Clinical research on liver reserve function by 13C-phenylalanine breath test in aged patients with chronic liver diseases

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to investigate whether the ¹³C-phenylalanine breath test could be useful for the evaluation of hepatic function in elderly volunteers and patients with chronic hepatitis B and liver cirrhosis.</p> <p>Methods</p> <p>L-[1-¹³C] phenylalanine was administered orally at a dose of 100 mg to 55 elderly patients with liver cirrhosis, 30 patients with chronic hepatitis B and 38 elderly healthy subjects. The breath test was performed at 8 different time points (0, 10, 20, 30, 45, 60, 90, 120 min) to obtain the values of Delta over baseline, percentage ¹³CO₂exhalation rate and cumulative excretion (Cum). The relationships of the cumulative excretion with the ¹³C-%dose/h and blood biochemical parameters were investigated.</p> <p>Results</p> <p>The ¹³C-%dose/h at 20 min and 30 min combined with the cumulative excretion at 60 min and 120 min correlated with hepatic function tests, serum albumin, hemoglobin, platelet and Child-Pugh score. Prothrombin time, total and direct bilirubin were significantly increased, while serum albumin, hemoglobin and platelet, the cumulative excretion at 60 min and 120 min values decreased by degrees of intensity of the disease in Child-Pugh A, B, and C patients (P < 0.01).</p> <p>Conclusions</p> <p>The ¹³C-phenylalanine breath test can be used as a non-invasive assay to evaluate hepatic function in elderly patients with liver cirrhosis. The ¹³C-%dose/h at 20 min, at 30 min and cumulative excretion at 60 min may be the key value for determination at a single time-point. ¹³C-phenylalanine breath test is safe and helpful in distinguishing different stages of hepatic dysfunction for elderly cirrhosis patients.</p

Continuum Double Exchange Model

We present a continuum model for doped manganites which consist of two species of quantum spin 1/2 fermions interacting with classical spin fields. The phase structure at zero temperature turns out to be considerably rich: antiferromagnetic insulator, antiferromagnetic two band conducting, canted two band conducting, canted one band conducting and ferromagnetic one band conducting phases are identified, all of them being stable against phase separation. There are also regions in the phase diagram where phase separation occurs.Comment: 14 pages, LaTeX2e file, two eps included figures. Published versio

Adaptive on-chip control of nano-optical fields with optoplasmonic vortex nanogates

A major challenge for plasmonics as an enabling technology for quantum information processing is the realization of active spatio-temporal control of light on the nanoscale. The use of phase-shaped pulses or beams enforces specific requirements for on-chip integration and imposes strict design limitations. We introduce here an alternative approach, which is based on exploiting the strong sub-wavelength spatial phase modulation in the near-field of resonantly-excited high-Q optical microcavities integrated into plasmonic nanocircuits. Our theoretical analysis reveals the formation of areas of circulating powerflow (optical vortices) in the near-fields of optical microcavities, whose positions and mutual coupling can be controlled by tuning the microcavities parameters and the excitation wavelength. We show that optical powerflow though nanoscale plasmonic structures can be dynamically molded by engineering interactions of microcavity-induced optical vortices with noble-metal nanoparticles. The proposed strategy of re-configuring plasmonic nanocircuits via locally-addressable photonic elements opens the way to develop chip-integrated optoplasmonic switching architectures, which is crucial for implementation of quantum information nanocircuits.Comment: 11 pages, 5 figure

Alteration in intracellular Zn2+ homeostasis as a result of TRPM2 channel activation contributes to ROS-induced hippocampal neuronal death

Transient receptor potential melastatin-related 2 (TRPM2) channel, a molecular sensor for reactive oxygen species (ROS), plays an important role in cognitive dysfunction associated with post-ischemia brain damage thought to result from ROS-induced TRPM2-dependent neuronal death during reperfusion. Emerging evidence further suggests that an alteration in the Zn2+ homeostasis is critical in ROS-induced TRPM2-dependent neuronal death. Here we applied genetic and pharmacological interventions to define the role of TRPM2 channel in ROS-induced neuronal death and explore the mechanisms contributing in the alteration in intracellular Zn2+ homeostasis in mouse hippocampal neurons. Exposure of neurons to 30-300 M H2O2 for 2-24 hr caused concentration/duration-dependent neuronal death, which was significantly suppressed, but not completely prevented, by TRPM2-knockout (TRPM2-KO) and pharmacological inhibition of the TRPM2 channel. H2O2-induced neuronal death was also attenuated by treatment with TPEN acting as a Zn2+ selective chelator. Single cell imaging demonstrated that H2O2 evoked a prominent increase in the intracellular Zn2+ concentration, which was completely prevented by TPEN as well as TRPM2-KO and inhibition of the TRPM2 channel. Furthermore, H2O2 induced lysosomal Zn2+ release and lysosomal dysfunction, and subsequent mitochondrial Zn2+ accumulation that provokes mitochondrial dysfunction and ROS generation. These H2O2-induced lysosomal/mitochondrial effects were prevented by TRPM2-KO or TPEN. Taken together, our results provide evidence to show that a dynamic alteration in the intracellular Zn2+ homeostasis as a result of activation of the TRPM2 channel contributes to ROS-induced hippocampal neuronal death

Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

HIV-1 Vpr-Induced Apoptosis Is Cell Cycle Dependent and Requires Bax but Not ANT

The HIV-1 accessory protein viral protein R (Vpr) causes G(2) arrest and apoptosis in infected cells. We previously identified the DNA damage–signaling protein ATR as the cellular factor that mediates Vpr-induced G(2) arrest and apoptosis. Here, we examine the mechanism of induction of apoptosis by Vpr and how it relates to induction of G(2) arrest. We find that entry into G(2) is a requirement for Vpr to induce apoptosis. We investigated the role of the mitochondrial permeability transition pore by knockdown of its essential component, the adenine nucleotide translocator. We found that Vpr-induced apoptosis was unaffected by knockdown of ANT. Instead, apoptosis is triggered through a different mitochondrial pore protein, Bax. In support of the idea that checkpoint activation and apoptosis induction are functionally linked, we show that Bax activation by Vpr was ablated when ATR or GADD45α was knocked down. Certain mutants of Vpr, such as R77Q and I74A, identified in long-term nonprogressors, have been proposed to inefficiently induce apoptosis while activating the G(2) checkpoint in a normal manner. We tested the in vitro phenotypes of these mutants and found that their abilities to induce apoptosis and G(2) arrest are indistinguishable from those of HIV-1(NL4–3) vpr, providing additional support to the idea that G(2) arrest and apoptosis induction are mechanistically linked

Accumulation of human-adapting mutations during circulation of A(H1N1)pdm09 influenza virus in humans in the United Kingdom

The influenza pandemic that emerged in 2009 provided an unprecedented opportunity to study adaptation of a virus recently acquired from an animal source during human transmission. In the United Kingdom, the novel virus spread in three temporally distinct waves between 2009 and 2011. Phylogenetic analysis of complete viral genomes showed that mutations accumulated over time. Second- and third-wave viruses replicated more rapidly in human airway epithelial (HAE) cells than did the first-wave virus. In infected mice, weight loss varied between viral isolates from the same wave but showed no distinct pattern with wave and did not correlate with viral load in the mouse lungs or severity of disease in the human donor. However, second- and third-wave viruses induced less alpha interferon in the infected mouse lungs. NS1 protein, an interferon antagonist, had accumulated several mutations in second- and third-wave viruses. Recombinant viruses with the third-wave NS gene induced less interferon in human cells, but this alone did not account for increased virus fitness in HAE cells. Mutations in HA and NA genes in third-wave viruses caused increased binding to alpha-2,6-sialic acid and enhanced infectivity in human mucus. A recombinant virus with these two segments replicated more efficiently in HAE cells. A mutation in PA (N321K) enhanced polymerase activity of third-wave viruses and also provided a replicative advantage in HAE cells. Therefore, multiple mutations allowed incremental changes in viral fitness, which together may have contributed to the apparent increase in severity of A(H1N1)pdm09 influenza virus during successive waves. IMPORTANCE: Although most people infected with the 2009 pandemic influenza virus had mild or unapparent symptoms, some suffered severe and devastating disease. The reasons for this variability were unknown, but the numbers of severe cases increased during successive waves of human infection in the United Kingdom. To determine the causes of this variation, we studied genetic changes in virus isolates from individual hospitalized patients. There were no consistent differences between these viruses and those circulating in the community, but we found multiple evolutionary changes that in combination over time increased the virus's ability to infect human cells. These adaptations may explain the remarkable ability of A(H1N1)pdm09 virus to continue to circulate despite widespread immunity and the apparent increase in severity of influenza over successive waves of infection

Baicalin Improves Survival in a Murine Model of Polymicrobial Sepsis via Suppressing Inflammatory Response and Lymphocyte Apoptosis

BACKGROUND: An imbalance between overwhelming inflammation and lymphocyte apoptosis is the main cause of high mortality in patients with sepsis. Baicalin, the main active ingredient of the Scutellaria root, exerts anti-inflammatory, anti-apoptotic, and even antibacterial properties in inflammatory and infectious diseases. However, the therapeutic effect of baicalin on polymicrobial sepsis remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Mice were infused with baicalin intraperitoneally at 1 h, 6 h and 12 h after CLP. Survival rates were assessed over the subsequent 8 days. Bacterial burdens in blood and peritoneal cavity were calculated to assess the bacterial clearance. Neutrophil count in peritoneal lavage fluid was also calculated. Injuries to the lung and liver were detected by hematoxylin and eosin staining. Levels of cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10 and IL-17, in blood and peritoneum were measured by enzyme-linked immunosorbent assay. Adaptive immune function was assessed by apoptosis of lymphocytes in the thymus and counts of different cell types in the spleen. Baicalin significantly enhanced bacterial clearance and improved survival of septic mice. The number of neutrophils in peritoneal lavage fluid was reduced by baicalin. Less neutrophil infiltration of the lung and liver in baicalin-treated mice was associated with attenuated injuries to these organs. Baicalin significantly reduced the levels of proinflammatory cytokines but increased the level of anti-inflammatory cytokine in blood and peritoneum. Apoptosis of CD3(+) T cell was inhibited in the thymus. The numbers of CD4(+), CD8(+) T lymphocytes and dendritic cells (DCs) were higher, while the number of CD4(+)CD25(+) regulatory T cells was lower in the baicalin group compared with the CLP group. CONCLUSIONS/SIGNIFICANCE: Baicalin improves survival of mice with polymicrobial sepsis, and this may be attributed to its antibacterial property as well as its anti-inflammatory and anti-apoptotic effects