bluuebunny/crossref_metadata_2025_split huggingface dataset:
Depression in the elderly: A review and update
Authors: Casey David A. 
Published: April 2012

AbstractDepression is a major source of suffering and disability among the elderly. It may be overlooked among elders because of its co‐occurrence with the aging process, grief, dementia, and medical illness. The author reviewed the field in 1994, and in this paper describes important developments of the past two decades. These include evolving concepts in diagnosis such as minor depression, vascular depression, and the depression of Alzheimer's disease. Complex inter‐relationships among depression and medical diseases have been explored, especially cardiovascular and cerebrovascular disease. During this period selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors have largely replaced tricyclic antidepressants and monoamine oxidase inhibitors, while electroconvulsive therapy has continued to be utilized. Repetitive transcranial stimulation is in its infancy and its role in geriatric depression is being defined. Developments in psychotherapy have solidified its place in the treatment of geriatric depression, particularly cognitive behavioral therapy.
Overcoming sink limitations in dissolution testing: a review of traditional methods and the potential utility of biphasic systems
Authors: Phillips Daniel J , Pygall Samuel R , Cooper V Brett , Mann James C 
Published: April 2012

Abstract

Objectives
The conventional dissolution test, particularly the USP apparatus I and II, remains an important tool in the armory of the pharmaceutical development scientist. For realistic dissolution characterization, sink conditions, where saturation solubility of a drug in the dissolution medium is at least three times more than the drug concentration, are critical. These conditions can be problematic to maintain with formulations containing poorly-soluble actives. This review summarizes the role of the dissolution test in the pharmaceutical industry, together with some traditional techniques/additives used to enhance solubility and facilitate the achievement of sink conditions. The biphasic dissolution system, an innovative model for the treatment of poorly-soluble species, will also be discussed.

Key findings
The biphasic dissolution model utilizes media comprising immiscible aqueous and organic layers whereby the drug, following initial aqueous dissolution, partitions into the organic layer. This step, which acts to remove all dissolved species from the aqueous layer, enables further aqueous dissolution to occur and hence the dissolution–partition cycle continues. Crucially, the aqueous layer does not saturate allowing sink conditions to be maintained and hence the experiment will, in theory, yield complete dissolution.

Summary
This review highlights important concepts regarding solubility/sink limitation and intends to provoke debate among analytical and formulation scientists as to the potential advantages, long-term development and widespread implementation of a biphasic dissolution system in drug development.
Sequence in the Influenza A Virus Nucleoprotein Required for Viral Polymerase Binding and RNA Synthesis
Authors: Marklund Jesper K. , Ye Qiaozhen , Dong Jinhui , Tao Yizhi Jane , Krug Robert M. 
Published: April 2012

ABSTRACT

Many proposed mechanisms for influenza A viral RNA synthesis include an interaction of the nucleoprotein (NP) with the viral polymerase. To identify an NP sequence required for this interaction, we used the cryoelectron microscopic structure of an influenza virus miniribonucleoprotein as a guide for choosing promising surface-exposed sequences. We show that three amino acids (R204, W207, and R208) located in a loop at the top of the head domain of NP are required for functional interaction with the viral polymerase. Quantitative reverse transcription-PCR (RT-PCR) measurements of RNAs synthesized in minigenome assays established that each of these NP amino acids is required for viral RNA synthesis. The mutation of these three amino acids does not affect nuclear localization or RNA-binding and oligomerization activities of NP.
In vitro
binding experiments with purified virus polymerase and NPs established that these three amino acids are required for NP binding to the viral polymerase.
Comparable Polyfunctionality of Ectromelia Virus- and Vaccinia Virus-Specific Murine T Cells despite Markedly DifferentIn VivoReplication and Pathogenicity
Authors: Hersperger Adam R. , Siciliano Nicholas A. , Eisenlohr Laurence C. 
Published: April 2012

ABSTRACTVaccinia virus (VACV) stimulates long-term immunity against highly pathogenic orthopoxvirus infection of humans (smallpox) and mice (mousepox [ectromelia virus {ECTV}]) despite the lack of a natural host-pathogen relationship with either of these species. Previous research revealed that VACV is able to induce polyfunctional CD8+T-cell responses after immunization of humans. However, the degree to which the functional profile of T cells induced by VACV is similar to that generated during natural poxvirus infection remains unknown. In this study, we monitored virus-specific T-cell responses following the dermal infection of C57BL/6 mice with ECTV or VACV. Using polychromatic flow cytometry, we measured levels of degranulation, cytokine expression (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-2 [IL-2]), and the cytolytic mediator granzyme B. We observed that the functional capacities of T cells induced by VACV and ECTV were of a similar quality in spite of the markedly different replication abilities and pathogenic outcomes of these viruses. In general, a significant fraction (≥50%) of all T-cell responses were positive for at least three functions both during acute infection and into the memory phase.In vivokilling assays revealed that CD8+T cells specific for both viruses were equally cytolytic (∼80% target cell lysis after 4 h), consistent with the similar levels of granzyme B and degranulation detected among these cells. Collectively, these data provide a mechanism to explain the ability of VACV to induce protective T-cell responses against pathogenic poxviruses in their natural hosts and provide further support for the use of VACV as a vaccine platform able to induce polyfunctional T cells.
Envelope Variable Region 4 Is the First Target of Neutralizing Antibodies in Early Simian Immunodeficiency Virus mac251 Infection of Rhesus Monkeys
Authors: Yeh Wendy W. , Brassard Laura M. , Miller Caroline A. , Basavapathruni Aravind , Zhang Jinrong , Rao Srinivas S. , Nabel Gary J. , Mascola John R. , Letvin Norman L. , Seaman Michael S. 
Published: April 2012

ABSTRACT

A major goal of AIDS vaccine development is to design vaccination strategies that can elicit broad and potent protective antibodies. The initial viral targets of neutralizing antibodies (NAbs) early after human or simian immunodeficiency virus (HIV/SIV) infection are not known. The identification of early NAb epitopes that induce protective immunity or retard the progression of disease is important for AIDS vaccine development. The aim of this study was to determine the Env residues targeted by early SIV NAbs and to assess the influence of prior vaccination on neutralizing antibody kinetics and specificity during early infection. We previously described stereotypic
env
sequence variations in SIVmac251-infected rhesus monkeys that resulted in viral escape from NAbs. Here, we defined the early viral targets of neutralization and determined whether the ability of serum antibody from infected monkeys to neutralize SIV was altered in the setting of prior vaccination. To localize the viral determinants recognized by early NAbs, a panel of mutant pseudoviruses was assessed in a TZM-bl reporter gene neutralization assay to define the precise changes that eliminate recognition by SIV Env-specific NAbs in 16 rhesus monkeys. Changing R420 to G or R424 to Q in V4 of Env resulted in the loss of recognition by NAbs in vaccinated monkeys. In contrast, mutations in the V1 region of Env did not alter the NAb profile. These findings indicate that early NAbs are directed toward SIVmac251 Env V4 but not the V1 region, and that this
env
vaccination regimen did not alter the kinetics or the breadth of NAbs during early infection.
Reovirus Variants with Mutations in Genome Segments S1 and L2 Exhibit Enhanced Virion Infectivity and Superior Oncolysis
Authors: Shmulevitz Maya , Gujar Shashi A. , Ahn Dae-Gyun , Mohamed Adil , Lee Patrick W. K. 
Published: April 2012

ABSTRACT
Reovirus preferentially replicates in transformed cells and is being explored as a cancer therapy. Immunological and physical barriers to virotherapy inspired a quest for reovirus variants with enhanced oncolytic potency. Using a classical genetics approach, we isolated two reovirus variants (T3v1 and T3v2) with superior replication relative to wild-type reovirus serotype 3 Dearing (T3wt) on various human and mouse tumorigenic cell lines. Unique mutations in reovirus λ2 vertex protein and σ1 cell attachment protein were associated with the large plaque-forming phenotype of T3v1 and T3v2, respectively. Both T3v1 and T3v2 exhibited higher infectivity (i.e., a higher PFU-to-particle ratio) than T3wt. A detailed analysis of virus replication revealed that virus cell binding and uncoating were equivalent for variant and wild-type reoviruses. However, T3v1 and T3v2 were significantly more efficient than T3wt in initiating productive infection. Thus, when cells were infected with equivalent input virus particles, T3v1 and T3v2 produced significantly higher levels of early viral RNAs relative to T3wt. Subsequent steps of virus replication (viral RNA and protein synthesis, virus assembly, and cell death) were equivalent for all three viruses. In a syngeneic mouse model of melanoma, both T3v1 and T3v2 prolonged mouse survival compared to wild-type reovirus. Our studies reveal that oncolytic potency of reovirus can be improved through distinct mutations that increase the infectivity of reovirus particles.
Antibodies against the gH/gL/UL128/UL130/UL131 Complex Comprise the Majority of the Anti-Cytomegalovirus (Anti-CMV) Neutralizing Antibody Response in CMV Hyperimmune Globulin
Authors: Fouts Ashley E. , Chan Pamela , Stephan Jean-Philippe , Vandlen Richard , Feierbach Becket 
Published: April 2012

ABSTRACT
Anti-cytomegalovirus (anti-CMV) hyperimmune globulin (HIG) has demonstrated efficacy in preventing CMV disease in solid-organ transplant patients as well as congenital disease when administered to pregnant women. To identify the neutralizing component of cytomegalovirus hyperimmune globulin (CMV-HIG), we performed serial depletions of CMV-HIG on cell-surface-expressed CMV antigens as well as purified antigens. Using this approach, we demonstrate that the major neutralizing antibody response is directed at the gH/gL/UL128/UL130/UL131 complex, suggesting little role for anti-gB antibodies in CMV-HIG neutralization.
RNA Structural Elements Determine Frequency and Sites of Nonhomologous Recombination in an Animal Plus-Strand RNA Virus
Authors: Austermann-Busch Sophia , Becher Paul 
Published: April 2012

ABSTRACT

For highly variable RNA viruses, RNA recombination significantly contributes to genetic variations which may lead to changes of virulence, adaptation to new hosts, escape from the host immune response, and emergence of new infectious agents. Using a system based on transfection of cells with synthetic nonreplicable subgenomic transcripts derived from bovine viral diarrhea virus (family
Flaviviridae
), the existence of a replication-independent mechanism of RNA recombination, in addition to the commonly accepted replicative copy-choice recombination, has been previously proven (A. Gallei et al., J. Virol. 78:6271–6281, 2004). To identify RNA signals involved in efficient joining of RNA molecules, RNA recombination in living cells was targeted to the 3′ nontranslated region. Molecular characterization of 40 independently emerged recombinant viruses revealed that the majority of recombination sites are located in single-stranded regions of the RNA molecules. Furthermore, the results of this study showed that the frequency of RNA recombination directly correlated with the RNA amounts of both recombination partners. The frequency can be strongly increased by modification of the 5′ triphosphates and 3′ hydroxyls of the recombining RNA molecules to 5′ hydroxyl and 3′ monophosphoryl ends, respectively. Analysis of recombinants that emerged after transfection with such modified RNA molecules revealed a complete integration and efficient end-to-end joining of the recombination partner(s) in at least 80% of recombinants, while unmodified RNA molecules recombined exclusively at internal positions. These results are in line with the hypothesis that endoribonucleolytic cleavage and a subsequent ligation reaction can cause RNA recombination.
Pathogenic Old World Arenaviruses Inhibit TLR2/Mal-Dependent Proinflammatory Cytokines
In Vitro
Authors: Hayes Melissa W. , Carrion Ricardo , Nunneley Jerritt , Medvedev Andrei E. , Salvato Maria S. , Lukashevich Igor S. 
Published: April 2012

ABSTRACT
Lymphocytic choriomeningitis virus (LCMV), the prototype arenavirus, and Lassa virus (LASV), the causative agent of Lassa fever (LF), have extensive strain diversity and significant variations in pathogenicity for humans and experimental animals. The WE strain of LCMV (LCMV-WE), but not the Armstrong (Arm) strain, induces a fatal LF-like disease in rhesus macaques. We also demonstrated that LASV infection of human macrophages and endothelial cells resulted in reduced levels of proinflammatory cytokines. Here we have shown that cells infected with LASV or with LCMV-WE suppressed Toll-like receptor 2 (TLR2)-dependent proinflammatory cytokine responses. The persisting isolate LCMV clone 13 (CL13) also failed to stimulate interleukin-6 (IL-6) in macrophages. In contrast, nonpathogenic Mopeia virus, which is a genetic relative of LASV and LCMV-Arm induced robust responses that were TLR2/Mal dependent, required virus replication, and were enhanced by CD14. Superinfection experiments demonstrated that the WE strain of LCMV inhibited the Arm-mediated IL-8 response during the early stage of infection. In cells transfected with the NF-κB–luciferase reporter, infection with LCMV-Arm resulted in the induction of NF-κB, but cells infected with LCMV-WE and CL13 did not. These results suggest that pathogenic arenaviruses suppress NF-κB-mediated proinflammatory cytokine responses in infected cells.
HIV-1 Infection
Ex Vivo
Accelerates Measles Virus Infection by Upregulating Signaling Lymphocytic Activation Molecule (SLAM) in CD4
+
T Cells
Authors: Mitsuki Yu-ya , Terahara Kazutaka , Shibusawa Kentaro , Yamamoto Takuya , Tsuchiya Takatsugu , Mizukoshi Fuminori , Ishige Masayuki , Okada Seiji , Kobayashi Kazuo , Morikawa Yuko , Nakayama Tetsuo , Takeda Makoto , Yanagi Yusuke , Tsunetsugu-Yokota Yasuko 
Published: April 2012

ABSTRACT

Measles virus (MV) infection in children harboring human immunodeficiency virus type 1 (HIV-1) is often fatal, even in the presence of neutralizing antibodies; however, the underlying mechanisms are unclear. Therefore, the aim of the present study was to examine the interaction between HIV-1 and wild-type MV (MVwt) or an MV vaccine strain (MVvac) during dual infection. The results showed that the frequencies of MVwt- and MVvac-infected CD4
+
T cells within the resting peripheral blood mononuclear cells (PBMCs) were increased 3- to 4-fold after HIV-1 infection, and this was associated with a marked upregulation of signaling lymphocytic activation molecule (SLAM) expression on CD4
+
T cells but not on CD8
+
T cells. SLAM upregulation was induced by infection with a replication-competent HIV-1 isolate comprising both the X4 and R5 types and to a lesser extent by a pseudotyped HIV-1 infection. Notably, SLAM upregulation was observed in HIV-infected as well as -uninfected CD4
+
T cells and was abrogated by the removal of HLA-DR
+
cells from the PBMC culture. Furthermore, SLAM upregulation did not occur in uninfected PBMCs cultured together with HIV-infected PBMCs in compartments separated by a permeable membrane, indicating that no soluble factors were involved. Rather, CD4
+
T cell activation mediated through direct contact with dendritic cells via leukocyte function-associated molecule 1 (LFA-1)/intercellular adhesion molecule 1 (ICAM-1) and LFA-3/CD2 was critical. Thus, HIV-1 infection induces a high level of SLAM expression on CD4
+
T cells, which may enhance their susceptibility to MV and exacerbate measles in coinfected individuals.
Inhibition of Interferon Regulatory Factor 3 Activation by Paramyxovirus V Protein
Authors: Irie Takashi , Kiyotani Katsuhiro , Igarashi Tomoki , Yoshida Asuka , Sakaguchi Takemasa 
Published: April 2012

ABSTRACT

The V protein of Sendai virus (SeV) suppresses innate immunity, resulting in enhancement of viral growth in mouse lungs and viral pathogenicity. The innate immunity restricted by the V protein is induced through activation of interferon regulatory factor 3 (IRF3). The V protein has been shown to interact with melanoma differentiation-associated gene 5 (MDA5) and to inhibit beta interferon production. In the present study, we infected MDA5-knockout mice with V-deficient SeV and found that MDA5 was largely unrelated to the innate immunity that the V protein suppresses
in vivo
. We therefore investigated the target of the SeV V protein. We previously reported interaction of the V protein with IRF3. Here we extended the observation and showed that the V protein appeared to inhibit translocation of IRF3 into the nucleus. We also found that the V protein inhibited IRF3 activation when induced by a constitutive active form of IRF3. The V proteins of measles virus and Newcastle disease virus inhibited IRF3 transcriptional activation, as did the V protein of SeV, while the V proteins of mumps virus and Nipah virus did not, and inhibition by these proteins correlated with interaction of each V protein with IRF3. These results indicate that IRF3 is important as an alternative target of paramyxovirus V proteins.
Single and Coexpression of CXCR4 and CXCR5 Identifies CD4 T Helper Cells in Distinct Lymph Node Niches during Influenza Virus Infection
Authors: Elsner Rebecca A. , Ernst David N. , Baumgarth Nicole 
Published: April 2012

ABSTRACT

Influenza virus infection results in strong, mainly T-dependent, extrafollicular and germinal center B cell responses, which provide lifelong humoral immunity against the homotypic virus strain. Follicular T helper cells (T
FH
) are key regulators of humoral immunity. Questions remain regarding the presence, identity, and function of T
FH
subsets regulating early extrafollicular and later germinal center B cell responses. This study demonstrates that ICOS but not CXCR5 marks T cells with B helper activity induced by influenza virus infection and identifies germinal center T cells (T
GC
) as lymph node-resident CD4
+
ICOS
+
CXCR4
+
CXCR5
+
PSGL-1
lo
PD-1
hi
cells. The CXCR4 expression intensity further distinguished their germinal center light and dark zone locations. This population emerged strongly in regional lymph nodes and with kinetics similar to those of germinal center B cells and were the only T
FH
subsets missing in influenza virus-infected, germinal center-deficient SAP
−/−
mice, mice which were shown previously to lack protective memory responses after a secondary influenza virus challenge, thus indicting the nonredundant functions of CXCR4- and CXCR5-coexpressing CD4 helper cells in antiviral B cell immunity. CXCR4-single-positive T cells, present in B cell-mediated autoimmunity and regarded as “extrafollicular” helper T cells, were rare throughout the response, despite prominent extrafollicular B cell responses, revealing fundamental differences in autoimmune- and infection-induced T-dependent B cell responses. While all ICOS
+
subsets induced similar antibody levels
in vitro
, CXCR5-single-positive T cells were superior in inducing B cell proliferation. The regulation of T cell localization, marked by the single and coexpression of CXCR4 and CXCR5, might be an important determinant of T
FH
function.
Enhanced Mammalian Transmissibility of Seasonal Influenza A/H1N1 Viruses Encoding an Oseltamivir-Resistant Neuraminidase
Authors: Bouvier Nicole M. , Rahmat Saad , Pica Natalie 
Published: April 2012

ABSTRACT

Between 2007 and 2009, oseltamivir resistance developed among seasonal influenza A/H1N1 (sH1N1) virus isolates at an exponential rate, without a corresponding increase in oseltamivir usage. We hypothesized that the oseltamivir-resistant neuraminidase (NA), in addition to being relatively insusceptible to the antiviral effect of oseltamivir, might confer an additional fitness advantage on these viruses by enhancing their transmission efficiency among humans. Here we demonstrate that an oseltamivir-resistant clinical isolate, an A/Brisbane/59/2007(H1N1)-like virus isolated in New York State in 2008, transmits more efficiently among guinea pigs than does a highly similar, contemporaneous oseltamivir-sensitive isolate. With reverse genetics reassortants and point mutants of the two clinical isolates, we further show that expression of the oseltamivir-resistant NA in the context of viral proteins from the oseltamivir-sensitive virus (a 7:1 reassortant) is sufficient to enhance transmissibility. In the guinea pig model, the NA is the critical determinant of transmission efficiency between oseltamivir-sensitive and -resistant Brisbane/59-like sH1N1 viruses, independent of concurrent drift mutations that occurred in other gene products. Our data suggest that the oseltamivir-resistant NA (specifically, one or both of the companion mutations, H275Y and D354G) may have allowed resistant Brisbane/59-like viruses to outtransmit sensitive isolates. These data provide
in vivo
evidence of an evolutionary mechanism that would explain the rapidity with which oseltamivir resistance achieved fixation among sH1N1 isolates in the human reservoir.
Hyperthyrotropinaemia in untreated subjects with down's syndrome aged 6 months to 64 years: a comparative analysis
Authors: Meyerovitch Joseph , Antebi Felice , Greenberg-Dotan Sari , Bar-Tal Ornit , Hochberg Ze'ev 
Published: April 2012

ObjectivesTo determine whether an altered hypothalamic-pituitary-thyroid axis is inherent to Down's syndrome or if a high level of thyroid-stimulating hormone (TSH) is a feature in a subset of patients with Down's syndrome.DesignComparative analysis.SettingMajor health maintenance organisation (3.8 million insured).PatientsA data warehouse search identified all subjects with Down's syndrome who attended Clalit Health Services in 2006 and were tested for TSH and free thyroxine (T4) level on the day of diagnosis (intention-to-treat population). The study group consisted of patients who were not diagnosed with thyroid disease or did not receive thyroid-modulating medication (n=428). Their findings were compared with a control group of healthy age- and sex-matched subjects who were randomly selected from the general population.Main outcome measuresDistribution of free T4, TSH and total T3 levels.ResultsThe distribution plot for TSH showed a significant shift of the curve to higher values in the study group compared with the controls (p≤0.0001). This finding held true on further analysis of the whole intention-to-treat population (p<0.006). The free T4 distribution curve also shifted significantly to higher levels in patients with Down's syndrome (p≤0.0001).ConclusionsDown's syndrome is associated with higher TSH levels. The results suggest that hyperthyrotropinaemia is an innate attribute of chromosome 21 trisomy. Therefore, T4 treatment should not be contemplated in Down's Syndrome unless the TSH is >95th centile in the presence of normal-range free T4 levels.