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On 17 August 2017, gravitational waves (GWs) were detected from a binary neutron star merger, GW170817, along with a coincident short gamma-ray burst, GRB 170817A. An optical transient source, Swope Supernova Survey 17a (SSS17a), was subsequently identified as the counterpart of this event. We present ultraviolet, optical, and infrared light curves of SSS17a extending from 10.9 hours to 18 days postmerger. We constrain the radioactively powered transient resulting from the ejection of neutron-rich material. The fast rise of the light curves, subsequent decay, and rapid color evolution are consistent with multiple ejecta components of differing lanthanide abundance. The late-time light curve indicates that SSS17a produced at least ~0.05 solar masses of heavy elements, demonstrating that neutron star mergers play a role in rapid neutron capture (r-process) nucleosynthesis in the universe., (Copyright © 2017, American Association for the Advancement of Science.)

Eleven hours after the detection of gravitational wave source GW170817 by the Laser Interferometer Gravitational-Wave Observatory and Virgo Interferometers, an associated optical transient, SSS17a, was identified in the galaxy NGC 4993. Although the gravitational wave data indicate that GW170817 is consistent with the merger of two compact objects, the electromagnetic observations provide independent constraints on the nature of that system. We synthesize the optical to near-infrared photometry and spectroscopy of SSS17a collected by the One-Meter Two-Hemisphere collaboration, finding that SSS17a is unlike other known transients. The source is best described by theoretical models of a kilonova consisting of radioactive elements produced by rapid neutron capture (the r-process). We conclude that SSS17a was the result of a binary neutron star merger, reinforcing the gravitational wave result., (Copyright © 2017, American Association for the Advancement of Science.)

Cases of human dirofilariasis have been reported in several countries around the world, including a large number in the Atlantic and Gulf Coast regions of the United States. Most commonly, these cases have subcutaneous or pulmonary involvement; however, there have been few reports of dirofilariasis involving structures such as large vessels, mesentery, the spermatic cord, and liver. We present a case of an unusual presentation of human dirofilariasis presenting as a shoulder abscess and what is presumed to be pulmonary and splenic involvement in a 55-year-old female.

In 1964, Refsdal hypothesized that a supernova whose light traversed multiple paths around a strong gravitational lens could be used to measure the rate of cosmic expansion. We report the discovery of such a system. In Hubble Space Telescope imaging, we have found four images of a single supernova forming an Einstein cross configuration around a redshift z = 0.54 elliptical galaxy in the MACS J1149.6+2223 cluster. The cluster's gravitational potential also creates multiple images of the z = 1.49 spiral supernova host galaxy, and a future appearance of the supernova elsewhere in the cluster field is expected. The magnifications and staggered arrivals of the supernova images probe the cosmic expansion rate, as well as the distribution of matter in the galaxy and cluster lenses., (Copyright © 2015, American Association for the Advancement of Science.)

Type Iax supernovae are stellar explosions that are spectroscopically similar to some type Ia supernovae at the time of maximum light emission, except with lower ejecta velocities. They are also distinguished by lower luminosities. At late times, their spectroscopic properties diverge from those of other supernovae, but their composition (dominated by iron-group and intermediate-mass elements) suggests a physical connection to normal type Ia supernovae. Supernovae of type Iax are not rare; they occur at a rate between 5 and 30 per cent of the normal type Ia rate. The leading models for type Iax supernovae are thermonuclear explosions of accreting carbon-oxygen white dwarfs that do not completely unbind the star, implying that they are 'less successful' versions of normal type Ia supernovae, where complete stellar disruption is observed. Here we report the detection of the luminous, blue progenitor system of the type Iax SN 2012Z in deep pre-explosion imaging. The progenitor system's luminosity, colours, environment and similarity to the progenitor of the Galactic helium nova V445 Puppis suggest that SN 2012Z was the explosion of a white dwarf accreting material from a helium-star companion. Observations over the next few years, after SN 2012Z has faded, will either confirm this hypothesis or perhaps show that this supernova was actually the explosive death of a massive star.

Sarcoid-like granulomatous lung disease (SLGLD) is a condition associated with the formation of noncaseating, nonnecrotizing granulomas. The final by-product of airbag deployment is alkaline silicates or glass. Silicates trapped and sequestered in the lung parenchyma are a potential mediator for immune system activation and development of sarcoid-like granulomatous lung disease.

Super-luminous supernovae that radiate more than 10(44) ergs per second at their peak luminosity have recently been discovered in faint galaxies at redshifts of 0.1-4. Some evolve slowly, resembling models of 'pair-instability' supernovae. Such models involve stars with original masses 140-260 times that of the Sun that now have carbon-oxygen cores of 65-130 solar masses. In these stars, the photons that prevent gravitational collapse are converted to electron-positron pairs, causing rapid contraction and thermonuclear explosions. Many solar masses of (56)Ni are synthesized; this isotope decays to (56)Fe via (56)Co, powering bright light curves. Such massive progenitors are expected to have formed from metal-poor gas in the early Universe. Recently, supernova 2007bi in a galaxy at redshift 0.127 (about 12 billion years after the Big Bang) with a metallicity one-third that of the Sun was observed to look like a fading pair-instability supernova. Here we report observations of two slow-to-fade super-luminous supernovae that show relatively fast rise times and blue colours, which are incompatible with pair-instability models. Their late-time light-curve and spectral similarities to supernova 2007bi call the nature of that event into question. Our early spectra closely resemble typical fast-declining super-luminous supernovae, which are not powered by radioactivity. Modelling our observations with 10-16 solar masses of magnetar-energized ejecta demonstrates the possibility of a common explosion mechanism. The lack of unambiguous nearby pair-instability events suggests that their local rate of occurrence is less than 6 × 10(-6) times that of the core-collapse rate.

Background: An enduring question surrounding sex chromosome evolution is whether effective hemizygosity in the heterogametic sex leads inevitably to dosage compensation of sex-linked genes, and whether this compensation has been observed in a variety of organisms. Incongruence in the conclusions reached in some recent reports has been attributed to different high-throughput approaches to transcriptome analysis. However, recent reports each utilizing RNA-seq to gauge X-linked gene expression relative to autosomal gene expression also arrived at diametrically opposed conclusions regarding X chromosome dosage compensation in mammals., Results: Here we analyze RNA-seq data from X-monosomic female human and mouse tissues, which are uncomplicated by genes that escape X-inactivation, as well as published RNA-seq data to describe relative X expression (RXE). We find that the determination of RXE is highly dependent upon a variety of computational, statistical and biological assumptions underlying RNA-seq analysis. Parameters implemented in short-read mapping programs, choice of reference genome annotation, expression data distribution, tissue source for RNA and RNA-seq library construction method have profound effects on comparing expression levels across chromosomes., Conclusions: Our analysis shows that the high number of paralogous gene families on the mammalian X chromosome relative to autosomes contributes to the ambiguity in RXE calculations, RNA-seq analysis that takes into account that single- and multi-copy genes are compensated differently supports the conclusion that, in many somatic tissues, the mammalian X is up-regulated compared to the autosomes.

In the cores of some clusters of galaxies the hot intracluster plasma is dense enough that it should cool radiatively in the cluster's lifetime, leading to continuous 'cooling flows' of gas sinking towards the cluster centre, yet no such cooling flow has been observed. The low observed star-formation rates and cool gas masses for these 'cool-core' clusters suggest that much of the cooling must be offset by feedback to prevent the formation of a runaway cooling flow. Here we report X-ray, optical and infrared observations of the galaxy cluster SPT-CLJ2344-4243 (ref. 11) at redshift z = 0.596. These observations reveal an exceptionally luminous (8.2 × 10(45) erg s(-1)) galaxy cluster that hosts an extremely strong cooling flow (around 3,820 solar masses a year). Further, the central galaxy in this cluster appears to be experiencing a massive starburst (formation of around 740 solar masses a year), which suggests that the feedback source responsible for preventing runaway cooling in nearby cool-core clusters may not yet be fully established in SPT-CLJ2344-4243. This large star-formation rate implies that a significant fraction of the stars in the central galaxy of this cluster may form through accretion of the intracluster medium, rather than (as is currently thought) assembling entirely via mergers.

The flare of radiation from the tidal disruption and accretion of a star can be used as a marker for supermassive black holes that otherwise lie dormant and undetected in the centres of distant galaxies. Previous candidate flares have had declining light curves in good agreement with expectations, but with poor constraints on the time of disruption and the type of star disrupted, because the rising emission was not observed. Recently, two 'relativistic' candidate tidal disruption events were discovered, each of whose extreme X-ray luminosity and synchrotron radio emission were interpreted as the onset of emission from a relativistic jet. Here we report a luminous ultraviolet-optical flare from the nuclear region of an inactive galaxy at a redshift of 0.1696. The observed continuum is cooler than expected for a simple accreting debris disk, but the well-sampled rise and decay of the light curve follow the predicted mass accretion rate and can be modelled to determine the time of disruption to an accuracy of two days. The black hole has a mass of about two million solar masses, modulo a factor dependent on the mass and radius of the star disrupted. On the basis of the spectroscopic signature of ionized helium from the unbound debris, we determine that the disrupted star was a helium-rich stellar core.

η Carinae is one of the most massive binary stars in the Milky Way. It became the second-brightest star in our sky during its mid-nineteenth-century 'Great Eruption', but then faded from view (with only naked-eye estimates of brightness). Its eruption is unique in that it exceeded the Eddington luminosity limit for ten years. Because it is only 2.3 kiloparsecs away, spatially resolved studies of the nebula have constrained the ejected mass and velocity, indicating that during its nineteenth-century eruption, η Car ejected more than ten solar masses in an event that released ten per cent of the energy of a typical core-collapse supernova, without destroying the star. Here we report observations of light echoes of η Carinae from the 1838-1858 Great Eruption. Spectra of these light echoes show only absorption lines, which are blueshifted by -210 km s(-1), in good agreement with predicted expansion speeds. The light-echo spectra correlate best with those of G2-to-G5 supergiants, which have effective temperatures of around 5,000 kelvin. In contrast to the class of extragalactic outbursts assumed to be analogues of the Great Eruption of η Carinae, the effective temperature of its outburst is significantly lower than that allowed by standard opaque wind models. This indicates that other physical mechanisms such as an energetic blast wave may have triggered and influenced the eruption.

Pulmonary embolism (PE), most commonly originating from thrombosis in the deep venous system of the lower extremities, remains a controversial area of medicine that frequently generates lively debate. Its clinical presentation varies from asymptomatic, incidentally detected pulmonary emboli to massive embolism resulting in sudden death. Despite the advances made in recent years, a number of fundamental questions remain unanswered regarding the pathogenesis, clinical presentation, diagnosis and treatment of this disease. The diagnosis of PE is confounded by a presentation that may be subtle, atypical, or obscured by a concomitant condition. Safe, minimally invasive techniques have been developed to improve the diagnostic accuracy of the clinical evaluation, and obviate the need to obtain pulmonary arteriography in all but a minority of patients. However, no single diagnostic test is sufficiently sensitive or specific for diagnosis in all patients. This dilemma has resulted in the development of numerous clinical scoring systems to stratify risk, pretest probability and help guide an appropriate diagnostic approach. Anticoagulation therapy with unfractionated heparin (UFH), low molecular weight heparin (LMWH), and Factor Xa inhibitors are the mainstay of therapy for acute PE. The choice of agent is influenced by disease severity, presence or absence of provokingfactors, patient comorbidities, and bleeding risk. These factors also determine whether measures such as thrombectomy, thrombolysis and vena cava filter placement may be employed as adjuncts to anticoagulation. Warfarin is the agent of choice for secondary prevention; newer agents such as direct thrombin and factor Xa inhibitors are emerging as safe and effective alternatives.

Pulmonary arterial hypertension (PAH) is a disease that leads to characteristic vascular wall remodeling and hemodynamic alterations. Consequently, this pulmonary vascular disease contributes to substantial morbidity and mortality in afflicted patients. PAH may be idiopathic in nature or associated with connective tissue disease, chronic liver disease, human immunodeficiency virus, congenital heart disease, and a growing list of other conditions. There are currently nine Food and Drug Administration-approved therapies for specific PAH treatment. Therapeutic targets include prostacyclin replacement, endothelin-1 antagonism, and phosphodiesterase-5 inhibition. This article focuses on the prostanoid treprostinil and explores its role in the management of patients with PAH.

We present an interesting case of tracheobronchial foreign body aspiration. A 29-year-old healthy female, with no history of pulmonary disease, presented on multiple occasions to healthcare providers with wheezing and cough. She was repeatedly diagnosed and treated for asthma with acute exacerbations. Upon further evaluation, the patient was subsequently found to have a tracheobronchial foreign body causing her symptoms. This case report highlights a clinical approach to wheezing illnesses and reviews the diagnosis and management of tracheobronchial foreign body aspiration.

Type Ia supernovae are key tools for measuring distances on a cosmic scale. They are generally thought to be the thermonuclear explosion of an accreting white dwarf in a close binary system. The nature of the mass donor is still uncertain. In the single-degenerate model it is a main-sequence star or an evolved star, whereas in the double-degenerate model it is another white dwarf. We show that the velocity structure of absorbing material along the line of sight to 35 type Ia supernovae tends to be blueshifted. These structures are likely signatures of gas outflows from the supernova progenitor systems. Thus, many type Ia supernovae in nearby spiral galaxies may originate in single-degenerate systems.

Background: Idiopathic pulmonary arterial hypertension (IPAH) is increasingly being diagnosed in patients of advanced years. We sought to investigate observed vs expected mortality among geriatric IPAH patients treated with specific pulmonary arterial hypertension (PAH) therapy., Methods: From the University of Connecticut's Pulmonary Vascular Disease Program database, 20 IPAH patients over 65 years of age were identified. Patient demographics, cardiopulmonary hemodynamics, PAH therapy, and mortality were retrospectively analyzed. Based on observed follow-up time, the probability of death was calculated for each subject using a prediction formula for PAH patients developed by the National Institutes of Health (NIH). Byar's method for Poisson counts was used to compare observed and expected tallies of deaths within the study sample. A P value < or = 0.05 was considered statistically significant., Results: The mean age of the 20 geriatric IPAH patients was 77 years (+/- 6.6) of which 70% were female. The mean cardiopulmonary hemodynamic values for the cohort were: right atrial pressure: 10 mmHg (+/- 4); mean pulmonary artery pressure: 45 mmHg (+/- 9); pulmonary artery occlusion pressure: 11 mmHg (+/- 3); cardiac output: 4.1 L/min (+/- 1.2); cardiac index: 2.3 L/min (+/- 0.5); and pulmonary vascular resistance: 712 dynes / sec / cm-5 (+/- 319). Fourteen subjects received PAH monotherapy with bosentan, sildenafil, or epoprostenol. Six subjects received PAH combination therapy with bosentan, sildenafil, iloprost, or treprostinil. Total follow-up across the 20 subjects was 58.7 years, with average follow-up of 2.9 yrs (+/- 1.7) per subject. Based upon the NIH formula, the expected number of deaths for this cohort was 9.4. During follow-up, three deaths actually occurred. Thus, observed mortality was only 31.9% of expected (P = 0.03, 95% C.I. = [6.4%, 93.2%])., Conclusion: Geriatric patients are increasingly being diagnosed with IPAH. Efficacy of PAH therapy in geriatric patients is unknown. In this cohort of subjects, the outcomes of older adults treated with specific PAH therapy demonstrates improved survival relative to that predicted by the NIH formula.

Supernovae are thought to arise from two different physical processes. The cores of massive, short-lived stars undergo gravitational core collapse and typically eject a few solar masses during their explosion. These are thought to appear as type Ib/c and type II supernovae, and are associated with young stellar populations. In contrast, the thermonuclear detonation of a carbon-oxygen white dwarf, whose mass approaches the Chandrasekhar limit, is thought to produce type Ia supernovae. Such supernovae are observed in both young and old stellar environments. Here we report a faint type Ib supernova, SN 2005E, in the halo of the nearby isolated galaxy, NGC 1032. The 'old' environment near the supernova location, and the very low derived ejected mass ( approximately 0.3 solar masses), argue strongly against a core-collapse origin. Spectroscopic observations and analysis reveal high ejecta velocities, dominated by helium-burning products, probably excluding this as a subluminous or a regular type Ia supernova. We conclude that it arises from a low-mass, old progenitor, likely to have been a helium-accreting white dwarf in a binary. The ejecta contain more calcium than observed in other types of supernovae and probably large amounts of radioactive (44)Ti.

Capnocytophaga canimorsus is a gram-negative rod that is a normal inhabitant of the oral flora of most dogs, cats and other animals. Clinically significant infections of humans by this common organism are extremely rare. We present a case of an 87-year-old woman who presented with septic shock and multiorgan system failure. Blood cultures were positive for a gram-negative rod that five days after admission was identified as C. canimorsus. She was treated aggressively with intravenous fluid resuscitation, vasopressors and parenteral antibiotics and recovered. The epidemiology, virulence factors, and treatment options for C. canimorsus are discussed.

Long duration gamma-ray bursts (GRBs) mark the explosive death of some massive stars and are a rare sub-class of type Ibc supernovae. They are distinguished by the production of an energetic and collimated relativistic outflow powered by a central engine (an accreting black hole or neutron star). Observationally, this outflow is manifested in the pulse of gamma-rays and a long-lived radio afterglow. Until now, central-engine-driven supernovae have been discovered exclusively through their gamma-ray emission, yet it is expected that a larger population goes undetected because of limited satellite sensitivity or beaming of the collimated emission away from our line of sight. In this framework, the recovery of undetected GRBs may be possible through radio searches for type Ibc supernovae with relativistic outflows. Here we report the discovery of luminous radio emission from the seemingly ordinary type Ibc SN 2009bb, which requires a substantial relativistic outflow powered by a central engine. A comparison with our radio survey of type Ibc supernovae reveals that the fraction harbouring central engines is low, about one per cent, measured independently from, but consistent with, the inferred rate of nearby GRBs. Independently, a second mildly relativistic supernova has been reported.

Stars with initial masses such that 10M[symbol: see text] or= 140M[symbol: see text] (if such exist) develop oxygen cores with masses, M(core), that exceed 50M[symbol: see text], where high temperatures are reached at relatively low densities. Conversion of energetic, pressure-supporting photons into electron-positron pairs occurs before oxygen ignition and leads to a violent contraction which triggers a nuclear explosion that unbinds the star in a pair-instability supernova. Transitional objects with 100M[symbol: see text] < M(initial) < 140M[symbol: see text] may end up as iron-core-collapse supernovae following violent mass ejections, perhaps as a result of brief episodes of pair instability, and may already have been identified. Here we report observations of supernova SN 2007bi, a luminous, slowly evolving object located within a dwarf galaxy. We estimate the exploding core mass to be M(core) approximately 100M[symbol: see text], in which case theory unambiguously predicts a pair-instability supernova. We show that >3M[symbol: see text] of radioactive (56)Ni was synthesized during the explosion and that our observations are well fitted by models of pair-instability supernovae. This indicates that nearby dwarf galaxies probably host extremely massive stars, above the apparent Galactic stellar mass limit, which perhaps result from processes similar to those that created the first stars in the Universe.

Long-duration gamma-ray bursts (GRBs) are thought to result from the explosions of certain massive stars, and some are bright enough that they should be observable out to redshifts of z > 20 using current technology. Hitherto, the highest redshift measured for any object was z = 6.96, for a Lyman-alpha emitting galaxy. Here we report that GRB 090423 lies at a redshift of z approximately 8.2, implying that massive stars were being produced and dying as GRBs approximately 630 Myr after the Big Bang. The burst also pinpoints the location of its host galaxy.

Objective: The Avon Area Health Authority was a first-phase site for introduction of universal newborn screening in the UK. The aims of this study were: to review the programme's results to date; to assess the impact screening would have on other services (e.g. the cochlear implant programme); and to assess the longer term outcome for children identified by the screening programme., Patients: All children identified by the Avon universal newborn hearing screening programme between April 2002 and July 2006., Results: Fifty-four children with a bilateral hearing impairment of worse than 40 dBHL were identified from a screened population of approximately 44 000. Nine of these children were put forward for cochlear implantation, and seven had been implanted at the time of writing. Thirteen of these children were identified with possible auditory neuropathy or dys-synchrony. All the newborn hearing screening programme criteria assessed were met., Conclusions: The screening programme was effective. Some areas may need review in order to optimise patient care.

Sarcoidosis is a systemic granulomatous disease of unknown etiology, in which the lungs and intrathoracic lymph nodes are predominant sites of involvement. Pulmonary hypertension is a known complication of sarcoidosis. Treatment of sarcoidosis-associated pulmonary hypertension has traditionally focused on the initiation of systemic corticosteroids, but has had inconsistent results. We present a patient with sarcoidosis-associated pulmonary hypertension who achieved substantial clinical improvement with the dual endothelin receptor antagonist bosentan., (Copyright (c) 2008 S. Karger AG, Basel)

We used the Luminex assay to compare serum cytokine profiles of breast cancer patients (BCa) to healthy controls, node-positive (NP) patients to node-negative (NN), and pre- and post-vaccination serum of BCa vaccinated with a HER2/neu E75 peptide vaccine. Sera from 36 pre- and post-vaccination BCa, (12 NP and 24 NN) and 13 healthy, female donors, were evaluated using Luminex technology. Levels of 22 cytokines consisting of interleukin (IL)-1alpha, -1beta, -2, -4, -5, -6, -7, -8, -10, -12, -13, -15, -17, IFN-gamma, G-CSF, GM-CSF, TNF-alpha, IP-10, MIP-1alpha, RANTES, eotaxin and monocyte chemotactic protein-1 (MCP-1) were assessed. Six of 22 cytokines showed significant differences between BCa and healthy controls. MCP-1, eotaxin, RANTES and GM-CSF levels were significantly elevated in BCa (P<0.009) and IL-1alpha and IL-4 levels were significantly decreased in BCa (P<0.015). Cytokine levels were generally elevated in NN patients compared to NP patients with the exception of eotaxin and IL-13, which were increased in NP patients. Three cytokines, IL-6, MIP-1alpha and G-CSF reached statistical significance (P<0.05). In 34 vaccinated BCa, MCP-1, eotaxin and IL-13 were significantly elevated post-vaccination with MCP-1 demonstrating the most significant response (median, 145.8-217.0 pg/ml, P=0.003). Using a multiplex assay we found significant differences in cytokine levels in sera of BCa compared to healthy controls, in NN compared to NP patients, and in vaccinated patients. Our results support an extended analysis of serum cytokine profiles for the potential development of predictive panels in diagnosis, staging and monitoring cancer vaccine trials.

Long-duration gamma-ray bursts (GRBs) are associated with type Ic supernovae that are more luminous than average and that eject material at very high velocities. Less-luminous supernovae were not hitherto known to be associated with GRBs, and therefore GRB-supernovae were thought to be rare events. Whether X-ray flashes--analogues of GRBs, but with lower luminosities and fewer gamma-rays--can also be associated with supernovae, and whether they are intrinsically 'weak' events or typical GRBs viewed off the axis of the burst, is unclear. Here we report the optical discovery and follow-up observations of the type Ic supernova SN 2006aj associated with X-ray flash XRF 060218. Supernova 2006aj is intrinsically less luminous than the GRB-supernovae, but more luminous than many supernovae not accompanied by a GRB. The ejecta velocities derived from our spectra are intermediate between these two groups, which is consistent with the weakness of both the GRB output and the supernova radio flux. Our data, combined with radio and X-ray observations, suggest that XRF 060218 is an intrinsically weak and soft event, rather than a classical GRB observed off-axis. This extends the GRB-supernova connection to X-ray flashes and fainter supernovae, implying a common origin. Events such as XRF 060218 are probably more numerous than GRB-supernovae.

Purpose: We are conducting clinical trials in breast cancer (BrCa) patients to test the HER2/neu peptide vaccine (E75). We have investigated the impact of this vaccine on circulating levels of regulatory T cells (Treg) and the resulting effects on antitumor responses., Experimental Design: Twenty-two blood samples from healthy individuals and from 22 BrCa patients including pre- and post-vaccination samples from seven vaccinated HLA-A2+ patients were stained for CD4, CD25, and CD69 as well as CD8 and E75:HLA-A2 Ig dimer and quantified by flow cytometry. Cytotoxic activity against HER2/neu+ tumors was measured by 51Cr-release. Serum from BrCa patients and normal subjects were analyzed for TGF-beta levels., Results: BrCa patients have a greater percentage of circulating Treg (CD4+CD25+, 4.45% versus 2.96%; p=0.007) than normal subjects. HLA-A2+ BrCa patients had more Treg compared to the HLA-A2- BrCa patients (CD4+CD25+, 5.63% versus 3.28%; p=0.001). E75 vaccination increased circulating activated CD4+ T cells post-vaccination (CD4+CD69+, 1.23 versus 3.81%; p=0.03). However, T(reg) were significantly reduced after vaccination (CD4+CD25+, 5.31-1.81%; p<0.0001). Furthermore, activated Treg also decreased (CD4+CD25+CD69+, 0.23% versus 0.08%; p=0.06). Importantly, post-vaccination decreases in Treg were temporally associated with increased E75 vaccine-specific CD8+ T cells and corresponding HER2/neu+ tumor cytotoxicity. Serum TGF-beta levels were significantly elevated in BrCa patients compared to normals (3548 pg/ml versus 1007 pg/ml; p=0.007). Four of seven vaccinated patients showed decreased serum TGF-beta levels post-vaccination., Conclusions: Treg, are increased in BrCa patients along with serum levels of TGF-beta. E75 vaccination resulted in CD4+ recruitment but was associated with a significant decrease in circulating Treg and TGF-beta levels in the majority of the vaccinated patients. Successful cancer vaccination strategies may require the alteration of complex immune interactions.

Objectives: We sought to determine the incidence of stress-induced pulmonary artery (PA) systolic hypertension in a referral population of patients with scleroderma, and to examine the relation between stress-induced pulmonary systolic hypertension and exercise capacity in this population., Background: Early detection of patients with scleroderma at risk for pulmonary hypertension (PHTN) could lead to more timely intervention and thus reduce morbidity and improve mortality. The change in PA systolic pressure (PASP) with exercise provides a possible tool for such detection., Methods: Sixty-five patients with scleroderma (9 men and 56 women; mean age 51 +/- 12 years [SD]), normal resting PASP, and normal resting left ventricular function underwent exercise Doppler echocardiography using a standard Bruce protocol. Tricuspid regurgitation velocity was measured before and after exercise. Exercise variables including workload achieved in metabolic equivalents (METS), total exercise time, percentage of target heart rate achieved, and PASP at rest and within 60 s after exercise were recorded., Results: Thirty patients (46%) demonstrated an increase in PASP to > 35 mm Hg plus an estimated right atrial pressure of 5 mm Hg. Postexercise PASP inversely correlated to both the maximum workload achieved (r = - 0.34, p = 0.006) and exercise time (r = - 0.31, p = 0.01). In women, the correlation was more significant (r = - 0.38, p = 0.003). Patients in the lowest quartile of exercise time, with the least cardiac workload achieved, produced the highest postexercise PASP., Conclusion: Stress-induced PHTN is common in patients with scleroderma, even when resting PASP is normal. Stress Doppler echocardiography identifies scleroderma patients with an abnormal rise in PASP during exertion. Peak PASP is linearly related to exercise time and maximum workload achieved. Measurement of PASP during exercise may prove to be a useful tool for the identification of future resting PHTN.

Background: E75 and GP2 are human leukocyte antigen (HLA)-A2-restricted immunogenic peptides derived from the HER2/neu protein. In a E75 peptide-based vaccine trial, preexisting immunity and epitope spreading to GP2 was detected. The purpose of this study was to further investigate GP2 for potential use in vaccination strategies. Importantly, a naturally occurring polymorphism (I-->V at position 2, 2VGP2) associated with increased breast cancer risk was addressed., Methods: Prevaccination peripheral blood samples (PBMC) from HLA-A2 breast cancer patients and CD8+ T cells from HLA-A2 healthy donors were stimulated with autologous dendritic cells (DC) pulsed with GP2 and tested in standard cytotoxicity assays with HER2/neu+ tumor cells or GP2- or 2VGP2-loaded T2 targets. Additional cytotoxicity experiments used effectors stimulated with DC pulsed with E75, GP2, or the combination of E75+GP2., Results: GP2-stimulated prevaccination PBMC from 28 patients demonstrated killing of MCF-7, SKOV3-A2, and the HLA-A2- control target SKOV3 of 28.8+/-3.7% (P<.01), 29.5+/-4.0% (P<.01), and 16.9+/-2.7%, respectively. When compared with E75, GP2-stimulated CD8+ T cells lysed HER2/neu+ targets at 43.8+/-5.2% versus 44.2+/-5.7% for E75 (P=.87). When combined, an additive effect was noted with 58.6+/-5.4% lysis (P=.05). GP2-stimulated CD8+ T cells specifically recognized both GP2-loaded (19.6+/-5.7%) and 2VGP2-loaded T2 targets (17.7+/-5.2%)., Conclusions: GP2 is a clinically relevant HER2/neu-derived peptide with immunogenicity comparable to that of E75. Importantly, GP2-specific effectors recognize 2VGP2-expressing targets; therefore, a GP2 vaccine should be effective in patients carrying this polymorphism. GP2 may be most beneficial used in a multiepitope vaccine.

An important and perhaps critical clue to the mechanism driving the explosion of massive stars as supernovae is provided by the accumulating evidence for asymmetry in the explosion. Indirect evidence comes from high pulsar velocities, associations of supernovae with long-soft gamma-ray bursts, and asymmetries in late-time emission-line profiles. Spectropolarimetry provides a direct probe of young supernova geometry, with higher polarization generally indicating a greater departure from spherical symmetry. Large polarizations have been measured for 'stripped-envelope' (that is, type Ic; ref. 7) supernovae, which confirms their non-spherical morphology; but the explosions of massive stars with intact hydrogen envelopes (type II-P supernovae) have shown only weak polarizations at the early times observed. Here we report multi-epoch spectropolarimetry of a classic type II-P supernova that reveals the abrupt appearance of significant polarization when the inner core is first exposed in the thinning ejecta (approximately 90 days after explosion). We infer a departure from spherical symmetry of at least 30 per cent for the inner ejecta. Combined with earlier results, this suggests that a strongly non-spherical explosion may be a generic feature of core-collapse supernovae of all types, where the asphericity in type II-P supernovae is cloaked at early times by the massive, opaque, hydrogen envelope.

Purpose: We studied serum monocyte chemotactic protein-1 (MCP-1) levels in breast cancer patients in relationship to their clinicopathologic variables and immune response to a /neu E75 vaccine., Experimental Design: We measured MCP-1 levels in 32 /neu(+) breast cancer patients before and after vaccination with a /neu E75 peptide + granulocyte macrophage colony-stimulating factor vaccine. Clinical prognostic variables were collected. Vaccine-specific immunologic responses were monitored., Results: Serum MCP-1 levels >250 pg/mL (MCP-high) correlated with favorable prognostic variables. MCP-high patients compared with MCP-low (<250 pg/mL) patients showed statistically significant later onset of disease, earlier stage of disease, fewer nodal metastasis, and less chemotherapy. MCP-high patients had increased levels of preexisting immunity when compared with MCP-low patients (69% versus 21%; P = 0.02). However, MCP-low patients showed higher inducible levels of MCP-1 compared with MCP-high patients (median increase, 41% versus 0%; P = 0.001) after vaccination. Moreover, MCP-low patients with >50% increase in MCP-1 levels (response-high) had worse clinical prognostic variables compared with patients with <50% increase (response-low). Response-high patients had statistically significant more poorly differentiated tumors, later stage of disease, and higher percentage of large tumors. Patients with >30% postvaccination MCP-1 increase also showed significant increases in E75-specific CD8(+) T-cells (0.05% versus 0.38%; P = 0.03) in response to vaccination., Conclusions: High serum MCP-1 levels in breast cancer patients correlate with favorable prognostic variables and increased preexisting /neu immunity. E75 vaccination induces the largest MCP-1 response in patients with unfavorable clinicopathologic variables. Therefore, low serum MCP-1 levels may identify patients with worse prognosis and those most likely to benefit from this vaccination.

Type Ic supernovae, the explosions after the core collapse of massive stars that have previously lost their hydrogen and helium envelopes, are particularly interesting because of their link with long-duration gamma ray bursts. Although indications exist that these explosions are aspherical, direct evidence has been missing. Late-time observations of supernova SN 2003jd, a luminous type Ic supernova, provide such evidence. Recent Subaru and Keck spectra reveal double-peaked profiles in the nebular lines of neutral oxygen and magnesium. These profiles are different from those of known type Ic supernovae, with or without a gamma ray burst, and they can be understood if SN 2003jd was an aspherical axisymmetric explosion viewed from near the equatorial plane. If SN 2003jd was associated with a gamma ray burst, we missed the burst because it was pointing away from us.

The brightness of type Ia supernovae, and their homogeneity as a class, makes them powerful tools in cosmology, yet little is known about the progenitor systems of these explosions. They are thought to arise when a white dwarf accretes matter from a companion star, is compressed and undergoes a thermonuclear explosion. Unless the companion star is another white dwarf (in which case it should be destroyed by the mass-transfer process itself), it should survive and show distinguishing properties. Tycho's supernova is one of only two type Ia supernovae observed in our Galaxy, and so provides an opportunity to address observationally the identification of the surviving companion. Here we report a survey of the central region of its remnant, around the position of the explosion, which excludes red giants as the mass donor of the exploding white dwarf. We found a type G0-G2 star, similar to our Sun in surface temperature and luminosity (but lower surface gravity), moving at more than three times the mean velocity of the stars at that distance, which appears to be the surviving companion of the supernova.

Background: The presence of a fistula has usually been a factor predicting high conversion and complication rates following laparoscopic procedures for Crohn's disease and diverticulitis., Methods: We studied retrospective data collected from the medical case notes of patients. A single surgeon carried out all these procedures from 1991 through 2001., Results: Fourteen patients underwent 15 procedures. Six patients were males and 8 were females. The diagnosis was Crohn's disease in 10 patients and diverticulitis in 4. In 10 cases, the operation was the primary procedure, but 5 procedures were for recurrences. Two patients with diverticulitis and 3 with Crohn's disease had only the fistulae divided with the application of an Endo-GIA stapier across the fistulae (stapled fistulectomy). No bowel resections were carried out in these 5 patients. Four cases had to be converted due to bleeding (23%). The only postoperative complication was a single case of wound infection after conversion., Conclusion: The presence of a fistula isn't necessarily an indication for conversion. If it is possible to dissect the loops free, we believe that a stapled fistulectomy is effective with a low incidence of fistula recurrence, especially in Crohn's disease.

Background: To identify factors that would predict conversion in patients undergoing laparoscopic surgery for Crohn's disease., Methods: Data were collected retrospectively. All procedures were performed by an experienced laparoscopic surgeon., Results: Forty-eight patients underwent 57 laparoscopic procedures. Twenty-six of these procedures were for recurrent disease. The conversion rate was 42.3% (11 of 26) for recurrent disease and 13% (4 of 31) for primary disease. On univariate analysis age (P = 0.02), surgery for recurrence (P = 0.02), time from diagnosis (P = 0.03), and the presence of a clinical mass (P = 0.03) were factors that predicted conversion. On multivariate analysis these factors except time from diagnosis still remained significant. Patients who did not undergo a conversion had significantly better post operative outcomes. There was no difference in the incidence of major or minor complications or the number of resections in both groups., Conclusions: The conversion rate for the whole group was 28%. The rate is higher in patients who are over 40 years of age who are undergoing procedures for recurrence.

Community-acquired pneumonia is a common disease in adults and substantially contributes to morbidity and mortality in the USA and worldwide. Due to the significant costs associated with this disease, there is increasing pressure to evaluate the variation in practices among healthcare providers. The processes of care related to the diagnosis, management and prevention of community-acquired pneumonia are reviewed. Furthermore, the cost-effective strategies for community-acquired pneumonia and the medical evidence that support their usage are outlined.

We have tried to evaluate the role of laparoscopy and laparoscopic-assisted surgery in the management of Crohn's disease. Over a 4-year period, we had 38 patients, of which 23 patients were suspected to have Crohn's disease and were admitted for diagnostic laparoscopy while 15 patients had already had a biopsy confirmation of Crohn's disease in the past and were admitted for specifically planned procedures. In the first group of 23 patients, 11 were found not to have Crohn's disease. In the remaining 12 patients, three were proven to have Crohn's disease, but no surgical procedure was undertaken. The remaining nine patients underwent laparoscopic-assisted procedures, of which two required conversion to a laparotomy because of intra-abdominal abscesses. All 15 patients in the second group underwent laparoscopic or laparoscopic-assisted procedures. In total, 14 patients were spared a potential diagnostic laparotomy and could go home the next day. The remaining 24 patients underwent procedures requiring longer hospital stays; five had a purely laparoscopic procedure, 17 had a laparoscopic-assisted procedure, and two required a laparotomy. Although there was little difference in the median stay for patients treated laparoscopically or by laparotomy, it is thought that the extent or severity of the disease process influenced the length of the stay rather than the approach used. The complication rate was similar to that found in Crohn's patients undergoing open surgery. It remains to be seen whether those in the laparoscopically treated group have less adhesive complications than those treated by laparotomy. It is our belief that laparoscopy is a valuable aid in the diagnosis of Crohn's disease. It remains to be proven whether or not laparoscopic-assisted surgery will be of significant value in the treatment of this condition.

Objective: To evaluate the safety and cost effectiveness of laparoscopic cholecystectomy as a day case procedure., Setting: District hospital, England., Subjects: 103 patients undergoing laparoscopic cholecystectomy., Interventions: Laparoscopic cholecystectomy by a standard four cannula technique. Propofol anaesthesia, prophylactic antiemetics and pre-emptive analgesia were given in all cases., Main Outcome Measures: Morbidity and cost., Results: 103 patients have undergone laparoscopic cholecystectomy, 51 of them as day cases. Patients were selected for day treatment if they were under 60 years old, they wanted to go home the same day, they had no history of jaundice or any anaesthetic contraindication, and if there was an adult at home to look after them. Three of those selected as day cases required overnight admission, one because of severe pain and two who required a drain overnight. The median hospital stay was 12 hours (range 10-28 hours) and the cost of the operation was about pounds 419., Conclusion: This is a safe and cost-effective procedure and should be considered in selected patients.

We categorize the three types of renal dysfunction associated with the use of nonsteroidal anti-inflammatory drugs (NSAID): acute renal failure, acute interstitial nephritis, and hyperkalemia. The paper provides clinical examples of each type, discusses pathophysiology, and describes response to therapy, in addition to outlining the usefulness of labeled leukocyte nuclear studies and kidney biopsy. We conclude that these drugs are relatively common causes of renal dysfunction, particularly in selected subpopulations.

Hyperkalemia was commonly observed in successful renal transplant patients treated with cyclosporine and prednisone. At 1, 3 and 6 months after transplantation, 13 of 50, 9 of 50, and 5 of 50 patients, respectively, had serum concentrations of potassium greater than 5 mEq/1. This contrasts with the finding of hyperkalemia in only 1 of 13 comparable patients treated with azathioprine and prednisone. Mean serum concentrations of potassium at these dates were significantly higher in cyclosporine-treated patients than azathioprine-treated patients. The 2 patient groups had similar mean serum concentrations of chloride, bicarbonate and creatinine, and mean creatinine clearances at 1 and 3 months. Exposure to diuretic agents and antihypertensive agents was similar in the 2 groups. Serum concentrations of electrolytes and renal function data in hyperkalemic and normokalemic transplant patients receiving cyclosporine were similar. These observations suggest an association between cyclosporine administration and hyperkalemia in renal transplant recipients.

A 32-year-old man had acute renal failure after ingesting amphetamines. The renal biopsy findings indicated acute interstitial nephritis. In contrast to other reports, which indicate an association between coexisting rhabdomyolysis, hyperpyrexia, or necrotizing angiitis and acute renal failure in amphetamine abusers, our case suggests that amphetamine alone may cause acute renal injury.