Central Review of Amyloid-Related Imaging Abnormalities in Two Phase III Clinical Trials of Bapineuzumab in Mild-To-Moderate Alzheimer's Disease Patients

BACKGROUND: Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]). OBJECTIVES: To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer’s disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE ɛ4 allele carriers or noncarriers). METHODS: Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is described. RESULTS: In the Final Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE ɛ4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs <10 mm (cerebral microhemorrhages) was higher in active groups versus placebo. CONCLUSION: ARIA was detected more often on MRI scans when every scan was reviewed by trained neuroradiologists and results adjudicated. There was increased incidence of ARIA-E in bapineuzumab-treated carriers who had a microhemorrhage at baseline. ARIA-E was a risk factor for incident ARIA-H and late onset ARIA-E was milder radiologically. Age-related white matter changes did not progress during the study

Massive Schwinger model and its confining aspects on curved space-time

Using a covariant method to regularize the composite operators, we obtain the bosonized action of the massive Schwinger model on a classical curved background. Using the solution of the bosonic effective action, the energy of two static external charges with finite and large distance separation on a static curved space-time is obtained. The confining behavior of this model is also explicitly discussed.Comment: A disscussion about the infrared regularization and also two references are added. Accepted for publication in Phys. Rev. D (2001

Whole Exome Sequencing and Molecular Modeling of a Missense Variant in TNFAIP3

Chronic urticaria is a common condition characterized by recurrent hives lasting several weeks or months and is usually idiopathic. Approximately half of the individuals with chronic urticaria will present with episodes of angioedema that can be severe and debilitating. In this report, we describe a 47-year-old Hispanic male who presented initially for an evaluation of chronic hives following hospitalization due to hive-induced anaphylaxis. The individual had a history significant for urticaria and angioedema beginning in his early 30s. Interestingly, both the individual’s 41-year-old sister and 12-year-old daughter were also affected with chronic urticaria and severe angioedema. Whole exome sequencing of the proband and several family members revealed a heterozygous variant of uncertain significance in exon 2 of TNFAIP3, denoted as c.65G>A (p.R22Q), in all affected members. Variants in TNFAIP3 have been associated with multiple autoimmune diseases, susceptibility to allergy and asthma, and periodic fever syndromes, suggesting that this variant could potentially play a role in disease

Whole exome sequencing and molecular modeling of a missense variant in TNFAIP3 that segregates with disease in a family with chronic urticaria and angioedema

Chronic urticaria is a common condition characterized by recurrent hives lasting several weeks or months and is usually idiopathic. Approximately half of the individuals with chronic urticaria will present with episodes of angioedema that can be severe and debilitating. In this report, we describe a 47-year-old Hispanic male who presented initially for an evaluation of chronic hives following hospitalization due to hive-induced anaphylaxis. The individual had a history significant for urticaria and angioedema beginning in his early 30s. Interestingly, both the individual’s 41-year-old sister and 12-year-old daughter were also affected with chronic urticaria and severe angioedema. Whole exome sequencing of the proband and several family members revealed a heterozygous variant of uncertain significance in exon 2 of TNFAIP3, denoted as c.65G&gt;A (p.R22Q), in all affected members. Variants in TNFAIP3 have been associated with multiple autoimmune diseases, susceptibility to allergy and asthma, and periodic fever syndromes, suggesting that this variant could potentially play a role in disease

Chronic Mechanical Circulatory Support for Inotrope-Dependent Heart Failure Patients Who Are Not Transplant Candidates Results of the INTrEPID Trial

ObjectivesThis study evaluated the impact of left ventricular assist device (LVAD) support on survival and quality of life in inotrope-dependent heart failure patients ineligible for cardiac transplantation.BackgroundThe role for LVADs as a bridge to cardiac transplantation has been established, but data supporting their role as permanent therapy in nontransplant candidates are limited.MethodsThe INTrEPID (Investigation of Nontransplant-Eligible Patients Who Are Inotrope Dependent) trial was a prospective, nonrandomized clinical trial comparing LVAD with optimal medical therapy (OMT). Fifty-five patients with New York Heart Association functional class IV symptoms who failed weaning from inotropic support were offered a Novacor LVAD. Eighteen of these patients did not receive an LVAD owing to patient preference (n = 14) or unavailability of the device (n = 4) but consented to follow-up and constitute a contemporaneous control group.ResultsThe LVAD and OMT patients were well matched for demographic and disease severity measures, except OMT patients had a lower mean serum sodium (128 mg/dl vs. 134 mg/dl; p = 0.001) and a higher mean blood urea nitrogen concentration (59 vs. 40; p = 0.02). The LVAD-treated patients had superior survival rates at 6 months (46% vs. 22%; p = 0.03) and 12 months (27% vs. 11%; p = 0.02). Adverse event rates were higher in the OMT group. Eighty-five percent of the LVAD-treated patients had minimal or no heart failure symptoms. Five LVAD patients and 1 OMT patient improved sufficiently while on therapy to qualify for cardiac transplantation.ConclusionsInotrope-dependent heart failure patients who are ineligible for transplantation have a high short-term mortality rate and derive a significant survival advantage from “destination” mechanical circulatory support

Geo-Biological Investigations on Azooxanthellate Cold-Water Coral Reefs on the Carbonate Mounds Along the Celtic Continental Slope

Northeast Atlantic 2004 Cruise No. 61, Leg 1 April 19 to May 4, 2004, Lisbon – Cor

Co-occurrence of a novel PDGFRB variant and likely pathogenic variant in CASR in an individual with extensive intracranial calcifications and hypocalcaemia

No abstract available

HE0107-5240, A Chemically Ancient Star.I. A Detailed Abundance Analysis

We report a detailed abundance analysis for HE0107-5240, a halo giant with [Fe/H]_NLTE=-5.3. This star was discovered in the course of follow-up medium-resolution spectroscopy of extremely metal-poor candidates selected from the digitized Hamburg/ESO objective-prism survey. On the basis of high-resolution VLT/UVES spectra, we derive abundances for 8 elements (C, N, Na, Mg, Ca, Ti, Fe, and Ni), and upper limits for another 12 elements. A plane-parallel LTE model atmosphere has been specifically tailored for the chemical composition of {\he}. Scenarios for the origin of the abundance pattern observed in the star are discussed. We argue that HE0107-5240 is most likely not a post-AGB star, and that the extremely low abundances of the iron-peak, and other elements, are not due to selective dust depletion. The abundance pattern of HE0107-5240 can be explained by pre-enrichment from a zero-metallicity type-II supernova of 20-25M_Sun, plus either self-enrichment with C and N, or production of these elements in the AGB phase of a formerly more massive companion, which is now a white dwarf. However, significant radial velocity variations have not been detected within the 52 days covered by our moderate-and high-resolution spectra. Alternatively, the abundance pattern can be explained by enrichment of the gas cloud from which HE0107-5240 formed by a 25M_Sun first-generation star exploding as a subluminous SNII, as proposed by Umeda & Nomoto (2003). We discuss consequences of the existence of HE0107-5240 for low-mass star formation in extremely metal-poor environments, and for currently ongoing and future searches for the most metal-poor stars in the Galaxy.Comment: 60 pages, 16 figures. Accepted for publication in Ap

de Sitter Thick Brane Solution in Weyl Geometry

In this paper, we consider a de Sitter thick brane model in a pure geometric Weyl integrable five-dimensional space-time, which is a generalization of Riemann geometry and is invariant under a so-called Weyl rescaling. We find a solution of this model via performing a conformal transformation to map the Weylian structure into a familiar Riemannian one with a conformal metric. The metric perturbations of the model are discussed. For gravitational perturbation, we get the effective modified P$\ddot{\text{o}}$schl-Teller potential in corresponding Schr$\ddot{\text{o}}$dinger equation for Kaluza-Klein (KK) modes of the graviton. There is only one bound state, which is a normalizable massless zero mode and represents a stable 4-dimensional graviton. Furthermore, there exists a mass gap between the massless mode and continuous KK modes. We also find that the model is stable under the scalar perturbation in the metric. The correction to the Newtonian potential on the brane is proportional to $e^{-3 r \beta/2}/r^2$, where $\beta$ is the de Sitter parameter of the brane. This is very different from the correction caused by a volcano-like effective potential.Comment: 24 pages, 13 figures, published versio

Differential Roles for L-Type Calcium Channel Subtypes in Alcohol Dependence

It has previously been shown that the inhibition of L-type calcium channels (LTCCs) decreases alcohol consumption, although the contribution of the central LTCC subtypes Cav1.2 and Cav1.3 remains unknown. Here, we determined changes in Cav1.2 (Cacna1c) and Cav1.3 (Cacna1d) mRNA and protein expression in alcohol-dependent rats during protracted abstinence and naive controls using in situ hybridization and western blot analysis. Functional validation was obtained by electrophysiological recordings of calcium currents in dissociated hippocampal pyramidal neurons. We then measured alcohol self-administration and cue-induced reinstatement of alcohol seeking in dependent and nondependent rats after intracerebroventricular (i.c.v.) injection of the LTCC antagonist verapamil, as well as in mice with an inducible knockout (KO) of Cav1.2 in Ca2+/calmodulin-dependent protein kinase parallel to alpha (CaMKII alpha)-expressing neurons. Our results show that Cacna1c mRNA concentration was increased in the amygdala and hippocampus of alcohol-dependent rats after 21 days of abstinence, with no changes in Cacna1d mRNA. This was associated with increased Cav1.2 protein concentration and L-type calcium current amplitudes. Further analysis of Cacna1c mRNA in the CA1, basolateral amygdala (BLA), and central amygdala (CeA) revealed a dynamic regulation over time during the development of alcohol dependence. The inhibition of central LTCCs via i. c. v. administration of verapamil prevented cue-induced reinstatement of alcohol seeking in alcohol-dependent rats. Further studies in conditional Cav1.2-KO mice showed a lack of dependence-induced increase of alcohol-seeking behavior. Together, our data indicate that central Cav1.2 channels, rather than Cav1.3, mediate alcohol-seeking behavior. This finding may be of interest for the development of new antirelapse medications