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Identification of individuals at high risk for rapid progression of motor and cognitive signs in Parkinson disease (PD) is clinically significant. Postural instability and gait dysfunction (PIGD) are associated with greater motor and cognitive deterioration. We examined the relationship between baseline clinical factors and the development of postural instability using 5-year longitudinal de-novo idiopathic data (n = 301) from the Parkinson's Progressive Markers Initiative (PPMI). Logistic regression analysis revealed baseline features associated with future postural instability, and we designated this cohort the emerging postural instability (ePI) phenotype. We evaluated the resulting ePI phenotype rating scale validity in two held-out populations which showed a significantly higher risk of postural instability. Emerging PI phenotype was identified before onset of postural instability in 289 of 301 paired comparisons, with a median progression time of 972 days. Baseline cognitive performance was similar but declined more rapidly in ePI phenotype. We provide an ePI phenotype rating scale (ePIRS) for evaluation of individual risk at baseline for progression to postural instability.

Accurate measurement of left ventricular volumes and Ejection Fraction from cine MRI is of paramount importance to the evaluation of cardiovascular functions, yet it usually requires laborious and tedious work of trained experts to interpret them. To facilitate this procedure, numerous computer aided diagnosis (CAD) methods and tools have been proposed, most of which focus on the left or right ventricle segmentation. However, the identification of ES and ED frames from cardiac sequences is largely ignored, which is a key procedure in the automated workflow. This seemingly easy task is quite challenging, due to the requirement of high accuracy (i.e., precisely identifying specific frames from a sequence) and subtle differences among consecutive frames. Recently, with the rapid growth of annotated data and the increasing computational power, deep learning methods have been widely exploited in medical image analysis. In this paper, we propose a novel deep learning architecture, named as temporal regression network (TempReg-Net), to accurately identify specific frames from MRI sequences, by integrating the Convolutional Neural Network (CNN) with the Recurrent Neural Network (RNN). Specifically, a CNN encodes the spatial information of a cardiac sequence, and a RNN decodes the temporal information. In addition, we design a new loss function in our network to constrain the structure of predicted labels, which further improves the performance. Our approach is extensively validated on thousands of cardiac sequences and the average difference is merely 0.4 frames, comparing favorably with previous systems.

Background Schizophrenia (SZ) is an illness whose heterogeneity has impeded understanding the underlying pathophysiology. In order to better understand this heterogeneity, here we used magnetoencephalography (MEG), 7T Magnetic Resonance Spectroscopy (MRS), and 7T fMRI during the Stroop task, on the same set of patients with first episode psychosis (SZ). Methods 22 minimally treated first episode SZ and 24 healthy controls (HC) matched for age, gender, and family socio-economic status were recruited. Neurometabolite levels were obtained from the bilateral anterior cingulate cortex using 7T proton MRS with an ultra-short echo time (5 ms) STEAM sequence, and referenced to water. MEG was performed in a 4D systems 148 channel magnetometer, and both the auditory evoked potential to 40 Hz tone clicks, and the resting state (eyes closed) were recorded. The fMRI BOLD response to the Stroop task was also recorded in a 7T scanner. Results The magnitude of the audio-evoked MEG responses to 40 Hz tone clicks was not significantly different between SZ and HC. However, many SZ showed high levels of theta-band activity during the resting state. The ratio of theta to alpha band activity in the anterior MEG sensors significantly differentiated SZ from HC, P

OPERA AND ORATORIO The Vienna Don Giovanni. By Ian Woodfield. Woodbridge, U.K.: Boydell Press, 2010. [xvii, 214 p. ISBN 9781843835868. $95.] Music examples, illustrations, appendices, bibliography, index. Ever since the 1788 Vienna revival of Don Giovanni, for which Mozart and Lorenzo Da Ponte made substantial modifications to the 1787 Prague original, the wealth of materials, versions, and options the creators left behind have challenged performers, editors, and scholars to bring the opera into clear focus. Ian Woodfield has grappled intensely with these challenges and his book is an important contribution to our understanding of the opera. Near the end of the book, he places his own efforts into the context of past and ongoing scholarly efforts to understand the versions. Since the nineteenth century, scholars had pursued a "quest to establish [the opera's] authentic form" (p. 145). In Woodfield's critique of this quest, past efforts idealized a "text-based conception of the identity of Don Giovanni, supported by the twin pillars of the autograph and the premiere" (p. 145). Ultimately, this narrow foundation provided an "unreal picture" of the opera's interaction with its world. Wood - field aligns himself clearly with a "changing consensus" that coalesced in recent decades around the work of Alan Tyson and Dexter Edge in particular. A central theme of the book will be that an eighteenth-century opera was a "fluid . . . enterprise" rather than a "fixed text" (p. 1). His book demonstrates that new, and certainly newly nuanced, perspectives can result from a thoroughgoing application of philological methods in the service of this new set of ideals. Woodfield opens his book with Da Ponte's account of the early Viennese reception of Don Giovanni, which he uses to set up this theme. According to the librettist, Mozart made changes, and then made more changes, in response to early reactions. Woodfield next lays out the foundations of his philological approach. He provides a list of thirty-one relevant sources (table 1), carefully sorted into versions (Prague and two "final" Viennese versions that he has identified), rough date (early and late), and origin (Bohemian or Viennese). He then discusses the complexities that result from taking seriously the view that opera is a process. First, the approach requires the inclusive consideration of many sources and the challenging evidence they provide of a messy creative process. Messiness comes from the complexity of copying (producing numerous theater materials, including scores, parts, and prompter's books, under great time pressure). Moreover, there are a variety of points at which the autograph could interact with copyists, and a variety of moments during rehearsal or performance at which the composer's views (changes or clarifications) could be registered on one or more of the documents. Before closing, Wood - field introduces one of his main speculative conclusions: "on philological grounds it seems certain that at least two copies of the full score were prepared" (p. 7) during the period leading up to the performance. He terms these two the "conductor's score" and the "reference score" (more later on the second type). Woodfield's two-pronged philological method relies chiefly on "error transmission and layout" (p. x). Tracking "patterns of errors" is a "traditional tool of philology" (p. 14), but his approach to layout rests on some original strategies. During his earlier study of Cosi (Mozart's Cosi fan tutte: a Com po - sitional History [Woodbridge: Boydell Press, 2008]), he discovered that "page- and linebreak analysis" (p. 14) proves remarkably effective in tracking transmission, in large part because replicating the exact layout of an exemplar was a typical procedure used in the copying ateliers of the era. Woodfield also relies on the manuscript work of other scholars, notably Dexter Edge, for judgments about watermarks and copyists, especially as they affect the dating of a source or section. …

Complexities in sample handling, instrument setup and data analysis are barriers to the effective use of flow cytometry to monitor immunological parameters in clinical trials. The novel use of a central laboratory may help mitigate these issues.

The pathogenesis associated with Dengue haemorrhagic fever, has yet to be fully elucidated, with no definitive in vivo evidence. The exceptional epidemiological circumstances in Cuba allow the evaluation of different mediators in a well-defined situation. In the present study, we describe the determination of levels of IL-12, IL-10 and RANTES in the sera of Cuban patients hospitalised with Dengue fever or Dengue haemorrhagic fever. The results showed that levels of serum IL-10 were higher in patients than controls, and those patients with secondary infections had consistently higher levels. All the Dengue haemorrhagic fever patients had increased levels of IL-10. In contrast, levels of IL-12 did not differ between patients and controls. Finally, RANTES serum levels detected in patients were lower than those observed in the controls. The association of increased levels of IL-10 in Dengue patients with a sequential infection suggests a possible role of this cytokine in the pathogenesis of Dengue disease.

Background Innate immune responses can be activated rapidly in response to infection and may contribute to control of early viral replication or conversely, mediate immunopathogenic effects. To gain insight into the nature and kinetics of the earliest cytokine responses activated in acute HIV-1 infection (AHI), we analysed changes in systemic and mucosal cytokine/chemokine levels during primary infection.

Previous studies from our laboratory indicated that human NK activity against HSV-infected fibroblasts (HSV-Fs) but not K562 targets was sensitive to treatment with anti-HLA-DR plus C. In the current study, we have selected Leu-11a+ (CD-16) cells by fluorescence activated cell sorting and found that although Leu-11a enriched populations lysed K562 targets in 14-h 51Cr-release assays, they were unable to kill HSV-Fs targets unless a Leu-11a-depleted population was added back to the effectors or unless known activators of NK cells (IFN-alpha or IL-2) were added to the assays. In contrast, Leu-11a-enriched populations were able to mediate ADCC against HSV-Fs in the presence of sera from HSV-seropositive individuals without the requirement for accessory cells. We have begun preliminary characterization of the accessory cells which allow lysis of HSV-Fs by NK cells: they are HLA-DR+ cells which enrich in the light density fractions of Metrizamide density gradients. They need be present in very small numbers for lysis to take place and are not MHC restricted in that heterologous add-backs between anti-HLA-DR plus C and anti-Leu-11b plus C-treated populations are capable of target cell lysis at levels similar to those achieved with the autologous add-backs. Further, the levels of lysis in heterologous add-back experiments reflected the lytic potential of the effector rather than the accessory cell donor. Finally, although the requirement for accessory cells for NK lysis has been demonstrated for fibroblasts infected with HSV-1, CMV, and VZV, lysis of HSV-infected Raji lymphoblastoid cells is relatively accessory-cell independent, indicating that the requirement for accessory cells for lysis by NK cells is not a property of all herpesvirus-infected targets.

Six children with the acquired immunodeficiency syndrome (AIDS) and 12 of their household contacts were investigated serologically for evidence of infection with human T-lymphotropic virus/lymphadenopathy-associated virus (HTLV-III/LAV), the presumed etiologic agent of AIDS. All six children had antibody against HTLV-III/LAV, as measured by enzyme-linked immunosorbent assay, in each specimen tested. Of the two mothers studied both were seropositive; one was diagnosed with and died from AIDS. Four of the remaining 10 household members were seropositive, including three adults in groups at high risk for the development of AIDS and one sibling who was younger than the child with AIDS. Among the seronegative household contacts were four foster mothers or grandmothers of the children with AIDS, three of whom had cared for the children since infancy. Household contact with children with AIDS may include persons in groups at high risk for AIDS who have been infected with HTLV-III/LAV. However, the negative findings in household contacts without risk factors for AIDS suggest that horizontal transmission of the virus within households by means other than sexual contact must be infrequent.

Of a variety of purine and pyrimidine nucleotides tested, only ADP and 5′AMP significantly inhibited the Mg 2+ -dependent activity of pea leaf glutamine synthetase. They were less effective inhibitors where Mn 2+ replaced Mg 2+ . They were competitive inhibitors with respect to ATP, with inhibition constant (K i ) values of 1.2 and 1.8 mm, respectively. The energy charge significantly affects the activity of glutamine synthetase, especially with Mg 2+ . Of a variety of amino acids tested, l-histidine and l-ornithine were the most inhibitory, but significant inhibition was seen only where Mn 2+ was present. Both amino acids appeared to compete with l-glutamate, and the K i values were 1.9 mm for l-histidine (pH 6.2) and 7.8 mm for l-ornithine (pH 6.2). l-Alanine, glycine, and l-serine caused slight inhibition (Mn 2+ -dependent activity) and were not competitive with ATP or l-glutamate. Carbamyl phosphate was an effective inhibitor only when Mn 2+ was present, and did not compete with substrates. Inorganic phosphate and pyrophosphate caused significant inhibition of the Mg 2+ -dependent activity.

An enzyme was extensively purified from jack bean leaves (Canavalia ensiformis L.) which produced o-ureidohomoserine from l-canaline and carbamyl phosphate. The most highly purified preparations catalyzed both this reaction and citrulline synthesis from ornithine and carbamyl phosphate, and the ratio of the two activities remained nearly constant during purification. When hydrated jack bean seeds were the enzyme source, ornithine carbamyltransferase (EC 2.1.3.3) activity was high but synthesis of ureidohomoserine was barely detectable. Both ornithine carbamyltransferase and the ureidohomoserine synthesizing enzyme had similar Km values for carbamyl phosphate. The purification data suggest that one enzyme may catalyze both reactions in jack bean leaves.

Carbamoyl phosphate synthetase of pea shoots (Pisum sativum L.) was purified 101-fold. Its stability was greatly increased by the addition of substrates and activators. The enzyme was strongly inhibited by micromolar amounts of UMP (Ki less than 2 mum). UDP, UTP, TMP, and ADP were also inhibitory. AMP caused either slight activation (under certain conditions) or was inhibitory. Uridine nucleotides were competitive inhibitors, as was AMP, while ADP was a noncompetitive inhibitor. Enzyme activity was increased manyfold by the activator ornithine. Ornithine acted by increasing the affinity for Mg.ATP by a factor of 8 or more. Other activators were IMP, GMP, ITP, and GTP, IMP, like ornithine, increased the Michaelis constant for Mg.ATP. The activators ornithine, GMP, and IMP (but not GTP and ITP) completely reversed inhibition caused by pyrimidine nucleotides while increasing the inhibition caused by ADP and AMP.

Similar to other lymphoid organs, the bone marrow (BM) is a potential reservoir for HIV-1. Although hematologic abnormalities are common in AIDS patients, the mechanisms by which HIV-1 contributes to these abnormalities are poorly understood. Hemapoietic suppression can be mediated by HIV-1 and some of its associated proteins. We have previously reported that AIDS peripheral blood sera inhibit normal CFU-granulocyte macrophage (GM). In this study, we have found that sera obtained from AIDS BM patients are more inhibitory to CFU-GM than those from peripheral blood (p < 0.05). To determine a candidate suppressor factor, we studied the role of p24 and found that it exerts varying degrees of suppression to CFU-GM, but minimal inhibition on erythroid colonies. We have found that the suppressive levels of p24 in in vitro assays are similar to the average circulating levels in AIDS patients. We have also observed that most of the inhibition caused by p24 is mediated by soluble factor(s) produced by the BM stroma. Cross-linking studies with membrane proteins from normal BM stroma and CD34+ cells indicated a putative 26-kDa p24 receptor, indicating that p24 binds to a receptor present on normal BM cells. These results implicate another HIV-1 protein, p24, in hemapoietic suppression and add another plausible mechanism by which HIV-1 contributes to BM failure in AIDS. Furthermore, these findings suggest a potential risk for similar in vivo suppression in the early phase of HIV-1 infection when viremia is elevated, and also in long-term survivors who have low, although persistent, HIV-1 replication.