Spinal epidural metastasis as the initial manifestation of malignancy: clinical features and diagnostic approach.
The objective of our study was to delineate clinical features and specific diagnostic and therapeutic implications of spinal epidural metastasis (SEM) occurring as the initial manifestation of malignancy (IMM)-a less common event than SEM in the setting of previously established malignancy (PEM). We performed a retrospective review of the clinical histories of 337 patients seen at Mayo Clinic with a radiographically verified diagnosis of SEM between January 1, 1985, and December 31, 1993. Twenty percent of all cases of SEM occurred as SEM-IMM. Carcinoma of the lung, cancer of unknown primary site, multiple myeloma, and non-Hodgkin's lymphoma were disproportionately represented in SEM-IMM, together accounting for 78% of SEM-IMM patients and only 26% of SEM-PEM patients. Inversely, breast and prostate carcinoma contributed only 12% of SEM-IMM patients but 51% of SEM-PEM patients. Only 27% of patients with SEM-IMM had nonspecific symptoms suggesting malignancy, and in only 24% did the history or physical examination suggest the primary site of malignancy. Percutaneous needle biopsy of the vertebral lesion was diagnostic of malignancy in 18 of 19 patients (95%), and no complications ensued. Fifteen patients underwent diagnostic laminectomy with biopsy, and one had a fatal complication. Survival after the diagnosis of SEM did not differ between patients with SEM-IMM and those with SEM-PEM; the median survival was 6.6 months. SEM not uncommonly occurs as the presentation of malignancy, and often it produces the only symptoms or signs of malignancy. The great majority of neoplasms presenting with SEM are carcinomas of the lung, unknown primary lesions, and hematologic malignancies. Computed tomography-guided needle biopsy is a safe, efficacious means of diagnosing malignancy, allowing for rational diagnostic workup and staging. In most patients it obviates a diagnostic spinal surgical procedure.


Predictive Role of p53 Protein as a Single Marker or Associated with ki67 Antigen in Oral Leukoplakia: A Retrospective Longitudinal Study.
Oral leukoplakia (OL) is the most common potentially malignant lesion of the oral cavity. Immunohistochemical analysis of p53 and Ki67 proteins is a simple and inexpensive method widely used in non-dysplastic OLs to reveal lesions predicted to develop oral cancer. The present longitudinal study evaluated the predictive role of p53 and Ki67 proteins alone or in combination in a group of OLs without dysplasia followed for many years. Seventy-seven OL patients referred to our Department between January 2006 and October 2013 underwent histochemical analysis of p53 and Ki67 expression. OLs were considered at high risk in the presence of either high p53 expression (>20%), or low/normal p53 expression associated with high Ki67 expression (Ki67/p53 ratio >3). Seven OLs evolved to OSCC during the follow-up period. Three cases had p53 overexpression, while four had a high Ki67/p53 ratio. Statistical significance was reached when samples with p53 overexpression were combined with samples with high Ki67/p53 ratio (Chi square 5.3; p<0.02). The combined immunohistochemical expression of p53 and Ki67 proteins could be a useful and simple molecular marker for early detection of non-dysplastic OLs at risk of developing oral cancer.


Liver transplantation for HELLP syndrome.
Of the approximately one in 1000 pregnant women who develop the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP), 2 to 3 per cent develop hepatic complications, including liver failure for which liver transplantation (LT) may be required. Between February 1, 1984, and December 31, 2006, eight women without a history of liver disease underwent LT for complications of HELLP syndrome. All received cadaveric grafts with a mean interval from delivery to LT of 7 days. The mean admission Child-Turcotte-Pugh score was 13.1 (class C), and the mean model for end-stage liver disease score was 40. Manifestations of liver failure included encephalopathy (seven patients), renal failure (four), disseminated intravascular coagulation (three), and respiratory failure (one). There were no intraoperative deaths. Complications of LT included biliary leaks (three patients), reoperation (three), and retransplantation (two). There was one death from sepsis on postoperative day 91 and one death from cholangitis/sepsis more than 5 years postoperatively. After LT, 1-, 5-, and 10-year patient survival rates were 88 per cent, 88 per cent, and 65 per cent; 1-, 5-, and 10-year graft survival rates were 64 per cent, 64 per cent, and 48 per cent. This is the largest single-center report of LT for HELLP. Early recognition and transfer to a transplant center will yield best results with this challenging complication of pregnancy.


National Trends in Antidepressant, Benzodiazepine, and Other Sedative-Hypnotic Treatment of Older Adults in Psychiatric and Primary Care.
To describe how use of antidepressants, benzodiazepines, and other anxiolytic/sedative-hypnotics among older adults (age ≥ 65 years) has changed over time among visits to primary care providers and psychiatrists. Data were from the National Ambulatory Medical Care Survey (years 2003-2005 and 2010-2012), a nationally representative cross-section of outpatient physician visits. Analysis focused on visits to primary care providers (n = 14,282) and psychiatrists (n = 1,095) at which an antidepressant, benzodiazepine, or other anxiolytic/sedative-hypnotic was prescribed, which were stratified by demographic and clinical characteristic (including ICD-9-CM diagnosis) and compared across study intervals. Odds of medication use were calculated for each stratum, adjusting for demographic and clinical characteristics. The visit rate by older adults to primary care providers where any of the medications were prescribed rose from 16.4% to 21.8% (adjusted odds ratio [AOR] = 1.43, P < .001) while remaining steady among psychiatrists (75.4% vs 68.5%; AOR = 0.69, P = .11). Primary care visits rose for antidepressants (9.9% to 12.3%; AOR = 1.28, P = .01) and other anxiolytic/sedative-hypnotics (3.4% to 4.7%; AOR = 1.39, P = .01), but the largest growth was among benzodiazepines (5.6% to 8.7%; AOR = 1.62, P < .001). Among patients in primary care, increases primarily occurred among men, non-Hispanic white patients, and those with pain diagnoses as well as those with no mental health or pain diagnoses. From 2003 to 2012, use of the most common psychotropic medications among older adults seen in primary care increased, with concentration among patients with no mental health or pain diagnosis. As the population of older adults grows and receives mental health treatment in primary care, it is critical to examine the appropriateness of psychotropic use.


True happiness: The role of morality in the folk concept of happiness.
Recent scientific research has settled on a purely descriptive definition of happiness that is focused solely on agents' psychological states (high positive affect, low negative affect, high life satisfaction). In contrast to this understanding, recent research has suggested that the ordinary concept of happiness is also sensitive to the moral value of agents' lives. Five studies systematically investigate and explain the impact of morality on ordinary assessments of happiness. Study 1 demonstrates that moral judgments influence assessments of happiness not only for untrained participants, but also for academic researchers and even in those who study happiness specifically. Studies 2 and 3 then respectively ask whether this effect may be explained by general motivational biases or beliefs in a just world. In both cases, we find evidence against these explanations. Study 4 shows that the impact of moral judgments cannot be explained by changes in the perception of descriptive psychological states. Finally, Study 5 compares the impact of moral and nonmoral value, and provides evidence that unlike nonmoral value, moral value is part of the criteria that govern the ordinary concept of happiness. Taken together, these studies provide a specific explanation of how and why the ordinary concept of happiness deviates from the definition used by researchers studying happiness. (PsycINFO Database Record


Acoustic Droplet Vaporization of Perfluorohexane Emulsions Induced by Heterogeneous Nucleation at an Ultrasonic Frequency of 1.1 MHz.
Droplets made of liquid perfluorocarbon undergo a phase transition and transform into microbubbles when triggered by ultrasound of intensity beyond a critical threshold; this mechanism is called acoustic droplet vaporization (ADV). It has been shown that if the intensity of the signal coming from high ultrasonic harmonics are sufficiently high, superharmonic focusing is the mechanism leading to ADV for large droplets (>3 μm) and high frequencies (>1.5 MHz). In such a scenario, ADV is initiated due to a nucleus occurring at a specific location inside the droplet volume. But the question on what induces ADV in the case of nanometer-sized droplets and/or at low ultrasonic frequencies (<1.5 MHz) still remains. We investigated ADV of perfluorohexane (PFH) nano- and microdroplets at a frequency of 1.1 MHz and at conditions where there is no superharmonic focusing. Three types of droplets produced by microfluidics were studied: plain PFH droplets, PFH droplets containing many nanometer-sized water droplets, and droplets made of a PFH corona encapsulating a single micron-sized water droplet. The probability to observe a vaporization event was measured as a function of acoustic pressure. As our experiments were performed on droplet suspensions containing a population of monodisperse droplets, we developed a statistical model to extrapolate, from our experimental curves, the ADV pressure thresholds in the case where only one droplet would be insonified. We observed that the value of ADV pressure threshold decreases as the radius of a plain PFH droplet increases. This value was further reduced when a PFH droplet encapsulates a micron-sized water droplet, while the encapsulation of many nanometer-sized water droplets did not modify the threshold. These results cannot be explained by a model of homogeneous nucleation. However, we developed a heterogeneous nucleation model, where the nucleus appears at the surface in contact with PFH, that successfully predicts our experimental ADV results.


[The intracavitary administration of contrast medium in the aftercare of complicated thoracic empyema with long-term drainage: x-ray fluoroscopy compared to computed tomography].
To define the value of conventional radiography compared with CT in the follow-up of complicated, long-term tube drained pleural empyema after intracavitary application of contrast medium. 28 patients with complicated pleural empyema (stage III) and long-term tube drainage were submitted to fluoroscopy of the pleural cavity and a CT of the thorax after contrast medium had been instilled into the pleural space. Both examinations were judged by the following criteria: number and morphology of pleural cavities, quality of drainage and accompanying thoracic disease. 49 pleural cavities were diagnosed. Judgement of drainage corresponded in 79% of cases and differed in 21% with proof of further not drained cavities only on CT. 4 bronchopleural fistulas were diagnosed by fluoroscopy, of which only 2 were evident on CT. Accompanying thoracic disease was reliably detected by CT only. Diagnosis of bronchopleural fistulas and judgement of the pleural drainage is best possible using fluoroscopy after application of contrast medium into the pleural space. CT is most accurate to detect further cavities that have not been drained, to look for concomitant thoracic disease, and to judge the morphology of the pleural cavity. Conventional radiography of the pleural space is effective and recommended to be used as a first line investigation for the follow-up of stage III empyemas. Patients in poor general condition (fever, elevated blood markers indicating inflammation) should be examined by both fluoroscopy and CT.


Vascular and cardiac contractile reserve in the dog heart with chronic multiple coronary occlusions.
Nineteen mongrel dogs survived chronic occlusion of the left circumflex and of the right coronary artery without infarction due to the timely development of a collateral circulation. Only 38 per cent of the conductance of the arteries before occlusion was restored by collateral vessels. In these animals and in 15 control dogs with normal coronary arteries myocardial contractility, contractility reserve, and myocardial blood flow were studied. The same was done in dogs with chronic coronary artery occlusion after aortocoronary bypass. Myocardial blood flow was determined woth the tracer microsphere technique. Contractility reserve was tested and defined as isovolumetric left ventricular pressure and dp/dt max with norepinephrine infusion and cross-clamping of the aorta. Contractile reserve was not significantly different between normal dogs and dogs with chronic coronary artery occlusion before and after aortocoronary bypass. Myocardial blood flow during control conditions was homogenously distributed in all three groups studied. The ratio of blood flow to the endocardium and the epicardium was not significantly different from inity. Coronary reserve was determined at peak reactive hyperemia following a 20 second period of coronary artery occlusion, with ongoing norepinephrine infusion. Under these conditions subendocardial fow in normal dogs rose by a factor of 7.9 while subepicardial flow increased 7.4 times. In dogs with chronic occlusion of two coronary arteries the increase of myocardial flow was nonnomogenous; subendocardial flow to areas supplied by a normal coronary artery rose by a factor of 7.0 while subepicardial flow increased 5.7 times control. Subendocardial collateral flow rose by a factor of 2.4 and subepicardial collateral flow increased 3.5 times control. In normal dogs norepinephrine alone did not result in maximal coronary flow but only 57 per cent thereof. Dogs with chronic coronary occlusion, however, required the entire coronary reserve in areas that were supplied by a normal coronary artery, whereas areas supplied by collaterals became ischemic. Opening of an aortocoronary bypass restored normal flow to previously ischemic areas, and reduced the flow to areas supplied by a normal artery. With the bypass open no differences existed between normal dogs and those with two occluded coronary arteries. We conclude that the norepinephrine-stimulated contractile reserve of hearts with chronic coronary occlusion was comparable to that of normal hearts; however, norepinephrine forced these hearts to spend the entire flow reserve of the remaining normal artery while producing ischemia in collateral-dependent areas. The same dose of norepinephrine did not require the entire flow reserve of normal dogs.


Maximal constant 45 min running velocity gives maximal lactate steady state.
The aim of the present study was to improve and confirm a time trial (TT) based method for determining anaerobic threshold (AnT) requiring minimal equipment. Eighteen participants underwent three to five all-out TTs for at the most 60 min. Velocity of the TTs was adapted in 0.1 or 0.2 m*s-1 steps until maximal velocity maintainable for at least 45 min (V(max45)) was identified. Exercise was interrupted every 5 min in order to take blood samples. After the participants had finished their last TT blood lactate concentration (BLC) was determined to identify maximal lactate steady state (MLSS). Velocity, BLC and heart rate (HR) at the TTs giving MLSS (TTMLSS) and giving V(max45) (TTV(max45)) were almost identical (3.45 ± 0.31 m*s-1 vs. 3.44 ± 0.31 m*s-1, 4.46 ± 1.28 mmol*L-1 vs. 4.52 ± 1.28 mmol*L-1, 177 ± 9.8 bpm vs. 178 ± 9.4 bpm). Coefficient of correlation (R) and standard error of estimate (SEE) between velocity at MLSS (VMLSS) and V(max45) were 0.96 and 0.09 m*s-1, respectively, indicating a very close relationship. Agreement between VMLSS and V(max45) was also very high. At VMLSS cardiovascular drift (CVD) was 8.4 ± 2.6 bpm from the 10th to 30th min. At V(max45) CVD was 7.9±2.8 bpm from the 10th to 30th min and 11.2 ± 3.8 bpm from the 10th to 45th min. Determination of V(max45) is a manageable, cost-saving and precise method for predicting velocity and CVD at MLSS in healthy, ambitious and at least moderately trained runners.


Tumour exosomes display differential mechanical and complement activation properties dependent on malignant state: implications in endothelial leakiness.
Exosomes have been implicated in tumour progression and metastatic spread. Little is known of the effect of mechanical and innate immune interactions of malignant cell-derived exosomes on endothelial integrity, which may relate to increased extravasation of circulating tumour cells and, therefore, increased metastatic spread. Exosomes isolated from non-malignant immortalized HCV-29 and isogenic malignant non-metastatic T24 and malignant metastatic FL3 bladder cells were characterized by nanoparticle tracking analysis and quantitative nanomechanical mapping atomic force microscopy (QNM AFM) to determine size and nanomechanical properties. Effect of HCV-29, T24 and FL3 exosomes on human umbilical vein endothelial cell (HUVEC) monolayer integrity was determined by transendothelial electrical resistance (TEER) measurements and transport was determined by flow cytometry. Complement activation studies in human serum of malignant and non-malignant cell-derived exosomes were performed. FL3, T24 and HCV-29 cells produced exosomes at similar concentration per cell (6.64, 6.61 and 6.46×10(4) exosomes per cell for FL3, T24 and HCV-29 cells, respectively) and of similar size (120.2 nm for FL3, 127.6 nm for T24 and 117.9 nm for HCV-29, respectively). T24 and FL3 cell-derived exosomes exhibited a markedly reduced stiffness, 95 MPa and 280 MPa, respectively, compared with 1,527 MPa with non-malignant HCV-29 cell-derived exosomes determined by QNM AFM. FL3 and T24 exosomes induced endothelial disruption as measured by a decrease in TEER in HUVEC monolayers, whereas no effect was observed for HCV-29 derived exosomes. FL3 and T24 exosomes traffic more readily (11.6 and 21.4% of applied exosomes, respectively) across HUVEC monolayers than HCV-29 derived exosomes (7.2% of applied exosomes). Malignant cell-derived exosomes activated complement through calcium-sensitive pathways in a concentration-dependent manner. Malignant (metastatic and non-metastatic) cell line exosomes display a markedly reduced stiffness and adhesion but an increased complement activation compared to non-malignant cell line exosomes, which may explain the observed increased endothelial monolayer disruption and transendothelial transport of these vesicles.


Ultralow Lattice Thermal Transport and Considerable Wave-like Phonon Tunneling in Chalcogenide Perovskite BaZrS3.
Chalcogenide perovskites provide a promising avenue for nontoxic, stable thermoelectric materials. Here, the thermal transport and thermoelectric properties of BaZrS3 as a typical orthorhombic perovskite are investigated. An extremely low lattice thermal conductivity κL of 1.84 W/mK at 300 K is revealed for BaZrS3, due to the softening effect of Ba atoms on the lattice and the strong anharmonicity caused by the twisted structure. We demonstrate that coherence contributions to κL, arising from wave-like phonon tunneling, lead to an 18% thermal transport contribution at 300 K. The increasing temperature softens the phonons, thus reducing the group velocity of materials and increasing the scattering phase space. However, it simultaneously reduces the anharmonicity, which is dominant in BaZrS3 and ultimately improves the particle-like thermal transport. In addition, via replacement of the S atom with Se- and Ti-alloying strategy, the ZT value of BaZrS3 is significantly increased from 0.58 to 0.91 at 500 K, making it an important candidate for thermoelectric applications.


Responsive Parenting Behaviors and Cognitive Function in Children With Sickle Cell Disease.
Children with sickle cell disease (SCD) are at increased risk for cognitive impairment as a result in part from biological characteristics of the disease; however, limited research has explored possible social and contextual factors associated with risk for cognitive problems. The primary aim of the present study was to examine the relation between children's cognitive functioning and responsive parenting, a potentially important contextual factor in children with SCD, accounting for family socioeconomic disadvantage, child disease severity, and caregivers' perceived stress. Forty-eight children completed standardized cognitive assessments and caregivers provided self-reports of general and disease-related stress. Parent-child dyads completed a video recorded puzzle-solving task and observed parenting was quantified using two coding systems. Bivariate Pearson correlations were used to assess preliminary hypotheses, and linear multiple regression analyses were used to assess the primary hypothesis. Results suggested that increased levels of parental stress were related to fewer observations of responsive parenting and provided evidence of an association between children's cognitive function and responsive parenting. Specifically, increased disease-related parent stress and reduced parental use of expansive language were associated with significantly lower cognitive functioning in children with SCD. Findings suggest that social environmental factors along with disease characteristics are sources of risk for cognitive problems with children with SCD. Further, these findings highlight the need to develop targeted interventions for parents of children with SCD to decrease levels of stress and enhance parenting skills, with the aim improving cognitive functioning in youth.


Dairy food intake, peripheral bone structure, and muscle mass in elderly ambulatory women.
Previous studies suggest that dairy intake may be associated with reduced bone and muscle loss with aging, but there are limited data in the very old. We evaluated the association between intake of dairy foods and peripheral bone structure and muscle mass in 564 elderly women aged 80 to 92 (mean 84.7) years, who were participants of the Calcium Intake Fracture Outcome Study/CAIFOS Aged Extension Study (CAIFOS/CARES) cohort and attended the 10-year follow-up. Assessments included dairy consumption (milk, yogurt, and cheese) by a validated food frequency questionnaire, 15% tibia bone mass, area and volumetric bone mineral density (vBMD) by peripheral quantitative computed tomography (pQCT), and appendicular bone and skeletal muscle mass by dual-energy X-ray absorptiometry (DXA). Women were categorized according to tertiles of dairy intake: first tertile (≤ 1.5 servings/d), second tertile (1.5 to 2.2 servings/d) and third tertile (≥ 2.2 servings/d). Controlling for confounding factors, pQCT assessment at the 15% tibia showed that compared with those in the first tertile of dairy intake, women in the third tertile had 5.7% greater total bone mass (p = 0.005), principally because of an increase in cortical and subcortical bone mass (5.9%, p = 0.050), resulting in a 6.2% increase in total vBMD (p = 0.013). Trabecular but not cortical and subcortical vBMD was also higher (7.8%, p = 0.044). DXA assessment showed that women in the third tertile of dairy intake had greater appendicular bone mass (7.1%, p = 0.007) and skeletal muscle mass (3.3%, p = 0.014) compared with tertile 1. The associations with bone measures were dependent on dairy protein and calcium intakes, whereas the association with appendicular muscle mass was not totally dependent on dairy protein intake. Our results suggest a positive association of dairy intake with appendicular bone mineralization and muscle mass in elderly women. Because many fractures in this age group are of the appendicular skeleton often associated with falls, dairy intake may be a modifiable lifestyle factor contributing to healthy aging.


Cu-catalyzed asymmetric borylative cyclization of cyclohexadienone-containing 1,6-enynes.
The first Cu-catalyzed asymmetric borylative cyclization of cyclohexadienone-containing 1,6-enynes is achieved through a tandem process: selective β-borylation of propargylic ether and subsequent conjugate addition to cyclohexadienone. The reaction proceeds with excellent regioselectivity and enantioselectivity to afford an optically pure cis-hydrobenzofuran framework bearing alkenylboronate and enone substructures. Furthermore, the resulting bicyclic products could be converted to bridged and tricyclic ring structures. This method extends the realm of Cu-catalyzed asymmetric tandem reactions using bis(pinacolato)diboron (B2pin2).


Limonene nanoemulsified with soya lecithin reduces the intensity of non-isothermal treatments for inactivation of Listeria monocytogenes.
Consumers' demands for ready-to-eat, fresh-like products are on the rise during the last years. This type of products have minimal processing conditions that can enable the survival and replication of pathogenic microorganisms. Among them, Listeria monocytogenes is of special concern, due to its relatively high mortality rate and its ability to replicate under refrigeration conditions. Previous research works have shown that nanoemulsified essential oils in combination with thermal treatments are effective for inactivating L. monocytogenes. However, previous research works were limited to isothermal conditions, whereas actual processing conditions in industry are dynamic. Under dynamic conditions, microorganism can respond unexpectedly to the thermal stress (e.g. adaptation, acclimation or increased sensitivity). In this work, we assess the combination of nanoemulsified D-limonene with thermal treatments under isothermal and dynamic conditions. The nanoemulsion was prepared following an innovative methodology using soya lecithin, a natural compound as well as the essential oil. Under isothermal heating conditions, the addition of the antimicrobial enables a reduction of the treatment time by a factor of 25. For time-varying treatments, dynamic effects were relevant. Treatments with a high heating rate (20 °C/min) are more effective than those with a slow heating rate (1 °C/min). This investigation demonstrates that the addition of nanoemulsified D-limonene can greatly reduce the intensity of the thermal treatments currently applied in the food industry. Hence, it can improve the product quality without impacting its safety.


Design, synthesis and insecticidal activities of novel pyrazole amides containing hydrazone substructures.
Pyrazole and hydrazone derivatives possess good insecticidal activities; their substructural units are widely used in pesticide design. In an effort to discover new molecules with good insecticidal activities, a series of pyrazole amide derivatives containing hydrazone substructures were synthesised and bioassayed. Bioassays demonstrated that some of the title compounds exhibited notable control of Plutella xylostella (Linnaeus), Helicoverpa armigera (Hübner), Culex pipiens pallens, Laphygma exigua (Hübner), Spodoptera litura (Fabricius), Nilaparvata lugens (Stål) and Rhopalosiphum maidis (Fitch) at 5, 10, 0.25, 200, 20, 100 and 500 mg L(-1) respectively. Comparative molecular field analysis (CoMFA) based on the bioactivities for P. xylostella was studied; the values of q(2) and r(2) for the CoMFA model were 0.701 and 0.964 respectively. Some of the title compounds displayed good and broad-spectrum insecticidal activities against different insect species; the CoMFA model revealed that a bulky and negatively charged group at the 4-position of benzene could enhance insecticidal activity. These results could provide useful information for the design of novel insecticide containing substructural units of pyrazole amide and hydrazone.


Präder-Willi syndrome fails to alter cardiac autonomic modulation.
Twenty-six healthy subjects with a diagnosis of Präder-Willi syndrome were compared with 26 age-, gender-, and body mass index-matched controls for autonomic modulation and baroreflex sensitivity. Electrocardiograms, beat-to-beat finger blood pressures, and respiration were recorded for several minutes in the following sequence: (1) supine, (2) after transition from supine to standing, (3) sitting, (4) during a Valsalva maneuver, (5) while performing moderate exercise, and (6) during recovery from exercise while seated. All recordings were channeled and stored in a computer; analyses were carried out at a later date. Power spectral analysis (fast-Fourier transform) of heart period variability was used to assess cardiac autonomic modulation. The slope of the regression equation between heart period and blood pressure rise after the Valsalva maneuver was used as an index of baroreflex sensitivity. Analysis of variance failed to reveal significant differences in any of the autonomic and baroreflex sensitivity variables between the two groups. Because breathing patterns entrain autonomic modulation, we verified respiration and found no differences between the two groups. Therefore, findings in the current investigation indicate that cardiac autonomic modulation in patients with Präder-Willi syndrome does not differ from age and body mass index-matched subjects.


A saturable high affinity binding site for transcobalamin II-vitamin B12 complexes in human placental membrane preparations.
Studies were designed to evaluate the binding of binding of vitamin B12 to cell membrane preparations from human placenta. The transcobalamin II-vitamin B12 complex (TCII-B12), which has a much greater affinity for the membranes than vitamin B12 alone, binds to a single saturable binding site with an approximate Ka = 7.2 mM-1. The binding requires a divalent cation and is temperature-dependent. Free TCII can compete with TCII-B12 for the binding site but has somewhat less affinity than does TCII-B12. Rat TCII-B12 has an affinity constant that is less than one-fifth that of human TCII-B12; human TCI-B12, bovine TCII-B12, hog intrinsic factor-B12 (IF-B12), and human IF-B12 do not bind to the membranes. Pretreating the membranes with trypsin causes a marked decrease in subsequent binding; this suggests the binding site includes a relatively exposed membrane protein. These data suggest that a specific cell surface receptor for the TCII-B12 complex exists in placenta. This TCII-B12 receptor can be solubilized with Triton X-100.


Drosophila Ctf4 is essential for efficient DNA replication and normal cell cycle progression.
Proper coordination of the functions at the DNA replication fork is vital to the normal functioning of a cell. Specifically the precise coordination of helicase and polymerase activity is crucial for efficient passage though S phase. The Ctf4 protein has been shown to be a central member of the replication fork and links the replicative MCM helicase and DNA polymerase α primase. In addition, it has been implicated as a member of a complex that promotes replication fork stability, the Fork Protection Complex (FPC), and as being important for sister chromatid cohesion. As such, understanding the role of Ctf4 within the context of a multicellular organism will be integral to our understanding of its potential role in developmental and disease processes. We find that Drosophila Ctf4 is a conserved protein that interacts with members of the GINS complex, Mcm2, and Polymerase α primase. Using in vivo RNAi knockdown of CTF4 in Drosophila we show that Ctf4 is required for viability, S phase progression, sister chromatid cohesion, endoreplication, and coping with replication stress. Ctf4 remains a central player in DNA replication. Our findings are consistent with what has been previously reported for CTF4 function in yeast, Xenopus extracts, and human tissue culture. We show that Ctf4 function is conserved and that Drosophila can be effectively used as a model to further probe the precise function of Ctf4 as a member of the replication fork and possible roles in development.


Spontaneous expression of the chromosome fragile site fra(10)(q25).
We report the spontaneous expression of the chromosome fragile site at 10q25 in a child with progressive cerebellar ataxia and in her phenotypically normal brother and father. Expression of this fragile site was increased in all three individuals by addition of bromodeoxyuridine (BrdU) to the medium. This fragile site has previously been described only following growth of cells in BrdU.


Investigating a Genetic Link Between Alzheimer's Disease and CADASIL-Related Cerebral Small Vessel Disease.
Monogenic forms of Alzheimer's disease (AD) have been identified through mutations in genes such as APP, PSEN1, and PSEN2, whilst other genetic markers such as the APOE ε carrier allele status have been shown to increase the likelihood of having the disease. Mutations in these genes are not limited to AD, as APP mutations can also cause an amyloid form of cerebral small vessel disease (CSVD) known as cerebral amyloid angiopathy, whilst PSEN1 and PSEN2 are involved in NOTCH3 signalling, a process known to be dysregulated in the monogenic CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The overlap between AD genes and causes of CSVD led to the hypothesis that mutations in other genes within the PANTHER AD-presenilin pathway may be novel causes of CSVD in a cohort of clinically suspicious CADASIL patients without a pathogenic NOTCH3 mutation. To investigate this, whole exome sequencing was performed on 50 suspected CADASIL patients with no NOTCH3 mutations, and a targeted gene analysis was completed on the PANTHER. ERN1 was identified as a novel candidate CSVD gene following predicted pathogenic gene mutation analysis. Rare variant burden testing failed to identify an association with any gene; however, it did show a nominally significant link with ERN1 and TRPC3. This study provides evidence to support a genetic overlap between CSVD and Alzheimer's disease.


The cutaneous microvascular architecture of human diabetic toe studied by corrosion casting and scanning electron microscopy analysis.
In this morphological study, we report on the three-dimensional microvascular architecture constituting the toes of a patient affected by diabetic microangiopathy. We applied corrosion casting (CC) technique to the toes of a patient affected by Type 2 diabetes, who underwent surgery for explantation of inferior left limb due to necrotic processes of soft tissues. The toes of a foot traumatically explanted in a motorcycle accident were kept as controls. According to technical protocols, toes were injected with a low-viscosity acrylic resin (Mercox) through the major digital artery, tissues were corroded in KOH solution (8%), and resulting casts processed for SEM observations. Already at low magnification, in diabetic toes, we found an impairment of the linear track-like disposition of the vessels of plantar side, with signs of vascular disruption and obliterations, stopped resin, and leakages. Capillaries under the nail and a lot of vascular villi in eponychium and nail borders were damaged, and vascular regression phenomena acting on them were clearly visible. Resin leakages and impairment of normal vascular architecture were also observed in the root of the nail. This preliminary report represents only the first step for further investigations regarding morphological three-dimensional appearance of diabetic microangiopathy. CC and scanning electron microscopy technique well documented these morphological modifications, highlighting on both structural and ultrastructural features of diabetic toes microvessels. In conclusion, our qualitative data try to better focus on the pathophysiological mechanisms involved in diabetic dermopathy and microangiopathy, proposing CC as useful method to investigate on them.


Heart failure with preserved ejection fraction in humans and mice: embracing clinical complexity in mouse models.
Heart failure (HF) with preserved ejection fraction (HFpEF) is a multifactorial disease accounting for a large and increasing proportion of all clinical HF presentations. As a clinical syndrome, HFpEF is characterized by typical signs and symptoms of HF, a distinct cardiac phenotype and raised natriuretic peptides. Non-cardiac comorbidities frequently co-exist and contribute to the pathophysiology of HFpEF. To date, no therapy has proven to improve outcomes in HFpEF, with drug development hampered, at least partly, by lack of consensus on appropriate standards for pre-clinical HFpEF models. Recently, two clinical algorithms (HFA-PEFF and H2FPEF scores) have been developed to improve and standardize the diagnosis of HFpEF. In this review, we evaluate the translational utility of HFpEF mouse models in the context of these HFpEF scores. We systematically recorded evidence of symptoms and signs of HF or clinical HFpEF features and included several cardiac and extra-cardiac parameters as well as age and sex for each HFpEF mouse model. We found that most of the pre-clinical HFpEF models do not meet the HFpEF clinical criteria, although some multifactorial models resemble human HFpEF to a reasonable extent. We therefore conclude that to optimize the translational value of mouse models to human HFpEF, a novel approach for the development of pre-clinical HFpEF models is needed, taking into account the complex HFpEF pathophysiology in humans.


Success of Tonsillectomy for Obstructive Sleep Apnea in Children With Down Syndrome.
Obstructive sleep apnea (OSA) is common in children with Down syndrome (DS) and associated with significant morbidity. In the current study we examined polysomnographic outcomes of children with DS who underwent tonsillectomy. A retrospective chart review of children with DS who underwent a tonsillectomy between 2009-2015 was performed. All children had either a concurrent adenoidectomy or had previously underwent an adenoidectomy. Children with preoperative and postoperative polysomnograms within 6 months of surgery were included in the analysis. Preoperative OSA severity was categorized by obstructive apnea-hypopnea index (OAHI) as follows: mild = 1.5-4.9 events/h; moderate = 5-9.9 events/h; severe ≥ 10 events/h. Seventy-five children with DS met inclusion criteria. The cohort included 41 males and 34 females with mean age of 5.1 years (± 3.6 years), range of 0.51-16.60 years. Preoperative OSA severity was as follows, mild = 8/75; moderate = 16/75; severe = 51/75. Cure rates varied depending on definition: 12% for OAHI < 1 event/h and 21% for OAHI < 2 events/h. 48% had residual OAHI < 5 events/h. On postoperative PSG 16/75 saw resolution (OAHI < 2) in OSA; mild = 21/75; moderate = 20/75; severe = 18/75. 48% moderate/severe patients saw conversion to mild or cure. Overall, tonsillectomy resulted in significant improvements in multiple respiratory parameters, including OAHI (OAHI; 21.3 ± 19.7 to 8.0 ± 8.1, P < .001), percent sleep time with oxygen saturations < 90% (19.0 ± 25.0 to 6.1 ± 10.1, P < .001), and percent sleep time with end-tidal carbon dioxide above 50 mmHg (7.7 ± 18.0 to 1.8 ± 6.6, P = .001). Average asleep oxygen saturation was associated with postoperative OSA severity. Children with DS and OSA who undergo tonsillectomy experience improvements in both respiratory event frequency and gas exchange but approximately half still have moderate to severe residual OSA.


Effect of OKY 046, a thromboxane synthase inhibitor, on lung vascular permeability after pulmonary embolism in sheep.
OKY 046, a specific thromboxane synthase inhibitor, was used to investigate whether large pulmonary emboli, like microemboli, cause an increase in thromboxane A2 and an associated increase in vascular permeability in sheep. Nineteen sheep were anaesthetised and had cannulas inserted into the afferent lymphatic of the caudal mediastinal lymph node and pulmonary and carotid arteries. Several days later the animals were pretreated with placebo or OKY 046 0.4 mg/kg one hour before being given clotted blood 0.5 g/kg intravenously. After embolisation in the control animals mean pulmonary artery pressure (MPAP) rose from 12 to 34 mm Hg and pulmonary artery wedge pressure (PAWP) fell from 4.4 to 1.5 mm Hg; the cardiac index did not change but the physiological shunt (QS/QT) rose from 17% to 50%. One hour after embolisation the platelet count fell from 76 to 32 x 10(6)/l whereas at 15 minutes thromboxane B2 rose from 116 to 560 pg/ml in plasma and from 324 to 795 pg/ml in lymph (p less than 0.05). By 2 hours the concentration of thromboxane B2 was higher in lymph than in plasma. Lymph flow rose from 8.7 to a maximum of 27.3 ml/h at 15 minutes but despite the increase in flow the lymph:plasma (L:P) protein ratio did not fall, indicating an increased permeability of the blood vessels to protein. Pretreatment with OKY 046 inhibited the rise in plasma and lymph thromboxane B2, and limited the rise of QS/QT. The changes in MPAP, PAWP, cardiac index, platelet count, lymph flow, and L:P protein ratio, however, were no different from those in untreated sheep. These results indicate that a large pulmonary embolus leads to an increase in plasma and lung lymph thromboxane A2, which moderates the rise in QS/QT in part but not the increase in vascular permeability.


Wave Vector Difference of Magnetic Bragg Reflections and Low Energy Magnetic Excitations in Charge-stripe Ordered La2NiO4.11.
We report on the magnetism of charge-stripe ordered La2NiO4.11±0.01 by neutron scattering and μSR. On going towards zero energy transfer there is an observed wave vector offset in the centring of the magnetic excitations and magnetic Bragg reflections, meaning the excitations cannot be described as Goldstone modes of the magnetic order. Weak transverse field μSR measurements determine the magnetically order volume fraction is 87% from the two stripe twins, and the temperature evolution of the magnetic excitations is consistent with the low energy excitations coming from the magnetically ordered volume of the material. We will discuss how these results contrast with the proposed origin of a similar wave vector offset recently observed in a La-based cuprate, and possible origins of this effect in La2NiO4.11.


Identification of the Xenopus DNA2 protein as a major nuclease for the 5'->3' strand-specific processing of DNA ends.
The first step of homology-dependent DNA double-strand break (DSB) repair is the 5' strand-specific processing of DNA ends to generate 3' single-strand tails. Despite extensive effort, the nuclease(s) that is directly responsible for the resection of 5' strands in eukaryotic cells remains elusive. Using nucleoplasmic extracts (NPE) derived from the eggs of Xenopus laevis as the model system, we have found that DNA processing consists of at least two steps: an ATP-dependent unwinding of ends and an ATP-independent 5'-->3' degradation of single-strand tails. The unwinding step is catalyzed by DNA helicases, the major one of which is the Xenopus Werner syndrome protein (xWRN), a member of the RecQ helicase family. In this study, we report the purification and identification of the Xenopus DNA2 (xDNA2) as one of the nucleases responsible for the 5'-->3' degradation of single-strand tails. Immunodepletion of xDNA2 resulted in a significant reduction in end processing and homology-dependent DSB repair. These results provide strong evidence that xDNA2 is a major nuclease for the resection of DNA ends for homology-dependent DSB repair in eukaryotes.


Husbandry stress exacerbates mycobacterial infections in adult zebrafish, Danio rerio (Hamilton).
Mycobacteria are significant pathogens of laboratory zebrafish, Danio rerio (Hamilton). Stress is often implicated in clinical disease and morbidity associated with mycobacterial infections but has yet to be examined with zebrafish. The aim of this study was to examine the effects of husbandry stressors on zebrafish infected with mycobacteria. Adult zebrafish were exposed to Mycobacterium marinum or Mycobacterium chelonae, two species that have been associated with disease in zebrafish. Infected fish and controls were then subjected to chronic crowding and handling stressors and examined over an 8-week period. Whole-body cortisol was significantly elevated in stressed fish compared to non-stressed fish. Fish infected with M. marinum ATCC 927 and subjected to husbandry stressors had 14% cumulative mortality while no mortality occurred among infected fish not subjected to husbandry stressors. Stressed fish, infected with M. chelonae H1E2 from zebrafish, were 15-fold more likely to be infected than non-stressed fish at week 8 post-injection. Sub-acute, diffuse infections were more common among stressed fish infected with M. marinum or M. chelonae than non-stressed fish. This is the first study to demonstrate an effect of stress and elevated cortisol on the morbidity, prevalence, clinical disease and histological presentation associated with mycobacterial infections in zebrafish. Minimizing husbandry stress may be effective at reducing the severity of outbreaks of clinical mycobacteriosis in zebrafish facilities.


Depressive symptoms and health-related quality of life: the Heart and Soul Study.
Little is known regarding the extent to which patient-reported health status, including symptom burden, physical limitation, and quality of life, is determined by psychosocial vs physiological factors among patients with chronic disease. To compare the contributions of depressive symptoms and measures of cardiac function to the health status of patients with coronary artery disease. Cross-sectional study of 1024 adults with stable coronary artery disease recruited from outpatient clinics in the San Francisco Bay Area between September 2000 and December 2002. Main Measures Measurement of depressive symptoms using the Patient Health Questionnaire (PHQ); assessment of cardiac function by measuring left ventricular ejection fraction on echocardiography, exercise capacity on treadmill testing, and ischemia on stress echocardiography; and measurement of a range of health status outcomes, including symptom burden, physical limitation, and quality of life, using the Seattle Angina Questionnaire. Participants were also asked to rate their overall health as excellent, very good, good, fair, or poor. Of the 1024 participants, 201 (20%) had depressive symptoms (PHQ score > or =10). Participants with depressive symptoms were more likely than those without depressive symptoms to report at least mild symptom burden (60% vs 33%; P<.001), mild physical limitation (73% vs 40%; P<.001), mildly diminished quality of life (67% vs 31%; P<.001), and fair or poor overall health (66% vs 30%; P<.001). In multivariate analyses adjusting for measures of cardiac function and other patient characteristics, depressive symptoms were strongly associated with greater symptom burden (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.3-2.7; P =.002), greater physical limitation (OR, 3.1; 95% CI, 2.1-4.6; P<.001), worse quality of life (OR, 3.1; 95% CI, 2.2-4.6; P<.001), and worse overall health (OR, 2.0; 95% CI, 1.3-2.9; P<.001). Although decreased exercise capacity was associated with worse health status, left ventricular ejection fraction and ischemia were not. Among patients with coronary disease, depressive symptoms are strongly associated with patient-reported health status, including symptom burden, physical limitation, quality of life, and overall health. Conversely, 2 traditional measures of cardiac function-ejection fraction and ischemia-are not. Efforts to improve health status should include assessment and treatment of depressive symptoms.


Task Difficulty Modulates the Disrupting Effects of Oral Respiration on Visual Search Performance.
Previous research has suggested that oral respiration may disturb cognitive function and health. The present study investigated whether oral respiration negatively affects visual attentional processing during a visual search task. Participants performed a visual search task in the following three breathing conditions: wearing a nasal plug, wearing surgical tape over their mouths, or no modification (oral vs. nasal vs. control). The participants searched for a target stimulus within different set sizes of distractors in three search conditions (orientation vs colour vs conjunction). Experiment 1 did not show any effect due to respiration. Experiment 2 rigorously manipulated the search efficiency and found that participants required more time to find a poorly discriminable target during oral breathing compared with other breathing styles, which was due to the heightened intercept under this condition. Because the intercept is an index of pre-search sensory processing or motor response in visual search, such cognitive processing was likely disrupted by oral respiration. These results suggest that oral respiration and attentional processing during inefficient visual search share a common cognitive resource.


Somatosensory-evoked potential induced by stimulation of the caudal tibial nerve in awake and barbiturate-anesthetized sheep.
The somatosensory-evoked potential (SEP) from caudal tibial nerve stimulation was recorded in sheep, using surgically implanted electrodes. Peak latencies of the SEP remained stable throughout the 3- to 5-month recording period. Wave-form and peak latencies from awake sheep and concomitant changes during barbiturate anesthesia were compared with those reported for other animal species, including man. Wave form components representing activities from the primary somesthetic cortex, association cortex, and non-specific diffuse projections were differentially susceptible to barbiturate anesthesia. The neural source of the initial positive peak (mean latency = 19 ms) was resistant to anesthesia and represented primary somesthetic activity of the cortex. Sheep with surgically implanted electrodes yielded stable latencies with SEP wave-form features essentially homologous to those reported for other animal species.


Mitochondrial mediated thimerosal-induced apoptosis in a human neuroblastoma cell line (SK-N-SH).
Environmental exposure to mercurials continues to be a public health issue due to their deleterious effects on immune, renal and neurological function. Recently the safety of thimerosal, an ethyl mercury-containing preservative used in vaccines, has been questioned due to exposure of infants during immunization. Mercurials have been reported to cause apoptosis in cultured neurons; however, the signaling pathways resulting in cell death have not been well characterized. Therefore, the objective of this study was to identify the mode of cell death in an in vitro model of thimerosal-induced neurotoxicity, and more specifically, to elucidate signaling pathways which might serve as pharmacological targets. Within 2 h of thimerosal exposure (5 microM) to the human neuroblastoma cell line, SK-N-SH, morphological changes, including membrane alterations and cell shrinkage, were observed. Cell viability, assessed by measurement of lactate dehydrogenase (LDH) activity in the medium, as well as the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, showed a time- and concentration-dependent decrease in cell survival upon thimerosal exposure. In cells treated for 24 h with thimerosal, fluorescence microscopy indicated cells undergoing both apoptosis and oncosis/necrosis. To identify the apoptotic pathway associated with thimerosal-mediated cell death, we first evaluated the mitochondrial cascade, as both inorganic and organic mercurials have been reported to accumulate in the organelle. Cytochrome c was shown to leak from the mitochondria, followed by caspase 9 cleavage within 8 h of treatment. In addition, poly(ADP-ribose) polymerase (PARP) was cleaved to form a 85 kDa fragment following maximal caspase 3 activation at 24 h. Taken together these findings suggest deleterious effects on the cytoarchitecture by thimerosal and initiation of mitochondrial-mediated apoptosis.


Ionic mechanism of muscarinic cholinergic depolarization of mouse spinal cord neurons in cell culture.
1. Muscarinic cholinergic actions were investigated in a population of large multipolar spinal cord neurons in primary dissociated cell culture using conventional intracellular recording and single-microelectrode voltage-clamp techniques. 2. Cholinergic agonists were applied to the surface of neuronal somata by pressure ejecting drug-containing bathing medium from small blunt (2-10 microns) glass micropipettes. Atropine was applied by diffusion from large (20-30 microns) blunt micropipettes positioned near the soma. 3. Muscarine increased action-potential firing and evoked slow sustained membrane depolarization. Action potentials but not slow membrane depolarizations were eliminated by the sodium channel blocker, tetrodotoxin. Muscarine-induced depolarizing responses were unaffected by the calcium channel blocker, cadmium. 4. Depolarizing responses evoked by selective and nonselective muscarinic cholinergic agonists were dose dependent, reversibly antagonized by atropine, and did not desensitize. 5. Muscarine depolarized neurons and decreased membrane conductance during recording with both 3 M KCl- and 4 M KAc-filled intracellular recording micropipettes. When membrane potential was held constant using the single-electrode voltage-clamp technique (KCl-filled micropipettes), muscarine and gamma-aminobutyric acid (GABA) evoked inward currents at resting membrane potential. GABA-induced inward current responses were decreased by depolarization and had reversal potentials near -30 mV, consistent with GABA increasing chloride conductance. Muscarine-induced inward current responses were increased by depolarization and had extrapolated reversal potentials near -80 mV, consistent with muscarine decreasing a potassium conductance. 6. Unlike GABA-induced currents, muscarine-induced currents evoked in normal Tris-buffered saline (5 mM potassium) did not vary as a linear function of membrane potential and did not reverse polarity in six of seven neurons near potassium equilibrium potential. However, in high-potassium medium (15 mM) muscarinic responses did reverse polarity and current was linearly related to membrane potential. Thus, the apparent voltage dependence of muscarine responses was probably due to voltage dependency of the potassium conductance and not due to potassium channel rectification. 7. Preliminary evidence (37) indicates that muscarine decreases a time- and voltage-dependent potassium current in some cultured spinal cord neurons. Whether reduction of m current can completely account for muscarine postsynaptic actions in these cells remains unclear. Muscarine may also block a small population of non-voltage-dependent potassium channels in addition to reducing m current.


Effects of Mobility and Cognition on Hospitalization and Inpatient Days in Women in Late Life.
This study examines effects of mobility and cognition on hospitalization and inpatient days among women late in life. Prospective study of 663 women (mean age 87.7 years) participating in the Study of Osteoporotic Fractures Year 20 examination (2006-2008) linked with their inpatient claims data. At Year 20, mobility ascertained by Short Physical Performance Battery categorized as poor, intermediate, or good. Cognitive status adjudicated based on neuropsychological tests and classified as normal, mild cognitive impairment, or dementia. Hospitalizations (n = 182) during 12 months following Year 20. Reduced mobility and poorer cognition were each associated in a graded manner with higher inpatient health care utilization, even after accounting for each other and traditional prognostic indicators. For example, adjusted mean inpatient days per year were 0.94 (95% confidence interval [CI] 0.52-1.45) among women with good mobility increasing to 2.80 (95% CI 1.64-3.89) among women with poor mobility and 1.59 (95% CI 1.08-2.03) among women with normal cognition increasing to 2.53 (95% CI 1.55-3.40) among women with dementia. Women with poor mobility/dementia had a nearly sixfold increase in mean inpatient days per year (4.83, 95% CI 2.73-8.54) compared with women with good mobility/normal cognition (0.84, 95% CI 0.49-1.44). Among women late in life, mobility limitations and cognitive deficits were each independent predictors of higher inpatient health care utilization even after considering each other and conventional predictors. Additive effects of reduced mobility and poorer cognition may be important to consider in medical decision making and health care policy planning for the growing population of adults aged ≥85 years.


Palpable migratory arciform erythema. Clinical morphology, histopathology, immunohistochemistry, and response to treatment.
Palpable migratory arciform erythema is clinically characterized by sharply circumscribed, infiltrated erythematous patches that tend to spread irregularly, resulting in arciform morphologic features. The histopathologic features are characterized by a patchy inflammatory perivascular and periadnexal T-lymphocytic infiltrate throughout the dermis. The disease runs a chronic course and is rarely described in the literature. Three middle-aged patients of both sexes had palpable migratory arciform erythema with 1, several, or multiple lesions on the trunk. There was a dense perivascular and periadnexal, predominantly lymphocytic infiltrate of the reticular dermis without any interstitial distribution of inflammatory cells. Absence of mucin deposits and plasma cells was a striking feature. The immunohistochemical profile showed an infiltrate dominated by T cells of polyclonal origin. In addition, polyclonal B cells and histiocytes were present in small numbers. In all 3 cases, oral antibacterial treatment resulted in a complete (2 patients) or temporary (1 patient) resolution of skin lesions. Palpable migratory arciform erythema shows distinctive differences in clinical and pathological features and treatment in contrast to other diseases with cutaneous lymphocytic infiltrates, including lymphocytic infiltration of Jessner and Kanof. Therefore, it is likely a distinct disease entity.


Intravesical foreign bodies: five-year review.
All manner of foreign bodies have been extracted from the bladder. Introduction into the bladder may be through self-insertion, iatrogenic means or migration from adjacent organs. Extraction should be tailored according to the nature of the foreign body and should minimise bladder and urethral trauma. Complete extraction should also be confirmed by panendoscopy at the end of the extraction procedure. A 5-year review of our experience in this field has been conducted and the management and complications of intravesical foreign bodies are described. Of the 15 patients presenting to this department, 11 presented acutely and 4 presented with chronic symptoms due to complications which arose later. The possibility of an intravesical foreign body should be considered in any patient with chronic unexplained lower urinary tract symptoms.


Different activity of the biological axis VEGF-Flt-1 (fms-like tyrosine kinase 1) and CXC chemokines between pulmonary sarcoidosis and idiopathic pulmonary fibrosis: a bronchoalveolar lavage study.
We have previously shown a different local and systemic angiogenic profile of CXC chemokines in Idiopathic Pulmonary Fibrosis (IPF) patients compared to sarcoidosis. In particular, sarcoidosis showed an angiostatic microenvironment, as compared with the angiogenic cytokine milieu seen in IPF. Purpose of the Study. Our aim was to further investigate the aforementioned finding by measuring the expression of different chemokines in granulomatous and fibrotic diseases. We estimated the levels of vascular endothelial growth factor (VEGF) and its high-affinity receptor, Flt-1 (fms-like tyrosine kinase 1), in bronchoalveolar lavage fluid (BALF) of patients with IPF and pulmonary sarcoidosis. We have also investigated the mRNA expression of angiogenetic chemokines' receptors such as CXCR2 and CXCR3 and the biological axis of stromal derived factor-1 alpha (SDF-1 alpha or CXCL12 alpha/CXCL12 beta) and receptor, CXCR4. We studied prospectively three groups of patients: (i) one group of 18 patients with IPF, (ii) one group of 16 patients with sarcoidosis, and (iii) 10 normal subjects. A statistically significant increase has been detected in VEGF mRNA expression in IPF in comparison with pulmonary sarcoidosis (P = .03). In addition, a significant increase has been measured in CXCL12 alpha in sarcoidosis in comparison to IPF (P = .02). Moreover, a statistically significant decrease has been found in Flt-1 protein levels in pulmonary sarcoidosis in comparison with IPF (P = .03). A significant increase in VEGF (P = .03) and CXCR4 (P = .03) mRNA levels has been also detected in sarcoidosis' patients when compared with healthy controls. Our data suggest that increased expression of Flt-1 and downregulation of CXCL12 alpha in IPF may further support the hypothesis of a different angiogenetic profile between fibrotic and granulomatous diseases. However, further studies are needed in order to better investigate these enigmatic diseases.


Protoplast and cytoplasmic membrane preparations from Streptococcus sanguis and Streptococcus mutans.
Protoplasts were prepared from Streptococcus sanguis and some S. mutans serotypes by use of lysozyme (EC 126.96.36.199) under particular conditions: cells had to be grown in DL-threonine (20 mM) and harvested in early exponential phase. The efficiency of protoplast formation was enhanced by two additional steps: plasmolysis (in 12% PEG), prior to addition of lysozyme, and a swirling phase, after the enzymic action. This procedure allowed us to obtain clean protoplasts, with only 0.5% contamination by bacterial cell walls. Up to 90% protoplast lysis was obtained in 0.5 M-NaCl. Cytoplasmic membrane purification was achieved by centrifugation on a glycerol cushion.


[The practice guideline 'Stable angina pectoris' (second revision) from the Dutch College of General Practitioners; a response from the perspective of cardiology].
The Dutch College of General Practitioners (Dutch acronym: NHG) practice guideline 'Stable angina pectoris' (second revision) provides a clear insight into the anamnesis, diagnosis and treatment of patients with stable angina pectoris. However, we would like the guideline to include more information about the indication areas for additional tests: these tests can also be useful for patients with less than a 30% risk or more than a 70% risk of significant obstructive coronary disease. The same applies for an exercise ECG or possible pharmacological stress tests for patients with ischaemia during rest or a left bundle branch block. Further, angiotensin-converting enzyme inhibitors can be effective as a form of secondary prevention among patients with stable angina pectoris who also have diabetes mellitus and/or a reduced left ventricular function.


Stress and puerperal psychosis.
Eighty-eight in-patients admitted to a psychiatric mother-and-baby unit and 80 randomly selected recently delivered women in the general population were interviewed using the LEDS. Only five of 33 patients (15%) with puerperal psychosis had provoking agents, which is less than the figure for women in the community (36%). Provoking agents were present in only 8 of 25 patients with post-natal depression, but they were present in seven of nine patients with pre-natal depression and eight of nine women in the community with pre-natal depression.


Restoration by vacuum inflation of original alveolar dimensions in small human lung specimens.
Resection of lung specimens results in deflated and distorted lung structures. If no major airway is present (as in the case of small lung specimens from biopsies), lung dimensions cannot be restored by inflation under 25 cmH20. This impedes morphological analysis of the tissue. This report describes a simple and easy procedure to restore alveolar dimensions in deflated small lung specimens. Small human lung samples were inflated using moderate vacuum conditions which are provided by a common water stream-driven vacuum device. Restoration of alveolar dimensions and morphology was evaluated for paraffin-embedded as well as frozen tissue, using morphometric and immunohistological analysis. Vacuum inflation results in restoration of original lung dimensions as judged by light and scanning electron microscopy, and by analysis of the mean linear intercept, and the average length, width, perimeter and surface area. It also results in markedly improved cutting characteristics, allowing reliable sectioning of 2 microm cryosections and achieving high resolution images in immunofluorescence. Vacuum inflation is a simple and easy procedure to restore lung architecture of small human lung specimens/biopsies with a concomitant improvement of cutting characteristics. It allows for correct histological analysis of small specimens which cannot be inflated otherwise.


Benefits of treating highly disabled migraine patients with zolmitriptan while pain is mild.
Clinical trials of migraine therapy often require treatment when migraine pain intensity is moderate or severe, but many physicians find this practice artificial and patients often prefer to treat while pain is mild. This randomized, placebo-controlled study assessed the efficacy of zolmitriptan 2.5 mg in treating migraine while pain is mild, in patients who typically experience migraine attacks that are initially mild, but progress to moderate or severe. The intent-to-treat population comprised 280 patients (138 zolmitriptan; 148 placebo), with mean MIDAS grades of 29.6 (zolmitriptan) and 27.6 (placebo). Zolmitriptan 2.5 mg provided a significantly higher pain-free rate at 2 h (43.4% vs. 18.4% placebo; P < 0.0001). Significantly fewer zolmitriptan patients reported progression of headache pain to moderate or severe intensity 2 h postdose (53.7% vs. 70.4% placebo; P < 0.01), or required further medication within 24 h (46.4% vs. 71.1% placebo; P < 0.0001). The efficacy of zolmitriptan was more pronounced in patients treating during the first 15 min following pain onset. Adverse events were reported in 31.2% of patients treated with zolmitriptan (vs. 11.3% for placebo), and the incidence was lower in patients who treated early after attack onset. Zolmitriptan provides high efficacy when treating migraine while pain is mild, with the clinical benefits being more pronounced when treating early after migraine onset.


Isolated gallbladder rupture following blunt abdominal trauma.
The gallbladder is a relatively well-protected organ; consequently its rupture following blunt abdominal injury is rare and usually associated with other visceral injuries. Isolated gallbladder rupture is extremely rare. We report a healthy Nigerian adult male who sustained isolated gallbladder rupture following blunt abdominal injury from riding a motor cycle (Okada). A high index of suspicion with positive bile aspirate might lead to early diagnosis. Open cholecystectomy is a safe option of treatment in a resource poor centre especially in delayed presentation and has a good outcome.


Dynamic range of quadrature radio-frequency time-integrating acousto-optic correlator.
A new time-integrating acousto-optic correlator (TIAOC) was developed. It combines relatively low complexity with an exceedingly wideband of signals analyzed. The main feature of the architecture is the use of the light beams interference to provide the quadrature processing channel. The dynamic range (DR) of the new TIAOC is calculated for the active and passive operating modes. Parameter optimization to achieve the maximum DR is performed. The photodetector charge handling capacity is shown to be the main DR limiter.


[Hygienic assessment of actual nutrition in Kuzbass miners].
The paper deals with nutrition and heath in Kuzbass miners. Studies were conducted in the Berezovskaya and Percomayskaya mines in the town of Berezovsk, Kemerovo Region. The actual nutrition was studied in 500 underground workers, by using a 24-hour reproduction method. The macrostructure of food intake by Kuzbass miners and the density of their daily rations were not shown to be in compliance with hygienic recommendations. This creates prerequisites for inadequate intake of nutrients and biologically active substances. Risks of inadequate provision with essential nutrients and biologically active substances are defined. It is necessary to develop miners' nutrition optimizing measures including hygienic nutrition education.


Effects of external protons on single cardiac sodium channels from guinea pig ventricular myocytes.
The effects of external protons on single sodium channel currents recorded from cell-attached patches on guinea pig ventricular myocytes were investigated. Extracellular protons reduce single channel current amplitude in a dose-dependent manner, consistent with a simple rapid channel block model where protons bind to a site within the channel with an apparent pKH of 5.10. The reduction in single channel current amplitude by protons is voltage independent between -70 and -20 mV. Increasing external proton concentration also shifts channel gating parameters to more positive voltages, consistent with previous macroscopic results. Similar voltage shifts are seen in the steady-state inactivation (h infinity) curve, the time constant for macroscopic current inactivation (tau h), and the first latency function describing channel activation. As pHo decreases from 7.4 to 5.5 the midpoint of the h infinity curve shifts from -107.6 +/- 2.6 mV (mean +/- SD, n = 16) to -94.3 +/- 1.9 mV (n = 3, P less than 0.001). These effects on channel gating are consistent with a reduction in negative surface potential due to titration of negative external surface charge. The Gouy-Chapman-Stern surface charge model incorporating specific proton binding provides an excellent fit to the dose-response curve for the shift in the midpoint of the h infinity curve with protons, yielding an estimate for total negative surface charge density of -1e/490 A2 and a pKH for proton binding of 5.16. By reducing external surface Na+ concentration, titration of negative surface charge can also quantitatively account for the reduction in single Na+ channel current amplitude, although we cannot rule out a potential role for channel block. Thus, titration by protons of a single class of negatively charged sites may account for effects on both single channel current amplitude and gating.


Fourier-domain optical coherence tomography imaging of gas tamponade following macular hole surgery.
In this prospective study, the authors report fourier-domain optical coherence tomography (FD-OCT) imaging of gas-inner retinal tamponade following surgery for full-thickness macular hole and evaluate postoperative posturing based on FD-OCT findings. Patients underwent FD-OCT 1 day after pars plana vitrectomy, internal limiting membrane peel, and gas injection. Three-dimensional FD-OCT and high-resolution line scans demonstrated gas-inner retinal tamponade across the macula with the apex of tamponade located at the fovea. Inner and outer retina landmarks could be accurately identified along the curvature of the eye using FD-OCT in x-, y-, and z-planes. No patients required face-down positioning postoperatively based on FD-OCT findings. Satisfactory gas-inner retinal tamponade with 75% fill of any gas agent in the upright position was observed. Full-thickness macular hole closure was successful in 90% at 1 day, 2 weeks, and 12 weeks postoperatively. These FD-OCT findings may support decisions to not require face-down positioning postoperatively.


Interval between onset of psoriasis and psoriatic arthritis comparing the UK Clinical Practice Research Datalink with a hospital-based cohort.
To describe the time interval between the onset of psoriasis and PsA in the UK primary care setting and compare with a large, well-classified secondary care cohort. Patients with PsA and/or psoriasis were identified in the UK Clinical Practice Research Datalink (CPRD). The secondary care cohort comprised patients from the Bath PsA longitudinal observational cohort study. For incident PsA patients in the CPRD who also had a record of psoriasis, the time interval between PsA diagnosis and first psoriasis record was calculated. Comparisons were made with the time interval between diagnoses in the Bath cohort. There were 5272 eligible PsA patients in the CPRD and 815 in the Bath cohort. In both cohorts, the majority of patients (82.3 and 61.3%, respectively) had psoriasis before their PsA diagnosis or within the same calendar year (10.5 and 23.8%), with only a minority receiving their PsA diagnosis first (7.1 and 14.8%). Excluding those who presented with arthritis before psoriasis, the median time between diagnoses was 8 years [interquartile range (IQR) 2-15] in the CPRD and 7 years (IQR 0-20) in the Bath cohort. In the CPRD, 60.1 and 75.1% received their PsA diagnosis within 10 and 15 years of their psoriasis diagnosis, respectively; this was comparable with 57.2 and 67.7% in the Bath cohort. A similar distribution for the time interval between psoriasis and arthritis was observed in the CPRD and secondary care cohort. These data can inform screening strategies and support the validity of data from each cohort.


Double frequency grating lateral shear interferometer.
A simple grating lateral shear interferometer is described that can be made to give simultaneously two interferograms having shear in two orthogonal directions. The shear for the two orthogonal directions is produced in one plane by one double frequency crossed diffraction grating that can easily be produced holographically. Translating the grating sideways causes the irradiance of the interferogram to vary sinusoidally with time enabling the interferometer to be used with real-time heterodyne phase detection.


Antioxidant and anti-diabetic potential of Passiflora alata Curtis aqueous leaves extract in type 1 diabetes mellitus (NOD-mice).
Leaves of Passiflora alata Curtis were characterized for their antioxidant capacity. Antioxidant analyses of DPPH, FRAP, ABTS, ORAC and phenolic compounds were made in three different extracts: aqueous, methanol/acetone and ethanol. Aqueous extract was found to be the best solvent for recovery of phenolic compounds and antioxidant activity, when compared with methanol/acetone and ethanol. To study the anti-inflammatory properties of this extract in experimental type 1 diabetes, NOD mice were divided into two groups: the P. alata group, treated with aqueous extract of P. alata Curtis, and a non-treated control group, followed by diabetes expression analysis. The consumption of aqueous extract and water ad libitum lasted 28 weeks. The treated-group presented a decrease in diabetes incidence, a low quantity of infiltrative cells in pancreatic islets and increased glutathione in the kidney and liver (p<0.05), when compared with the diabetic and non-diabetic control-groups. In conclusion, our results suggest that the consumption of aqueous extract of P. alata may be considered a good source of natural antioxidants and compounds found in its composition can act as anti-inflammatory agents, helping in the control of diabetes.


HIV-associated psoriasis: Epidemiology, pathogenesis, and management.
People living with HIV (PLWH) are affected by a higher incidence skin disorders, which are often associated with high morbidity and mortality. In particular, psoriasis affects PLWH severely and for a longer time than the general population. Human immunodeficiency virus (HIV) infection is characterized by a progressive decrease in CD4+ T-cell count, and it could seem paradoxical that psoriasis exacerbations are more frequent in this subset of patients than the general population, even though it is commonly observed at any stage of infection. For a long time, there have been limited therapeutic choices for PLWH affected by psoriasis. The introduction of the combined antiretroviral therapy dramatically changed the natural course of both HIV and psoriasis in PLWH, leading to an improvement of quality and duration of life. However, the clinical severity of psoriasis in PLWH often requires the use of immunosuppressant drugs. Knowledge about their safety and efficacy are limited to case-reports, small case-series and studies, therefore their use has not yet entered the routine. Further studies are needed to determine if immunosuppressive drugs can be safely and effectively used in PLWH affected by psoriasis and other autoimmune disorders.


The safety of vedolizumab for ulcerative colitis and Crohn's disease.
Vedolizumab is a gut-selective antibody to α4β7 integrin for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We report an integrated summary of the safety of vedolizumab. Safety data (May 2009-June 2013) from six trials of vedolizumab were integrated. Adverse events were evaluated in patients who received ≥1 dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Predictors of serious infection were assessed using a Cox proportional hazards model. In total, 2830 patients had 4811 PYs of vedolizumab exposure (median exposure range, 1-1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). No cases of progressive multifocal leucoencephalopathy were observed. Independent risk factors for serious infection in UC were prior failure of a tumour necrosis factor α antagonist (HR, 1.99; 95% CIs 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003), and in CD were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p<0.0001), corticosteroid (HR, 1.88; 95% CI 1.35 to 2.63; p=0.0002) or narcotic analgesic use (HR, 2.72; 95% CI 1.90 to 3.89; p<0.0001). Investigator-defined infusion-related reactions were reported for ≤5% of patients in each study. Eighteen vedolizumab-exposed patients (<1%) were diagnosed with a malignancy. Vedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period. NCT01177228, NCT00619489, NCT00783718, NCT00783692, NCT01224171, NCT00790933.


Veterinary practice, competition and advertising: 1985-1994.
In 1985, members of the veterinary profession and four other professional groups in New Zealand were surveyed to establish their attitudes towards the developing commercialisation of their professions, and particularly towards advertising. This survey was repeated in 1988, and again in 1994. The results of the three surveys are presented in this paper. There was a sharp movement towards acceptance of advertising, and toward a competitive orientation in general, between 1985 and 1988, with a consolidation of these changes during the following 6 years. The acceptance of the idea of an openly competitive profession now has widespread support among veterinarians. Similarly, there is general support for the use of most kinds of informative advertising, with many practitioners viewing advertising as a business building tool, but with the advertising of fees remaining an area over which there is still considerable caution. Although clients are seen as more demanding than in the past, the client-practitioner relationship is still expected to be an enduring one. We suggest that, in view of the relaxed attitudes towards advertising that now exists among members of the veterinary profession, control of advertising should cease to be a concern to the profession.


Operationalisation and validation of the Stopping Elderly Accidents, Deaths, and Injuries (STEADI) fall risk algorithm in a nationally representative sample.
Preventing falls and fall-related injuries among older adults is a public health priority. The Stopping Elderly Accidents, Deaths, and Injuries (STEADI) tool was developed to promote fall risk screening and encourage coordination between clinical and community-based fall prevention resources; however, little is known about the tool's predictive validity or adaptability to survey data. Data from five annual rounds (2011-2015) of the National Health and Aging Trends Study (NHATS), a representative cohort of adults age 65 years and older in the USA. Analytic sample respondents (n=7392) were categorised at baseline as having low, moderate or high fall risk according to the STEADI algorithm adapted for use with NHATS data. Logistic mixed-effects regression was used to estimate the association between baseline fall risk and subsequent falls and mortality. Analyses incorporated complex sampling and weighting elements to permit inferences at a national level. Participants classified as having moderate and high fall risk had 2.62 (95% CI 2.29 to 2.99) and 4.76 (95% CI 3.51 to 6.47) times greater odds of falling during follow-up compared with those with low risk, respectively, controlling for sociodemographic and health-related risk factors for falls. High fall risk was also associated with greater likelihood of falling multiple times annually but not with greater risk of mortality. The adapted STEADI clinical fall risk screening tool is a valid measure for predicting future fall risk using survey cohort data. Further efforts to standardise screening for fall risk and to coordinate between clinical and community-based fall prevention initiatives are warranted.


Cardiovascular and sensory responses to forearm ischemia and dynamic hand exercise.
The relationship between cardiovascular responses and pain produced by the submaximal-effort tourniquet procedure was evaluated in healthy humans. Graded increases in ischemic pain were associated with graded elevations in arterial blood pressure, forearm vascular resistance, and venous tone. Many of the vascular responses to muscle ischemia were typical of the cardiovascular components of the defense reaction and correlated with both the sensory and affective aspects of ischemic pain. The cardiovascular responses to arm ischemia were distinguishable from those produced by rhythmic hand exercise used to produce ischemia. Dynamic hand exercise produced a transient increase in arterial blood pressure, heart rate, and measures of hand discomfort. These responses were enhanced when dynamic hand exercise was conducted under ischemic conditions. The tightly coupled and coordinated cardiovascular responses elicited by ischemic pain represent integrated adaptive responses to painful stimulation.


Detection and Management of Diabetes in England: Results from the Health Survey for England.
As part of a control strategy current guidance in the UK recommends more intense surveillance of HbA1C levels among those of South-east Asian or Chinese ethnicity above specified BMI thresholds. The objective of this study was to determine whether disparities in the identification and control of diabetes in England persisted despite these guidelines and assess current strategies in light of these findings. Data were extracted from the 2013 Health Survey for England that included ethnicity, BMI status and HbA1C levels. Descriptive statistics and logistic regression analyses were used to examine relationships among undetected diabetes, poorly controlled diabetes and a range of covariates including ethnicity and BMI. Concentration indices were used to examine the socio-economic gradient in disease detection and control among and between ethnic groups. In regression models that controlled for a range of covariates Asians were found to have a 5% point higher risk of undetected diabetes than Whites. With respect to disease management, Bangladeshis and Pakistanis were found to be at a 28% point and 21% point higher risk of poor disease control respectively than Whites. Concentration indices revealed better disease control among more affluent Whites than poor Whites, no significant pattern between income and disease management was found among Pakistanis and poorer disease control was more evident among more affluent than poorer Bangladeshis. In the UK current guidance recommends practitioners consider testing for diabetes among South-east Asians and Chinese where BMI exceeds 23. Our findings suggest that the risk experienced by Asians in disease detection is independent of BMI and may warrant a more active screening policy than currently recommended. With respect to disease management, our findings suggest that Indians and Pakistanis experience particularly high levels of poor disease control that may also be usefully reflected in guidance.


Necrosis of a pulmonary lobe in a dog.
A six-year old female pug had very severe dysponea. A radiographic opacity was observed in the right cranial area of the thorax. After thoracotomy, the cranial lobe of the lung was removed. Microscopic examination revealed necrosis of the lung and vacular thrombosis. The possibility of a torsion of the affected lobe is discussed.


Pediatric renal transplantation: indications and special considerations. A position paper from the Pediatric Committee of the American Society of Transplant Physicians.
Renal transplantation of children with chronic renal insufficiency (CRI) and end-stage renal disease (ESRD) appears to be the optimal form of renal replacement therapy. This report, which expresses the opinions of the nephrology members of the Pediatric Committee of the American Society of Transplant Physicians, discusses the indications for pediatric renal transplantation and identifies the unique aspects of caring for children with CRI and ESRD. Indications for pediatric renal transplantation include: 1) symptoms of uremia not responsive to standard therapy; 2) failure to thrive due to limitations in total caloric intake; 3) delayed psychomotor development; 4) hypervolemia; 5) hyperkalemia; and 6) metabolic bone disease due to renal osteodystrophy. The urgency and timing of renal transplantation in children must be considered in the context of a number of issues unique to children with CRI and ESRD such as delayed cognitive and educational performance, growth retardation, delayed puberty, etiology of ESRD, and timing of immunizations. In addition, these children frequently display various inherited and sporadic syndromes with multiorgan involvement requiring the expertise of a variety of pediatric subspecialists including the pediatric urologist, who plays a critical role in the evaluation of children with obstructive uropathy and other anomalies of the genito-urinary system. The advantages of a living-related donor are also delineated. The importance of adequate immunosuppression on graft function, early recognition of the signs and symptoms acute rejection, preventive strategies for minimizing the morbidity and mortality from viral infections in the post-transplant period, and the impact of transplantation on cognitive function, educational status, and catch-up growth are also discussed. To address these complex issues, transplant care of pediatric patients must be provided by a multidisciplinary team of pediatric health care professionals.


Molecular analysis of transferable tetracycline resistance plasmids from Clostridium perfringens.
Conjugative tetracycline resistance plasmids from 15 Clostridium perfringens isolates from piggeries were analyzed by restriction endonuclease digestion and agarose gel electrophoresis. Seven isolates from one farm were found to carry a 47-kilobase pair (kb) plasmid, pJIR5, which had EcoRI, XbaI, and ClaI profiles that were identical to those of a previously characterized plasmid, pCW3. An isolate from a second farm was found to carry a plasmid, pJIR6, which also was indistinguishable from pCW3. Five additional isolates from a third farm carried a 67-kb plasmid, pJIR2, which had at least 29 kb of DNA in common with pCW3. Finally, two isolates from a fourth farm were found to carry a 50-kb plasmid pJIR4, which appeared to consist of an entire pCW3 molecule with a 3-kb insertion. Comparative restriction maps of pCW3, pJIR2, and pJIR4 that identified the regions of homology among these plasmids were constructed. We suggest that many conjugative tetracycline resistance plasmids in C. perfringens may contain a pCW3-like core.


Sparsity-motivated automatic target recognition.
We present an automatic target recognition algorithm using the recently developed theory of sparse representations and compressive sensing. We show how sparsity can be helpful for efficient utilization of data for target recognition. We verify the efficacy of the proposed algorithm in terms of the recognition rate and confusion matrices on the well known Comanche (Boeing-Sikorsky, USA) forward-looking IR data set consisting of ten different military targets at different orientations.


Is menopause still evolving? Evidence from a longitudinal study of multiethnic populations and its relevance to women's health.
To reflect on the impact of changing patterns of delayed marriage and reproduction and to seek evidence as to whether menopause is still evolving, characteristics of the menopause transition were investigated within and between ethnic populations in this study. A cross-sectional analysis was conducted using data on 747 middle-aged women obtained from the Study of Women's Health Across the Nation (SWAN) from 1996 to 2008. The ethnic groups included: Afro-American, Chinese, Japanese, Caucasian, and Hispanic. Perimenopause age and duration, menopause age, and hormonal indicators of menopause were examined across five ethnicities. We found a similar window of menopause age within populations, but no significant difference in perimenopause and menopause age between populations. The rate of increase of follicle-stimulating hormone and testosterone differed significantly in Hispanics and African-Americans during the menopause transition period. The broad window of variation in age at menopause within the population and the absence of significant differences between populations, in combination with population variation in menopause symptoms, suggest that menopause is a relatively recently evolved and still evolving trait. Under the mate choice theory of menopause, menopause is the result of the accumulation of infertility mutations in older women due to men's preference for younger mates. We propose a shifting mate choice-shifting menopause model which posits that, as the age of mate choice/marriage shifts to older ages, so will the age at menopause, and that menopause is a transient phase of female fertility; it can de-evolve, be delayed, if not disappear completely. Integrated longitudinal menopausal studies linked with genomics and hormonal studies on diverse ethnic populations can provide valuable information bearing on women's health and personalized medicine.


The Genomic Context for the Evolution and Transmission of Community-Associated Staphylococcus aureus ST59 Through the Food Chain.
Sequence type 59 (ST59) is a predominant clonal lineage of community-acquired, methicillin-resistant Staphylococcus aureus (CA-MRSA) in Asia. Despite its increasing clinical relevance in China, the evolution and geographic expansion of ST59 has been relatively uncared for. Previous study has shown that ST59 was the predominant clone in food-related MRSA in China. This study compared the genomes of 87 clonal complex (CC) 59 S. aureus isolates sourced from food chain and infection cases to reconstruct the molecular evolution and geographical spread of ST59. Accordingly, three major sub-clades of ST59 were identified and these did not correlate with isolation source or location. Phylogenetic analysis estimated that ST59 in mainland China diverged from a most common recent ancestor around 1974, and most of the cases of cross-country transmission occurred between 1987 and 2000. Notably, two recent events of cross-country transmission through the food chain were observed, the isolates from these events diverged within relatively short time intervals. These isolates also showed high similarity in terms of their core genome, accessory genes, and antibiotic resistance patterns. These findings provide a valuable insight into the potential route of ST59 expansion in China and indicate a need for robust food chain surveillance to prevent the spread of this pathogen.


A Review on the State of the Art in Atrial Fibrillation Detection Enabled by Machine Learning.
Atrial Fibrillation (AF) the most commonly occurring type of cardiac arrhythmia is one of the main causes of morbidity and mortality worldwide. The timely diagnosis of AF is an equally important and challenging task because of its asymptomatic and episodic nature. In this paper, state-of-the-art ECG data-based machine learning models and signal processing techniques applied for auto diagnosis of AF are reviewed. Moreover, key biomarkers of AF on ECG and the common methods and equipment used for the collection of ECG data are discussed. Besides that, the modern wearable and implantable ECG sensing technologies used for gathering AF data are presented briefly. In the end, key challenges associated with the development of auto diagnosis solutions of AF are also highlighted. This is the first review paper of its kind that comprehensively presents a discussion on all these aspects related to AF auto-diagnosis in one place. It is observed that there is a dire need for low energy and low cost but accurate auto diagnosis solutions for the proactive management of AF.


The image of the "brain surgeon" in American culture: the influence of Harvey Cushing.
In contemporary American culture, the term "brain surgeon" conjures up the image of an intensely single-minded professional, who deals with terribly complex matters of life and death. These descriptors find their personification in Harvey Cushing, because they are derived directly from him. This hypothesis was tested by a complete search of the New York Times Index and the Reader's Guide to Periodical Literature for the years 1919 to 1942. All entries for Harvey Cushing were reviewed in the original sources. In the New York Times, Cushing's first significant exposure was in response to his winning a Pulitzer Prize in 1925. Major editorial coverage began in 1934, and was especially prominent with the publication of From a Surgeon's Journal in 1936. The process of lionizing Cushing by creating an overdrawn caricature reached its apotheosis in Time magazine in 1939. The Time article was actually a report of Cushing's 70th birthday party. It expounded all of the descriptors that are now associated with "brain surgeon". Thus, it was Cushing's literary skills that initially brought him recognition from editors who were arbiters of public opinion. This attention seems to have been the conduit to his mythologization by the larger public. Although unnamed, it is really Cushing's image that still persists as the prototypical "brain surgeon" in the collective American consciousness.


Association Between CYP17A1, CYB5A Polymorphisms and Efficacy of Abiraterone Acetate/Prednisone Treatment in Castration-Resistant Prostate Cancer Patients.
The purpose of this study was to investigate the association between single nucleotide polymorphisms (SNPs) of CYP17A1, CYB5A and the efficacy of abiraterone acetate treatment in patients with castration-resistant prostate cancer (CRPC). Data were collected from 58 CRPC patients who had been treated with abiraterone acetate/prednisone (AA/P). The SNPs rs743572 and rs10883783 on CYP17A1 and SNPs rs1790834 and rs1790858 on CYB5A were assayed, and their relationship with prostate-specific antigen (PSA) response in patients after AA/P treatment, overall survival (OS) and progression-free survival (PFS) were analyzed by logistic regression, Cox regression, Kaplan-Meier and Log rank analyses. The SNP rs1790834 on CYB5A showed significant association with PSA response in CRPC patients treated with AA/P (P < 0.05), but rs743572, rs10883783 and rs1790858 did not. The rs1790834 variant significantly decreased both PFS and OS (P < 0.05). The CYB5A rs790834 genotype is a novel SNP related to CRPC and may be used as a biomarker for CRPC treatment.


The application of deep brain stimulation in the treatment of psychiatric disorders.
Deep brain stimulation (DBS) is a last-resort treatment for neurological and psychiatric disorders that are refractory to standard treatment. Over the last decades, the progress of DBS in psychiatry has been slower than in neurology, in part owing to the heterogenic symptomatology and complex neuroanatomy of psychiatric disorders. However, for obsessive-compulsive disorder (OCD) DBS is now an accepted treatment. This study first reviews clinical outcomes and mechanisms of DBS for OCD, and then discusses these results in an overview of current and future psychiatric applications, including DBS for mood disorders, Tourette's syndrome, addiction, anorexia nervosa, autism, schizophrenia, and anxiety disorders. In addition, it will focus on novel techniques that may enhance the application of DBS in psychiatry.


Ursolic Acid and Its Nanoparticles Are Potentiators of Oncolytic Measles Virotherapy against Breast Cancer Cells.
Oncolytic viruses (OVs) and phytochemical ursolic acid (UA) are two efficacious therapeutic candidates in development against breast cancer, the deadliest women's cancer worldwide. However, as single agents, OVs and UA have limited clinical efficacies. As a common strategy of enhancing monotherapeutic anticancer efficacy, we explored the combinatorial chemovirotherapeutic approach of combining oncolytic measles virus (MV), which targets the breast tumor marker Nectin-4, and the anticancer UA against breast adenocarcinoma. Our findings revealed that in vitro co-treatment with UA synergistically potentiated the killing of human breast cancer cells by oncolytic MV, without UA interfering the various steps of the viral infection. Mechanistic studies revealed that the synergistic outcome from the combined treatment was mediated through UA's potentiation of apoptotic killing by MV. To circumvent UA's poor solubility and bioavailability and strengthen its clinical applicability, we further developed UA nanoparticles (UA-NP) by nanoemulsification. Compared to the non-formulated UA, UA-NP exhibited improved drug dissolution property and similarly synergized with oncolytic MV in inducing apoptotic breast cancer cell death. This oncolytic potentiation was partly attributed to the enhanced autophagic flux induced by the UA-NP and MV combined treatment. Finally, the synergistic effect from the UA-NP and MV combination was also observed in BT-474 and MDA-MB-468 breast cancer cells. Our study thus highlights the potential value of oncolytic MV and UA-based chemovirotherapy for further development as a treatment strategy against breast cancer, and the feasibility of employing nanoformulation to enhance UA's applicability.