New challenges in heart failure

Heart failure has received much publicity in the last five years. In all western countries, the numbers of patients admitted to hospital with heart failure is rising sharply. There is now widespread agreement about the poor prognosis, which is worse than many forms of cancer (1). Heart failure has also become, rather belatedly, a topic of considerable interest for cardiologists. As well as new drugs available, there are increasingly sophisticated procedures involving biventricular pacing and the use of defibrillators which, though costly, can significantly improve prognosis in certain patient groups (2)

The isomorphism problem for some universal operator algebras

This paper addresses the isomorphism problem for the universal (nonself-adjoint) operator algebras generated by a row contraction subject to homogeneous polynomial relations. We find that two such algebras are isometrically isomorphic if and only if the defining polynomial relations are the same up to a unitary change of variables, and that this happens if and only if the associated subproduct systems are isomorphic. The proof makes use of the complex analytic structure of the character space, together with some recent results on subproduct systems. Restricting attention to commutative operator algebras defined by radical relations yields strong resemblances with classical algebraic geometry. These commutative operator algebras turn out to be algebras of analytic functions on algebraic varieties. We prove a projective Nullstellensatz connecting closed ideals and their zero sets. Under some technical assumptions, we find that two such algebras are isomorphic as algebras if and only if they are similar, and we obtain a clear geometrical picture of when this happens. This result is obtained with tools from algebraic geometry, reproducing kernel Hilbert spaces, and some new complex-geometric rigidity results of independent interest. The C*-envelopes of these algebras are also determined. The Banach-algebraic and the algebraic classification results are shown to hold for the weak-operator closures of these algebras as well.Comment: 46 pages. Final version, to appear in Advances in Mathematic

Using Electronic Drug Monitor Feedback to Improve Adherence to Antiretroviral Therapy Among HIV-Positive Patients in China

Effective antiretroviral therapy (ART) requires excellent adherence. Little is known about how to improve ART adherence in many HIV/AIDS-affected countries, including China. We therefore assessed an adherence intervention among HIV-positive patients in southwestern China. Eighty subjects were enrolled and monitored for 6 months. Sixty-eight remaining subjects were randomized to intervention/control arms. In months 7–12, intervention subjects were counseled using EDM feedback; controls continued with standard of care. Among randomized subjects, mean adherence and CD4 count were 86.8 vs. 83.8% and 297 vs. 357 cells/μl in intervention vs. control subjects, respectively. At month 12, among 64 subjects who completed the trial, mean adherence had risen significantly among intervention subjects to 96.5% but remained unchanged in controls. Mean CD4 count rose by 90 cells/μl and declined by 9 cells/μl among intervention and control subjects, respectively. EDM feedback as a counseling tool appears promising for management of HIV and other chronic diseases.Boston University and the Office of Health and Nutrition of the United States Agency for International Development (GHS-A-00-03-00030-00); World Health Organization; United States Centers for Disease Control; National Institutes of Health, National Institute of Allergy and Infectious Diseases (K23 AI 62208); Mid-Career Mentoring Award (K24 RR020300

Stability of a Spherical Accretion Shock with Nuclear Dissociation

We examine the stability of a standing shock wave within a spherical accretion flow onto a gravitating star, in the context of core-collapse supernova explosions. Our focus is on the effect of nuclear dissociation below the shock on the linear growth, and non-linear saturation, of non-radial oscillations of the shocked fluid. We combine two-dimensional, time-dependent hydrodynamic simulations using FLASH2.5 with a solution to the linear eigenvalue problem, and demonstrate the consistency of the two approaches. Previous studies of this `Standing Accretion Shock Instability' (SASI) have focused either on zero-energy accretion flows without nuclear dissociation, or made use of a detailed finite-temperature nuclear equation of state and included strong neutrino heating. Our main goal in this and subsequent papers is to introduce equations of state of increasing complexity, in order to isolate the various competing effects. In this work we employ an ideal gas equation of state with a constant rate of nuclear dissociation below the shock, and do not include neutrino heating. We find that a negative Bernoulli parameter below the shock significantly lowers the real frequency, growth rate, and saturation amplitude of the SASI. A decrease in the adiabatic index has similar effects. The non-linear development of the instability is characterized by an expansion of the shock driven by turbulent kinetic energy at nearly constant internal energy. Our results also provide further insight into the instability mechanism: the rate of growth of a particular mode is fastest when the radial advection time from the shock to the accretor overlaps with the period of a standing lateral sound wave. The fastest-growing mode can therefore be modified by nuclear dissociation.Comment: Version accepted by ApJ. Consistent parameter range, and additional plots with eigenfrequencies in units of inverse postshock advection timescale. Minor changes otherwis

TeV Right-handed Neutrinos and the Flavor-symmetry-improved Seesaw Mechanism

Horizontal flavor symmetries can drastically suppress Dirac neutrino masses well below those of the corresponding charged leptons. We show that models can be constructed where the light neutrino mass eigenvalues are small enough to give the MSW solution to the solar neutrino problem, with a right-handed neutrino scale no larger than a TeV. We present a model of this type where the right-handed neutrino scale is generated by the spontaneous breakdown of gauged U(1)$_{B-L}$, in a radiative breaking scenario driven by the right-handed neutrino Yukawa couplings. The model allows for a solution to the $\mu$ problem, and predicts the existence of a $Z'$ boson within the reach of the LHC or the Tevatron.Comment: 16 pp. LaTe

The XMM Cluster Survey: a massive galaxy cluster at z = 1.45

We report the discovery of XMMXCS J2215.9-1738, a massive galaxy cluster at z=1.45, which was found in the XMM Cluster Survey. The cluster candidate was initially identified as an extended X-ray source in archival XMM data. Optical spectroscopy shows that six galaxies within a ~60" diameter region lie at z=1.45+/-0.01. Model fits to the X-ray spectra of the extended emission yield kT=7.4+2.7-1.8 keV (90% confidence); if there is an undetected central X-ray point source, then kT=6.5+2.6-1.8 keV. The bolometric X-ray luminosity is LX=4.4+0.8-0.6C 1044 ergs s-1 over a 2 Mpc radial region. The measured TX, which is the highest for any known cluster at z>1, suggests that this cluster is relatively massive for such a high redshift. The redshift of XMMXCS J2215.9-1738 is the highest currently known for a spectroscopically confirmed cluster of galaxies

Vitamin A and zinc supplementation among pregnant women to prevent placental malaria: a randomized, double-blind, placebo-controlled trial in Tanzania

BACKGROUND: Malaria causes nearly 200 million clinical cases and approximately half a million deaths each year, primarily in sub-Saharan Africa.1 The risk of malaria increases during pregnancy,2 a period during which its prevention is especially important. Not only do pregnant women experience greater severity of illness compared with nonpregnant women,2 but studies have shown strong associations between prenatal malaria and maternal anemia,2 fetal loss, low birthweight, and infant mortality.2 Improving preventive measures that specifically target malaria in pregnancy is a global health priority.3 METHODS: Study design and participants. This randomized, doubleblind, placebo-controlled trial was implemented at 8 antenatal care clinics in the urban Temeke and Ilala districts of Dar es Salaam, Tanzania. The trial was registered RESULTS: A total of 2,500 screened participants were enrolled in the trial. The trial profile is shown in Figure 1. It was not possible to collect placentas from 875 participants for the following reasons: miscarriages (fetal loss before 28 weeks of gestation) (N = 234), delivery outside of Dar es Salaam or at a non-study hospital (N = 577), or withdrawal from the study (N = 34). Of the remaining 1,589 women, 1,404 placental samples were obtained (88%); histology results were available for 1,361 participants. PCR results were available for 1,158 participants, and 1,404 participants had either histology or PCR results available. CONCLUSION: This study is the first to examine the impact of vitamin A and zinc supplementation starting in early pregnancy on placental malaria. We observed that supplementation with 25 mg zinc per day from the first trimester until delivery was associated with a 36% (95% CI = 9–56%) reduced risk of histopathology-positive placental infection, but not PCRpositive infection. Vitamin A supplementation had no impact on placental malaria, but was associated with an increased risk for severe anemia

Shell Neurons of the Master Circadian Clock Coordinate the Phase of Tissue Clocks Throughout the Brain and Body

Background: Daily rhythms in mammals are programmed by a master clock in the suprachiasmatic nucleus (SCN). The SCN contains two main compartments (shell and core), but the role of each region in system-level coordination remains ill defined. Herein, we use a functional assay to investigate how downstream tissues interpret region-specific outputs by using in vivo exposure to long day photoperiods to temporally dissociate the SCN. We then analyze resulting changes in the rhythms of clocks located throughout the brain and body to examine whether they maintain phase synchrony with the SCN shell or core. Results: Nearly all of the 17 tissues examined in the brain and body maintain phase synchrony with the SCN shell, but not the SCN core, which indicates that downstream oscillators are set by cues controlled specifically by the SCN shell. Interestingly, we also found that SCN dissociation diminished the amplitude of rhythms in core clock gene and protein expression in brain tissues by 50–75 %, which suggests that light-driven changes in the functional organization of the SCN markedly influence the strength of rhythms in downstream tissues. Conclusions: Overall, our results reveal that body clocks receive time-of-day cues specifically from the SCN shell, which may be an adaptive design principle that serves to maintain system-level phase relationships in a changing environment. Further, we demonstrate that lighting conditions alter the amplitude of the molecular clock in downstream tissues, which uncovers a new form of plasticity that may contribute to seasonal changes in physiology and behavior

Fostering collaborative research for rare genetic disease: The example of Niemann-Pick type C disease

Rare disease represents one of the most significant issues facing the medical community and health care providers worldwide, yet the majority of these disorders never emerge from their obscurity, drawing little attention from the medical community or the pharmaceutical industry. The challenge therefore is how best to mobilize rare disease stakeholders to enhance basic, translational and clinical research to advance understanding of pathogenesis and accelerate therapy development. Here we describe a rare, fatal brain disorder known as Niemann-Pick type C (NPC) and an innovative research collaborative known as Support of Accelerated Research for NPC (SOAR-NPC) which illustrates one pathway through which knowledge of a rare disease and its possible treatments are being successfully advanced. Use of the “SOAR” mechanism, we believe, offers a blueprint for similar advancement for many other rare disorders

Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling

Deregulated extracellular signal-regulated kinase (ERK) signaling drives cancer growth. Normally, ERK activity is self-limiting by the rapid inactivation of upstream kinases and delayed induction of dual-specificity MAP kinase phosphatases (MKPs/DUSPs). However, interactions between these feedback mechanisms are unclear. Here we show that, although the MKP DUSP5 both inactivates and anchors ERK in the nucleus, it paradoxically increases and prolongs cytoplasmic ERK activity. The latter effect is caused, at least in part, by the relief of ERK-mediated RAF inhibition. The importance of this spatiotemporal interaction between these distinct feedback mechanisms is illustrated by the fact that expression of oncogenic BRAF(V600E), a feedback-insensitive mutant RAF kinase, reprograms DUSP5 into a cell-wide ERK inhibitor that facilitates cell proliferation and transformation. In contrast, DUSP5 deletion causes BRAF(V600E)-induced ERK hyperactivation and cellular senescence. Thus, feedback interactions within the ERK pathway can regulate cell proliferation and transformation, and suggest oncogene-specific roles for DUSP5 in controlling ERK signaling and cell fate