Modulation of Myocardial Mitochondrial Mechanisms during severe Polymicrobial Sepsis in the Rat

Background: We tested the hypothesis that 5-Hydroxydecanoic acid (5HD), a putative mitoKATP channel blocker, will reverse sepsis-induced cardiodynamic and adult rat ventricular myocyte (ARVM) contractile dysfunction, restore mitochondrial membrane permeability alterations and improve survival. Methodology/Principal Findings: Male Sprague-Dawley rats (350-400 g) were made septic using 400 mg/kg cecal inoculum, ip. Sham animals received 5% dextrose water, ip. The Voltage Dependent Anion Channels (VDAC1), Bax and cytochrome C levels were determined in isolated single ARVMs obtained from sham and septic rat heart. Mitochondria and cytosolic fractions were isolated from ARVMs treated with norepinephrine (NE, 10 µmoles) in the presence/absence of 5HD (100 µmoles). A continuous infusion of 5HD using an Alzet pump reversed sepsis-induced mortality when administered at the time of induction of sepsis (-40%) and at 6 hr post-sepsis (-20%). Electrocardiography revealed that 5HD reversed sepsis-induced decrease in the average ejection fraction, Simpsons+m Mode (53.5±2.5 in sepsis and 69.2±1.2 at 24 hr in sepsis+5HD vs. 79.9±1.5 basal group) and cardiac output (63.3±1.2 mL/min sepsis and 79.3±3.9 mL/min at 24 hr in sepsis+5HD vs. 85.8±1.5 mL/min basal group). The treatment of ARVMs with 5HD also reversed sepsis-induced depressed contractility in both the vehicle and NE-treated groups. Sepsis produced a significant downregulation of VDAC1, and upregulation of Bax levels, along with mitochondrial membrane potential collapse in ARVMs. Pretreatment of septic ARVMs with 5HD blocked a NE-induced decrease in the VDAC1 and release of cytochrome C. Conclusion: The data suggest that Bax activation is an upstream event that may precede the opening of the mitoKATP channels in sepsis. We concluded that mitoKATP channel inhibition via decreased mitochondrial membrane potential and reduced release of cytochrome C provided protection against sepsis-induced ARVM and myocardial contractile dysfunction. © 2011 Chopra et al

Differential regulation by leukotrienes and calcium of Fcγ receptorâ induced phagocytosis and Syk activation in dendritic cells versus macrophages

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141597/1/jlb1234.pd

Little Higgses from an Antisymmetric Condensate

We construct an SU(6)/Sp(6) non-linear sigma model in which the Higgses arise as pseudo-Goldstone bosons. There are two Higgs doublets whose masses have no one-loop quadratic sensitivity to the cutoff of the effective theory, which can be at around 10 TeV. The Higgs potential is generated by gauge and Yukawa interactions, and is distinctly different from that of the minimal supersymmetric standard model. At the TeV scale, the new bosonic degrees of freedom are a single neutral complex scalar and a second copy of SU(2)xU(1) gauge bosons. Additional vector-like pairs of colored fermions are also present.Comment: 13 page

Cost-Effectiveness of HIV Screening in STD Clinics, Emergency Departments, and Inpatient Units: A Model-Based Analysis

Identifying and treating persons with human immunodeficiency virus (HIV) infection early in their disease stage is considered an effective means of reducing the impact of the disease. We compared the cost-effectiveness of HIV screening in three settings, sexually transmitted disease (STD) clinics serving men who have sex with men, hospital emergency departments (EDs), settings where patients are likely to be diagnosed early, and inpatient diagnosis based on clinical manifestations.We developed the Progression and Transmission of HIV/AIDS model, a health state transition model that tracks index patients and their infected partners from HIV infection to death. We used program characteristics for each setting to compare the incremental cost per quality-adjusted life year gained from early versus late diagnosis and treatment. We ran the model for 10,000 index patients for each setting, examining alternative scenarios, excluding and including transmission to partners, and assuming HAART was initiated at a CD4 count of either 350 or 500 cells/µL. Screening in STD clinics and EDs was cost-effective compared with diagnosing inpatients, even when including only the benefits to the index patients. Screening patients in STD clinics, who have less-advanced disease, was cost-effective compared with ED screening when treatment with HAART was initiated at a CD4 count of 500 cells/µL. When the benefits of reduced transmission to partners from early diagnosis were included, screening in settings with less-advanced disease stages was cost-saving compared with screening later in the course of infection. The study was limited by a small number of observations on CD4 count at diagnosis and by including transmission only to first generation partners of the index patients.HIV prevention efforts can be advanced by screening in settings where patients present with less-advanced stages of HIV infection and by initiating treatment with HAART earlier in the course of infection

Impact of distributed energy resources on the reliability of a critical telecommunications facility.

This report documents a probabilistic risk assessment of an existing power supply system at a large telecommunications office. The focus is on characterizing the increase in the reliability of power supply through the use of two alternative power configurations. Telecommunications has been identified by the Department of Homeland Security as a critical infrastructure to the United States. Failures in the power systems supporting major telecommunications service nodes are a main contributor to major telecommunications outages. A logical approach to improve the robustness of telecommunication facilities would be to increase the depth and breadth of technologies available to restore power in the face of power outages. Distributed energy resources such as fuel cells and gas turbines could provide one more onsite electric power source to provide backup power, if batteries and diesel generators fail. The analysis is based on a hierarchical Bayesian approach and focuses on the failure probability associated with each of three possible facility configurations, along with assessment of the uncertainty or confidence level in the probability of failure. A risk-based characterization of final best configuration is presented

Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes

<p>Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.</p> <p>Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.</p> <p>Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.</p&gt

Uses and Abuses of Effective Lagrangians

Motivated by past and recent analyses we critically re-examine the use of effective lagrangians in the literature to constrain new physics and to determine the `physics reach' of future experiments. We demonstrate that many calculations, such as those involving anomalous trilinear gauge-boson couplings, either considerably overestimate loop-induced effects, or give ambiguous answers. The source of these problems is the use of cutoffs to evaluate the size of such operators in loop diagrams. In contrast to other critics of these loop estimates, we prove that the inclusion of nonlinearly-realized gauge invariance into the low-energy lagrangian is irrelevant to this conclusion. We use an explicit example using known multi-Higgs physics above the weak scale to underline these points. We show how to draw conclusions regarding the nature of the unknown high-energy physics without making reference to low-energy cutoffs.Comment: 36 page

Model-Independent Global Constraints on New Physics

Using effective-lagrangian techniques we perform a systematic survey of the lowest-dimension effective interactions through which heavy physics might manifest itself in present experiments. We do not restrict ourselves to special classes of effective interactions (such as `oblique' corrections). We compute the effects of these operators on all currently well-measured electroweak observables, both at low energies and at the $Z$ resonance, and perform a global fit to their coefficients. Despite the fact that a great many operators arise in our survey, we find that most are quite strongly bounded by the current data. We use our survey to systematically identify those effective interactions which are {\it not} well-bounded by the data -- these could very well include large new-physics contributions. Our results may also be used to efficiently confront specific models for new physics with the data, as we illustrate with an example.Comment: plain TeX, 68 pages, 2 figures (postscript files appended), McGill-93/12, NEIPH-93-008, OCIP/C-93-6, UQAM-PHE-93/08, UdeM-LPN-TH-93-15