Synergistic Effects of Methylglyoxal and Hyperglycemia on ROS Generation and the Viability of Cultured H9c2 Myoblast Cells

Heart damage in diabetics may be closely related to the possible synergistic cellular damage from hyperglycemia and increased methylglyoxal levels. This study investigated the effects of glucose and/or methylglyoxal and/or metformin on H9c2 reactive oxygen species (ROS) generation measured by a dichlorofluorescein diacetate (DCFDA) assay and cell viability measured by a cell counting kit-8 assay after various treatments for 24 hours. Glucose treatment (5 mM-40 mM) displayed similar cell viability (n=4) and ROS generation (n=7) when compared to control cells. By contrast, methylglyoxal (5 µM-1400 µM) decreased cell viability at higher concentration (1000 µM (51 ± 8%); 1200 µM (41 ± 5%); 1400 µM (36 ± 8%); all p\u3c0.05, n=5) compared to control cells, which was accompanied by significantly higher ROS generation (1000 µM (167 ± 27%); 1200 µM (204 ± 22%); 1400 µM (201 ± 15%); all p\u3c0.05, n=3). Furthermore, metformin (1 mM-40 mM) reduced methylglyoxal (1200 µM) induced ROS generation and cell death. When H9c2 cells were treated with glucose (25 mM or 40 mM) and different doses of methylglyoxal (600 µM -1400 µM), only higher glucose (40 mM) with different doses of methylglyoxal (600 µM -1400 µM) consistently showed lower cell viability and higher ROS when compared to individual glucose or methylglyoxal. The data suggest that higher concentrations of methylglyoxal, not glucose, induces H9c2 cell damage and metformin can protect cells from the methylglyoxal insult possibly by reduction of ROS production. Moreover, hyperglycemia and methylglyoxal tend to synergistically induce cell damage associated with increased ROS production

Point-of-admission hypothermia among high-risk Nigerian newborns

<p>Abstract</p> <p>Background</p> <p>Facilities which manage high-risk babies should frequently assess the burden of hypothermia and strive to reduce the incidence.</p> <p>Objective</p> <p>To determine the incidence and outcome of point-of-admission hypothermia among hospitalized babies.</p> <p>Methods</p> <p>The axillary temperatures of consecutive admissions into a Nigerian Newborn Unit were recorded. Temperature <36.5°C defined hypothermia. The biodata and outcome of these babies were studied.</p> <p>Results</p> <p>Of 150 babies aged 0 to 648 hours, 93 had hypothermia with an incidence of 62%. Mild and moderate hypothermia accounted for 47.3% and 52.7% respectively. The incidence of hypothermia was highest (72.4%) among babies aged less than 24 hours. It was also higher among out-born babies compared to in-born babies (64.4% <it>vs </it>58.3%). Preterm babies had significantly higher incidence of hypothermia (82.5%) compared with 54.5% of term babies (RR = 1.51; CI = 1.21 – 1.89). The incidence of hypothermia was also highest (93.3%) among very-low-birth-weight babies.</p> <p>The Case-Fatality-Rate was significantly higher among hypothermic babies (37.6% vs 16.7%; RR = 2.26, CI = 1.14 – 4.48) and among out-born hypothermic babies (50% vs 17.1%; RR = 0.34, CI = 0.16 – 0.74). CFR was highest among hypothermic babies with severe respiratory distress, sepsis, preterm birth and asphyxia.</p> <p>Conclusion</p> <p>The high incidence and poor outcome of hypothermia among high-risk babies is important. The use of the 'warm chain' and skin-to-skin contact between mother and her infant into routine delivery services in health facilities and at home may be useful.</p

2:1 for Naturalness at the LHC?

A large enhancement of a factor of 1.5 - 2 in Higgs production and decay in the diphoton channel, with little deviation in the ZZ channel, can only plausibly arise from a loop of new charged particles with large couplings to the Higgs. We show that, allowing only new fermions with marginal interactions at the weak scale, the required Yukawa couplings for a factor of 2 enhancement are so large that the Higgs quartic coupling is pushed to large negative values in the UV, triggering an unacceptable vacuum instability far beneath the 10 TeV scale. An enhancement by a factor of 1.5 can be accommodated if the charged fermions are lighter than 150 GeV, within reach of discovery in almost all cases in the 8 TeV run at the LHC, and in even the most difficult cases at 14 TeV. Thus if the diphoton enhancement survives further scrutiny, and no charged fermions beneath 150 GeV are found, there must be new bosons far beneath the 10 TeV scale. This would unambiguously rule out a large class of fine-tuned theories for physics beyond the Standard Model, including split SUSY and many of its variants, and provide strong circumstantial evidence for a natural theory of electroweak symmetry breaking at the TeV scale. Alternately, theories with only a single fine-tuned Higgs and new fermions at the weak scale, with no additional scalars or gauge bosons up to a cutoff much larger than the 10 TeV scale, unambiguously predict that the hints for a large diphoton enhancement in the current data will disappear.Comment: 18 pages, 6 figures; typos corrected and references adde

Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth

Background: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy. Methods and Findings: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-α/β response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-γ and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5) antibodies. Conclusion: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion

Search for long-lived charginos based on a disappearing-track signature in pp collisions at s √ =13 s=13 TeV with the ATLAS detector

This paper presents a search for direct electroweak gaugino or gluino pair production with a chargino nearly mass-degenerate with a stable neutralino. It is based on an integrated luminosity of 36.1 fb−1 of pp collisions at s √ =13 s=13 TeV collected by the ATLAS experiment at the LHC. The final state of interest is a disappearing track accompanied by at least one jet with high transverse momentum from initial-state radiation or by four jets from the gluino decay chain. The use of short track segments reconstructed from the innermost tracking layers significantly improves the sensitivity to short chargino lifetimes. The results are found to be consistent with Standard Model predictions. Exclusion limits are set at 95% confidence level on the mass of charginos and gluinos for different chargino lifetimes. For a pure wino with a lifetime of about 0.2 ns, chargino masses up to 460 GeV are excluded. For the strong production channel, gluino masses up to 1.65 TeV are excluded assuming a chargino mass of 460 GeV and lifetime of 0.2 ns