Variable phenotypic manifestations of a K44N mutation in the TGIF gene

The etiologies and clinical spectra of HPE are extremely heterogeneous. Here, we report a Brazilian boy with lobar holoprosencephaly who was ascertained in a sample of 60 patients with HPE and HPE-like phenotypes and screened for molecular analysis of the major HPE causative genes: SHH, PTCH, SIX3, GLI2, and TGIF This boy presented a p.K44N (c.132G > T) mutation in exon 2 of the TGIF gene which was inherited from his phenotypically normal mother. This mutation leads to lysine to arginine amino acid change and is predicted to be a damaging mutation. Clinical aspects involving variable phenotypical manifestations in different mutations of TGIF are discussed. (c) 2007 Elsevier B.V. All rights reserved.

An assessment of the latent and sensible heat flux on the simulated regional climate over Southwestern South Atlantic Ocean

A Regional Climate Model (RegCM3) 10-year (1990-1999) simulation over southwestern South Atlantic Ocean (SAO) is evaluated to assess the mean climatology and the simulation errors of turbulent fluxes over the sea. Moreover, the relationship between these fluxes and the rainfall over some cyclogenetic areas is also analyzed. The RegCM3 results are validated using some reanalyses datasets (ERA40, R2, GPCP and WHOI). The summer and winter spatial patterns of latent and sensible heat fluxes simulated by the RegCM3 are in agreement with the reanalyses (WHOI, R2 and ERA40). They show large latent heat fluxes exchange in the subtropical SAO and at higher latitudes in the warm waters of Brazil Current. In particular, the magnitude of RegCM3 latent heat fluxes is similar to the WHOI, which is probably related to two factors: (a) small specific humidity bias, and (b) the RegCM3 flux algorithm. In contrast, the RegCM3 presents large overestimation of sensible heat flux, though it simulates well their spatial pattern. This simulation error is associated with the RegCM3 underestimation of the 2-m air temperature. In southwestern SAO, in three known cyclogenetic areas, the reanalyses and the RegCM3 show the existence of different physical mechanisms that control the annual cycles of latent/sensible heating and rainfall. It is shown that over the eastern coast of Uruguay (35A degrees-43A degrees S) and the southeastern coast of Argentina (44A degrees-52A degrees S) the sea-air moisture and heat exchange play an important role to control the annual cycle of precipitation. This does not happen on the south/southeastern coast of Brazil.

A two-armed pattern in flickering maps of the nova-like variable UU aquarii

We report the analysis of a uniform sample of 31 light curves of the nova-like variable UU Aqr with eclipse-mapping techniques. The data were combined to derive eclipse maps of the average steady-light component, the long-term brightness changes, and the low- and high-frequency flickering components. The long-term variability responsible for the ""low-brightness`` and ""high-brightness`` states is explained in terms of the response of a viscous disk to changes of 20%-50% in the mass transfer rate from the donor star. Low- and high-frequency flickering maps are dominated by emission from two asymmetric arcs reminiscent of those seen in the outbursting dwarf nova IP Peg, and they are similarly interpreted as manifestations of a tidally induced spiral shock wave in the outer regions of a large accretion disk. The asymmetric arcs are also seen in the map of the steady light aside from the broad brightness distribution of a roughly steady-state disk. The arcs account for 25% of the steady-light flux and are a long-lasting feature in the accretion disk of UU Aqr. We infer an opening angle of 10 degrees +/- 3 degrees for the spiral arcs. The results suggest that the flickering in UU Aqr is caused by turbulence generated after the collision of disk gas with the density-enhanced spiral wave in the accretion disk.

ON THE NATURE OF THE PROTOTYPE LUMINOUS BLUE VARIABLE AG CARINAE. II. WITNESSING A MASSIVE STAR EVOLVING CLOSE TO THE EDDINGTON AND BISTABILITY LIMITS

We show that the significantly different effective temperatures (T(eff)) achieved by the luminous blue variable AG Carinae during the consecutive visual minima of 1985-1990 (T(eff) similar or equal to 22,800 K) and 2000-2001 (T(eff) similar or equal to 17,000 K) place the star on different sides of the bistability limit, which occurs in line-driven stellar winds around T(eff) similar to 21,000 K. Decisive evidence is provided by huge changes in the optical depth of the Lyman continuum in the inner wind as T(eff) changes during the S Dor cycle. These changes cause different Fe ionization structures in the inner wind. The bistability mechanism is also related to the different wind parameters during visual minima: the wind terminal velocity was 2-3 times higher and the mass-loss rate roughly two times smaller in 1985-1990 than in 2000-2003. We obtain a projected rotational velocity of 220 +/- 50 km s(-1) during 1985-1990 which, combined with the high luminosity (L(star) = 1.5 x 10(6) L(circle dot)), puts AG Car extremely close to the Eddington limit modified by rotation (Omega Gamma limit): for an inclination angle of 90 degrees, Gamma(Omega) greater than or similar to 1.0 for M(circle dot) less than or similar to 60. Based on evolutionary models and mass budget, we obtain an initial mass of similar to 100 M(circle dot) and a current mass of similar to 60-70 M(circle dot) for AG Car. Therefore, AG Car is close to, if not at, the Omega Gamma limit during visual minimum. Assuming M = 70 M(circle dot), we find that Gamma(Omega) decreases from 0.93 to 0.72 as AG Car expands toward visual maximum, suggesting that the star is not above the Eddington limit during maximum phases.

Patterns of Antibodies Against Latent and Lytic Antigens of Human Herpesvirus 8 in an Endemic Population and Patients With Kaposi`s Sarcoma in Mozambique

The patterns of antibodies against latent and lytic antigens of human herpesvirus 8 (HHV-8) were assessed using immunofluorescence assays of samples from 155 persons seropositive for HHV-8 seen at public health centers and 24 patients with Kaposi`s sarcoma (KS) from Mozambique. Of the 155 persons without KS, 48(31%) had antibodies against latent antigens only, 29 (18.7%) had antibodies against lytic antigens only, and 78 (50.3%) had antibodies against both types of antigen. The HHV-8 antibody titer tended to increase with age until age 40, after which it began to decrease. High titers of antibodies against latent and lytic antigens of HHV-8 were detected mostly in persons co-infected with HIV, and these increased titers could have a predictive value. All patients with KS except four patients who were seronegative for HHV-8 had elevated titers of HHV-8 antibodies, predominantly against latent antigens. The data suggest the potential for an increase in the development of KS in this endemic area for HHV-8. J. Med. Virol. 82:1576-1581, 2010. (C) 2010 Wiley-Liss, Inc.

A Comparative Study of the Frequency of Antibody and Titers Against Human Herpesvirus 8 Latent and Lytic Antigens in ""At-Risk"" Individuals and Among Patients With Kaposi`s Sarcoma

Differences in the prevalence of human herpesvirus 8 (HHV-8) and Kaposi`s sarcoma (KS) have been described, depending on the study population and their geographic origin. A cross-sectional study aimed at detecting the frequency and titers of antibodies against HHV-8 latent and lytic antigens in serum samples from individuals with different risk-factors for HHV-8 infection, as well as predictive marker identification in patients with KS, was conducted. Serum samples were collected from seven groups of individuals: 75 patients with AIDS-KS, 5 with classic KS, 16 with African KS, 495 with HIV/AIDS, 805 patients with chronic kidney disease, 683 handicapped individuals, and 757 health care workers. Samples were evaluated for the presence and titers of HHV-8-specific antibodies to latent and lytic antigens using ""in house"" immunofluorescence assays. The results were analyzed by the Chi-square, Fisher`s exact test, Kruskal-Wallis and/or Mann-Whitney U-tests. The frequencies of HHV-8 antibodies were as follows: 87.5-100% in patients with KS, 20.4% in patients with HIV/AIDS, 18% in patients with chronic kidney disease, 1.6% in handicapped individuals, and 1.1% in health care workers. A greater number of samples were antibody positive to lytic antigens. Elevated titers of antibodies to latent and lytic antigens, mostly among patients with KS, were detected. Using established serological assays, different ""at-risk"" populations for HHV-8 infection/disease were detected in this geographic area, confirming HIV/AIDS and identifying patients with chronic kidney disease as high-risk groups. It is suggested that a longitudinal evaluation of antibody titers in patients with chronic kidney disease be undertaken to confirm their predictive value in the development of KS. J. Med. Virol. 81: 1292-1297, 2009. (C) 2009 Wiley-Liss, Inc.

Autoimmunity in common variable immunodeficiency

immunodeficiency (CVID), the most common symptomatic primary immunodeficiency in adulthood. Different authors report high prevalences of autoimmune diseases in CVID, and several mechanisms have been proposed to explain this apparent paradox. Genetic predisposition, under current surveillance, innate and adaptive immunity deficiencies leading to persistent/recurrent infections, variable degrees of immune dysregulation, and possible failure in central and peripheral mechanisms of tolerance induction or maintenance may all contribute to increased autoimmunity. Conclusions Data on the clinical/immunological profile of affected patients and treatment are available mostly concerning autoimmune cytopenias, the most common autoimmune diseases in CVID. Treatment is based on conventional alternatives, in association with short experience with new agents, including rituximab and infliximab. Benefits of early immunoglobulin substitutive treatment and hypothetical premature predictors of autoimmunity are discussed as potential improvements to CVID patients` follow-up.

Slower rescue of ER homeostasis by the unfolded protein response pathway associated with common variable immunodeficiency

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinemia and recurrent infections. Herein we addressed the role of unfolded protein response (UPR) in the pathogenesis of the disease. Augmented unspliced X-box binding protein 1 (XBP-1) mRNA concurrent with co-localization of IgM and BiP/GRP78 were found in one CVID patient. At confocal microscopy analysis this patient`s cells were enlarged and failed to present the typical surface distribution of IgM, which accumulated within an abnormally expanded endoplasmic reticulum. Sequencing did not reveal any mutation on XBP-1, neither on IRE-1 alpha that could potentially prevent the splicing to occur. Analysis of spliced XBP-1, IRE-1 alpha and BiP messages after LPS or Brefeldin A treatment showed that, unlike healthy controls that respond to these endoplasmic reticulum (ER) stressors by presenting waves of transcription of these three genes, this patient`s cells presented lower rates of transcription, not reaching the same level of response of healthy subjects even after 48 h of ER stress. Treatment with DMSO rescued IgM and IgG secretion as well as the expression of spliced XBP-1. Our findings associate diminished splicing of XBP-1 mRNA with accumulation of IgM within the ER and lower rates of chaperone transcription, therefore providing a mechanism to explain the observed hypogammaglobulinemia. (C) 2008 Elsevier Ltd. All rights reserved.

Reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells and diminished FOXP3 expression in patients with Common Variable Immunodeficiency: A link to autoimmunity?

Common Variable Immunodeficiency (CVID) is a primary immunodeficiency disease characterized by defective immunoglobulin production and often associated with autoimmunity. We used flow cytometry to analyze CD4(+)CD25(HIGH)FOXP3(+) T regulatory (Treg) cells and ask whether perturbations in their frequency in peripheral blood could underlie the high incidence of autoimmune disorders in CVID patients. In this study, we report for the first time that CVID patients with autoimmune disease have a significantly reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells in their peripheral blood accompanied by a decreased intensity of FOXP3 expression. Notably, although CVID patients in whom autoimmunity was not diagnosed had a reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells, FOXP3 expression levels did not differ from those in healthy controls. In conclusion, these data suggest compromised homeostasis of CD4(+)CD25(HIGH)FOXP3(+) cells in a subset of CVID patients with autoimmunity, and may implicate Treg cells in pathological mechanisms of CVID. (C) 2009 Elsevier Inc. All rights reserved.

Discontinuous local semiflows for Kurzweil equations leading to LaSalle`s invariance principle for differential systems with impulses at variable times

In this paper, we consider an initial value problem for a class of generalized ODEs, also known as Kurzweil equations, and we prove the existence of a local semidynamical system there. Under certain perturbation conditions, we also show that this class of generalized ODEs admits a discontinuous semiflow which we shall refer to as an impulsive semidynamical system. As a consequence, we obtain LaSalle`s invariance principle for such a class of generalized ODEs. Due to the importance of LaSalle`s invariance principle in studying stability of differential systems, we include an application to autonomous ordinary differential systems with impulse action at variable times. (C) 2011 Elsevier Inc. All rights reserved.

Loops, Chains, Sheets, and Networks from Variable Coordination of Cu(hfac)(2) with a Flexibly Hinged Aminoxyl Radical Ligand

One pair of reactants, Cu(hfac)(2) = M and the hinge-flexible radical ligand 5-(3-N-tert-butyl-N-aminoxylphenyl)pyrimidine (3PPN = L), yields a diverse set of five coordination complexes: a cyclic loop M(2)L(1) dimer; a 1:1 cocrystal between an M(2)L(2) loop and an ML(2) fragment; a ID chain of M(2)L(2) loops linked by M; two 2D M(3)L(2) networks of (M-L)(n) chains crosslinked by M with different repeat length pitches; a 3D M(3)L(2) network of M(2)L(2) loops cross-linking (M-L)(n)-type chains with connectivity different from those in the 2D networks. Most of the higher dimensional complexes exhibit reversible, temperature-dependent spin-state conversion of high-temperature paramagnetic states to lower magnetic moment states having antiferromagnetic exchange within Cu-ON bonds upon cooling, with accompanying bond contraction. The 3D complex also exhibited antiferromagnetic exchange between Cu(II) ions linked in chains through pyrimidine rings.

Global minimization using an Augmented Lagrangian method with variable lower-level constraints

A novel global optimization method based on an Augmented Lagrangian framework is introduced for continuous constrained nonlinear optimization problems. At each outer iteration k the method requires the epsilon(k)-global minimization of the Augmented Lagrangian with simple constraints, where epsilon(k) -> epsilon. Global convergence to an epsilon-global minimizer of the original problem is proved. The subproblems are solved using the alpha BB method. Numerical experiments are presented.

Performance of balanced two-stage empirical predictors of realized cluster latent values from finite populations: A simulation study

Predictors of random effects are usually based on the popular mixed effects (ME) model developed under the assumption that the sample is obtained from a conceptual infinite population; such predictors are employed even when the actual population is finite. Two alternatives that incorporate the finite nature of the population are obtained from the superpopulation model proposed by Scott and Smith (1969. Estimation in multi-stage surveys. J. Amer. Statist. Assoc. 64, 830-840) or from the finite population mixed model recently proposed by Stanek and Singer (2004. Predicting random effects from finite population clustered samples with response error. J. Amer. Statist. Assoc. 99, 1119-1130). Predictors derived under the latter model with the additional assumptions that all variance components are known and that within-cluster variances are equal have smaller mean squared error (MSE) than the competitors based on either the ME or Scott and Smith`s models. As population variances are rarely known, we propose method of moment estimators to obtain empirical predictors and conduct a simulation study to evaluate their performance. The results suggest that the finite population mixed model empirical predictor is more stable than its competitors since, in terms of MSE, it is either the best or the second best and when second best, its performance lies within acceptable limits. When both cluster and unit intra-class correlation coefficients are very high (e.g., 0.95 or more), the performance of the empirical predictors derived under the three models is similar. (c) 2007 Elsevier B.V. All rights reserved.