific models to their patient populations.


Adverse effects of chemotherapy and their management in Pediatric patients with Non-Hodgkin's Lymphoma in Kenya: A descriptive, situation analysis study.
Chemotherapy-related side effects and their management in patients with Non-Hodgkin's Lymphoma (NHL) are not well defined in developing countries, including Kenya. This needs addressing considering the high number of patients with cancer in these countries. Consequently, we sought to determine the common side effects of chemotherapy used to treat NHL in pediatric patients and its implications. Observational study conducted at the Kenyatta National Hospital in patients aged ≤15 years. Some data was collected by reviewing patients' records admitted to the pediatric oncology ward, December 2016 to May 2017; and additional data was collected retrospectively (review of patients' records with NHL, January-2014 to May-2017). Data were analyzed descriptively. Overall, out of the identified NHL patients (n = 85), 93% (n = 79) had chemotherapy-related side effects. The majority of patients suffered from side effects were managed; apart from 23% to 24% of the documented anemia and hypersensitivity, respectively. Whilst the majority of the reported side-effects were being managed, the lack of management of some side effects raises real concerns since this indicates either failure to manage or failure to document their management in patients' records, both of which should be addressed appropriately to improve future care.


Delayed complications from expanded endonasal surgery for intracranial tumors.
Delayed complications after endoscopic endonasal approaches to the skull base, defined as complications greater than 1 month postoperatively, are uncommon. These complications are divided into categories including sinonasal, neuroanatomic, endocrine and vascular. This review highlights the most up-to-date advancements and reviews the management of delayed complications for skull base patients. Over the last 10 years, the field of endoscopic endonasal skull base surgery has expanded with new data highlighting the long-term patient outcomes. The majority of patients experience increased quality of life (QOL) after these interventions. However, delayed complications including alterations to sinonasal function, delayed encephaloceles from the bony skull base defect and resulting endocrinopathies can significantly impact patient's QOL. Awareness of these complications and their current management is valuable for endoscopic surgeons. Endonasal approaches to the skull base are safe and well tolerated in properly selected patients. This article highlights the delayed complications that require recognition and management by skull base surgeons to ensure the best possible care for patients.


Carbon Nanotubes for Radiation-Tolerant Electronics.
Electronics for space applications have stringent requirements on both performance and radiation tolerance. The constant exposure to cosmic radiation damages and eventually destroys electronics, limiting the lifespan of all space-bound missions. Thus, as space missions grow increasingly ambitious in distance away from Earth, and therefore time in space, the electronics driving them must likewise grow increasingly radiation-tolerant. In this work, we show how carbon nanotube (CNT) field-effect transistors (CNFETs), a leading candidate for energy-efficient electronics, can be strategically engineered to simultaneously realize a robust radiation-tolerant technology. We demonstrate radiation-tolerant CNFETs by leveraging both extrinsic CNFET benefits owing to CNFET device geometries enabled by their low-temperature fabrication, as well as intrinsic CNFET benefits owing to CNTs' inherent material properties. By performing a comprehensive study and optimization of CNFET device geometries, we demonstrate record CNFET total ionizing dose (TID) tolerance (above 10 Mrad(Si)) and show transient upset testing on complementary metal-oxide-semiconductor (CMOS) CNFET-based 6T SRAM memories via X-ray prompt dose testing (threshold dose rate = 1.3 × 1010 rad(Si)/s). Taken together, this work demonstrates CNFETs' potential as a technology for next-generation space applications.


Antigenicity of "monocomponent" pork insulin in diabetic subjects.
"Single-peak," "single-component," and "monocomponent" insulins have been produced in an attempt to eliminate insulin antigenicity. Recently "single-peak insulin" has been shown to be antigenic. From animal experiments and preliminary human studies it has been claimed that monocomponent (MC) insulin is nonantigenic or only negligibly so. In this study the antigenicity of MC insulin was determined in two groups of diabetic patients. In group 1, seven patients treated with insulin for the first time were given MC insulin for seven to fifteen months. Four of the seven patients developed significant IgG insulin antibodies after four to ten months. In one patient the IgG insulin antibody concentration was high (8.51 mU./ml.). In two patients, IgG proinsulin-specific antibodies were detected. In group 2, fourteen patients with unstable diabetes, insulin allergy, or resistance were changed from conventional to MC insulin. Treatment with MC insulin did not decrease insulin requirement or improve diabetic control when assayed by the M factor. After seven to eleven months of therapy there was no significant fall in insulin antibodies except in two patients in whom corticosteroids had been administered simultaneously. These results differ significantly from those previously reported and could be interpreted as suggesting that insulin itself is antigenic. When the purity of the MC insulin was determined, significant contaminants could be demonstrated in all of ten separate batches of MC insulin. Gel chromatography, polyacrylamide gel electrophoresis, and proinsulin radioimmunoassay were used to identify the presence of nonconvertible insulin dimer, proinsulin, and monodesamido insulin in antigenically significant concentrations. The generation of IgG insulin antibodies in MC-insulin-treated patients cannot be interpreted as a true indication that insulin itself is antigenic. The problem of insulin antigenicity has not been resolved and will not be until a highly purified insulin is available. Unfortunately, the MC insulins do not meet these requirements.


The impact of a formal complaint on Dutch dentists' professional practice: a survey study.
A complaint from a patient can have a serious impact on the well-being of dentists. Little is known, however, about the nature and the extent of this impact. Therefore in 2013 an anonymous survey was conducted among 955 dentists and dental specialists who were involved in a complaints procedure dealt with by the Complaints Committee of the Royal Dutch Dental Association (KNMT) in the period of mid-2008 to mid-2013. In total 413 (43 %) of these dentists participated in the study. As a result of a formal complaint 71 % of the respondents experienced a considerable impact in their professional practising, while 52 % stated that it had (also) seriously influenced their attitude towards colleagues and patients. Furthermore, 60 % (also) mentioned effects of a complaints procedure regarding their mental and/or physical well-being. Being confronted with a formal complaint from a patient leads to a considerable impact on dentists' professional practice and personal well-being. It is remarkable this did not only pertain to a 'negative' impact, but also to a 'positive' impact. Despite unpleasant feelings, several dentists regarded the complaint as a 'wake-up call'. Furthermore, given the relatively high number of successful mediation attempts it can be concluded that this form of complaint handling appears to be a successful way of solving problems that have arisen between patients and dentists.


Effectiveness of the ketogenic diet used to treat resistant childhood epilepsy in Scandinavia.
This Scandinavian collaborative retrospective study of children treated with ketogenic diet (KD) highlights indications and effectiveness over two years follow-up. Five centres specialised in KD collected data retrospectively on 315 patients started on KD from 1999 to 2009. Twenty-five patients who stopped the diet within four weeks because of compliance-problems and minor side-effects were excluded. Seizure-type(s), seizure-frequency, anti-epileptic drugs and other treatments, mental retardation, autism-spectrum disorder and motor-dysfunction were identified and treatment-response was evaluated. An intention-to-treat analysis was used. Responders (>50% seizure-frequency reduction) at 6, 12 and 24 months were 50%, 46% and 28% respectively, seizure-free were 16%, 13% and 10%. Still on the diet were 80%, 64% and 41% after 6, 12 and 24 months. No child had an increased seizure-frequency. The best seizure outcome was seen in the group with not-daily seizures at baseline (n = 22), where 45%, 41% and 32% became seizure-free at 6, 12 and 24 months A significant improvement in seizure-frequency was seen in atonic seizures at three months and secondary generalised seizures at three and six months. Side-effects were noted in 29 subjects; most could be treated and only two stopped due to hyperlipidaemia and two due to kidney-stones. In 167 patients treated with potassium-citrate, one developed kidney-stones, compared with six of 123 without potassium-citrate treatment (relative risk = 8.1). As the first study of implementing KD in children in the Scandinavian countries, our survey of 290 children showed that KD is effective and well tolerated, even in such severe patients with therapy-resistant epilepsy, more than daily seizures and intellectual disability in the majority of patients. Long-term efficacy of KD was comparable or even better than reported in newer AEDs. Addition of potassium citrate reduced risk of kidney-stones. Our data indicate that the response might be predicted by seizure-frequency before initiation of the diet but not by age, seizure-type or aetiology.


Emergence of tigecycline resistance in Escherichia coli co-producing MCR-1 and NDM-5 during tigecycline salvage treatment.
Here, we report a case of severe infection caused by Escherichia coli that harbored mcr-1, bla NDM-5, and acquired resistance to tigecycline during tigecycline salvage therapy. Antimicrobial susceptibility testing, Southern blot hybridization, and complete genome sequence of the strains were carried out. The genetic characteristics of the mcr-1 and bla NDM-5 plasmids were analyzed. The whole genome sequencing of mcr-1-containing plasmid was completed. Finally, putative single nucleotide polymorphisms and deletion mutations in the tigecycline-resistant strain were predicted. Three E. coli isolates were obtained from ascites, pleural effusion, and stool of a patient; they were resistant to almost all the tested antibiotics. The first two strains separated from ascites (E-FQ) and hydrothorax (E-XS) were susceptible to amikacin and tigecycline; however, the third strain from stool (E-DB) was resistant to tigecycline after nearly 3 weeks' treatment with tigecycline. All three isolates possessed both mcr-1 and bla NDM-5. The bla NDM-5 gene was found on the IncX3 plasmid, whereas the mcr-1, fosA3 and blaCTX-M-14 were located on the IncHI2 plasmid. Mutations in acrB and lon were the reason for the resistance to tigecycline. This is the first report of a colistin-, carbapenem-, and tigecycline-resistant E. coli in China. Tigecycline resistance acquired during tigecycline therapy is of great concern for us because tigecycline is a drug of last resort to treat carbapenem-resistant Gram-negative bacterial infections. Furthermore, the transmission of such extensively drug-resistant isolates may pose a great threat to public health.


Comparison of posture-induced intraocular pressure changes in medically treated and surgically treated eyes with open-angle glaucoma.
To compare the posture-induced IOP changes in medically treated eyes with those in surgically treated eyes having open-angle glaucoma (OAG) and low IOP. Fifty-one posttrabeculectomized OAG eyes with a cystic filtering bleb and 51 nonoperated, medically treated OAG eyes were studied. The IOP measured with a Goldmann applanation tonometer (GAT) was 12 mm Hg or less in both groups. It was measured in the sitting and lateral decubitus positions with a rebound tonometer. The IOP was measured in the upper eye 5 minutes after assuming the lateral decubitus position. The mean (SD) IOP measured with the GAT was 9.7 (1.5) mm Hg in the trabeculectomized eyes and 9.7 (1.4) mm Hg in the medically treated eyes (P = 0.892, unpaired t-test). In the surgically treated group, the mean (SD) IOP measured with the rebound tonometer was 10.3 (2.3) mm Hg in the sitting position and 11.3 (2.8) mm Hg in the lateral decubitus position (P < 0.001, paired t-test). In the medically treated group, the mean (SD) IOP measured with the rebound tonometer was 10.8 (2.0) mm Hg in the sitting position and 14.1 (2.9) mm Hg in the lateral decubitus position (P < 0.001, paired t-test). The greater IOP increase of 3.3 mm Hg in the medically treated group compared with the 1.0 mm Hg in the surgically treated group was significant (P < 0.001, unpaired t-test). The lower posture-induced IOP change in the successfully trabeculectomized eyes indicates that trabeculectomy will not only lead to a decrease in the IOP but also lower the posture-induced IOP change.


Evolution of minimal specificity and promiscuity in steroid hormone receptors.
Most proteins are regulated by physical interactions with other molecules; some are highly specific, but others interact with many partners. Despite much speculation, we know little about how and why specificity/promiscuity evolves in natural proteins. It is widely assumed that specific proteins evolved from more promiscuous ancient forms and that most proteins' specificity has been tuned to an optimal state by selection. Here we use ancestral protein reconstruction to trace the evolutionary history of ligand recognition in the steroid hormone receptors (SRs), a family of hormone-regulated animal transcription factors. We resurrected the deepest ancestral proteins in the SR family and characterized the structure-activity relationships by which they distinguished among ligands. We found that that the most ancient split in SR evolution involved a discrete switch from an ancient receptor for aromatized estrogens--including xenobiotics--to a derived receptor that recognized non-aromatized progestagens and corticosteroids. The family's history, viewed in relation to the evolution of their ligands, suggests that SRs evolved according to a principle of minimal specificity: at each point in time, receptors evolved ligand recognition criteria that were just specific enough to parse the set of endogenous substances to which they were exposed. By studying the atomic structures of resurrected SR proteins, we found that their promiscuity evolved because the ancestral binding cavity was larger than the primary ligand and contained excess hydrogen bonding capacity, allowing adventitious recognition of larger molecules with additional functional groups. Our findings provide an historical explanation for the sensitivity of modern SRs to natural and synthetic ligands--including endocrine-disrupting drugs and pollutants--and show that knowledge of history can contribute to ligand prediction. They suggest that SR promiscuity may reflect the limited power of selection within real biological systems to discriminate between perfect and "good enough."


Influence of disorder strength on phase-field models of interfacial growth.
We study the influence of disorder strength on the interface roughening process in a phase-field model with locally conserved dynamics. We consider two cases where the mobility coefficient multiplying the locally conserved current is either constant throughout the system (the two-sided model) or becomes zero in the phase into which the interface advances (one-sided model). In the limit of weak disorder, both models are completely equivalent and can reproduce the physical process of a fluid diffusively invading a porous media, where super-rough scaling of the interface fluctuations occurs. On the other hand, increasing disorder causes the scaling properties to change to intrinsic anomalous scaling. In the limit of strong disorder this behavior prevails for the one-sided model, whereas for the two-sided case, nucleation of domains in front of the invading front are observed.


Changes in tissue water content measured with multiple-frequency bioimpedance and metabolism measured with 31P-MRS during progressive forearm exercise.
Multiple-frequency bioimpedance analysis (MFBIA) has been used to determine the cellular water composition in the human body. It is noninvasive and has demonstrated good correlations with other invasive measures of tissue water. However, the ability of this method to study transient changes in tissue water in specific muscle groups has not been explored. In this study, MFBIA was used to assess changes in forearm intracellular water (ICW), extracellular water (ECW), and total water (TW) in seven healthy volunteers during and after a progressive wrist flexion exercise protocol. In an identical trial, (31)P magnetic resonance spectroscopy ((31)P-MRS) was used to assess changes in intracellular pH and phosphocreatine (PCr). At the completion of exercise, forearm ICW increased 12.6% (SD 0.07, P = 0.003), TW increased 10.1% (SD 0.06, P = 0.005), and no significant changes were recorded for ECW. A significant correlation was found between the changes in intracellular pH and changes in ICW during exercise (r = -0.84, P = 0.018). With the use of regression analysis, average changes in P(i), PCr, and pH were found to predict changes in ICW (R(2) = 0.98, P = 0.005). In conclusion, MFBIA was sensitive enough to measure transient changes in the exercising forearm muscle. The changes seen were consistent with the hypothesis that intracellular acidification and PCr hydrolysis are important mediators of cellular osmolality and therefore may be responsible for the increased volume of water in the intracellular space that is often recorded after short-term high-intensity exercise.


Effect of surgery on the outcome of midgut carcinoid disease with lymph node and liver metastases.
We have evaluated survival and tumor-related symptoms in the presence of mesenteric lymph node and liver metastases in relation to surgical procedures in 314 patients (148 women, mean age at diagnosis 61 years; 249 with liver metastases) treated for midgut carcinoid tumors. Of the operated patients, 46% presented with severe abdominal pain and intestinal obstruction and were operated on before the diagnosis. Medical treatment (somatostatin analogs, interferon-a) was initiated in 67% and 86%, respectively. Surgical attempts included small intestine or ileocecal/right-sided colon resection with excision of mesenteric lymph node metastases. Most of the patients (n = 286) had mesenteric lymph node metastases; 33% of them had unresectable mesenteric lymph node metastases and underwent surgery without mesenteric dissection. Patients who underwent resection for the primary tumor had a longer survival than those with no resection (median survival 7.4 vs. 4.0 years; p <0.01). Patients who underwent successful excision of mesenteric metastases had a significantly longer survival than those with remaining lymph node metastases. Patients operated on for a primary tumor but with remaining lymph nodes but no liver metastases and who subsequently received interferon and somatostatin analog treatment had a median survival of 7.4 years. Resection of the primary tumor and the mesenteric lymph node metastases led to a significant reduction in tumor-related symptoms. Surgery to remove the primary intestinal tumor including mesenteric lymph node metastases is supported by the present results, even in the presence of liver metastases. Liver metastases and significant preoperative weight loss are identified as major negative prognostic factors for survival.


Outcome of Recurrent Surgery in Dupuytren's Disease: Comparison with Initial Treatment.
There are multiple studies about the effectiveness of primary treatment in Dupuytren's disease. However, such studies concerning treatment effectiveness of recurrent disease are scarce. Therefore, the primary aim of this study was to compare treatment effectiveness of initial and repeated surgery in patients with Dupuytren's disease. Patients who underwent both initial and repeated treatment were selected from a prospectively maintained database. Outcome measurements consisted of finger goniometry, the Michigan Hand Outcomes Questionnaire, and complications. Treatment effectiveness was defined as improvement in extension deficit and patient-reported hand function. In addition, measurements at intake of both treatments were compared. Subgroup analyses were performed to evaluate influence of type of surgery of initial treatment on outcomes of repeated treatment. One hundred fourteen patients were included in the analyses. Improvement in extension deficit and Michigan Hand Outcomes Questionnaire outcomes was equal for initial and repeated treatments. Extension deficit and Michigan Hand Outcomes Questionnaire scores were worse at intake of repeated treatment compared to these outcomes at intake of initial treatment. In addition, patients who initially underwent needle fasciotomy achieved a better contracture reduction after repeated treatment. This study demonstrates that treatment of recurrent Dupuytren's disease is as effective as initial treatment, despite larger extension deficit and worse self-assessed hand function before undergoing repeated treatment. Complication rates were similar for initial and repeated treatments. Furthermore, needle fasciotomy for initial treatment results in better outcomes of repeated treatment compared to patients who initially underwent limited fasciectomy. These findings can be used for a more evidence-based preoperative counseling with patients with recurrent Dupuytren's disease. Therapeutic, III.