Emerging evidence implied that chronic stress has been exerting detrimental impact on immune system functions in both humans and animals. Toll-like receptors (TLRs) have been shown to play an essential role in modulating immune responses and cell survival.We have recently shown that TLR9 deficiency protects against lymphocyte apoptosis induced by chronic stress. However, the exact role of TLR9 in stress-mediated change of macrophage function remains unclear. The results of the current study showed that when BALB/c mice were treated with restraint stress (12 h daily for 2 days), the number of macrophages recruited to the peritoneal cavity was obviously increased. Results also demonstrated that the sustained effects of stress elevated cytokine IL-1β, TNF-α and IL-10 production yet diminished IFN-γ production from macrophage, which led to apoptotic cell death. However, TLR9 deficiency prevented the chronic stress-mediated accumulation of macrophages. In addition, knocking out TLR9 significantly abolished the chronic stress-induced imbalance of cytokine levels and apoptosis in macrophage. TLR9 deficiency was also found to reverse elevation of plasma IL-1β, IL-10 and IL-17 levels and decrease of plasma IFN-γ level under the condition of chronic stress. These results indicated that TLR9-mediated macrophage responses were required for chronic stress-induced immunosuppression. Further exploration showed that TLR9 deficiency prevented the increment of p38 MAPK phosphorylation and reduction of Akt/Gsk-3β phosphorylation; TLR9 deficiency also attenuated the release of mitochondrial cytochrome c into cytoplasm, caused upregulation of Bcl-2/Bax protein ratio, downregulation of cleavage of caspase-3 and PARP, as well as decreased TUNEL-positive cells in macrophage of stressed mice. Collectively, our studies demonstrated that deficiency of TLR9 maintained macrophage function by modulating macrophage accumulation and attenuating macrophage apoptosis, thus preventing immunosuppression in restraint-stressed mice.

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Recent studies reveal that multifunctional protein β-arrestin 2 (Arrb2) modulates cell apoptosis. Survival and various aspects of liver injury were investigated in WT and Arrb2KO mice after bile duct ligation (BDL). We found that deficiency of Arrb2 enhances survival and attenuates hepatic injury and fibrosis. Following BDL, Arrb2-deficient mice as compared with WT controls displayed a significant reduction of hepatocyte apoptosis as demonstrated by the TUNEL assay. Following BDL, the levels of phospho-Akt and phospho-glycogen synthase kinase 3β (GSK3β) in the livers were significantly increased in Arrb2 KO compared with WT mice, although p-p38 increased in WT but not in Arrb2-deficient mice. Inhibition of GSK3β following BDL decreases hepatic apoptosis and decreased p-p38 in WT mice but not in Arrb2 KO mice. Activation of Fas receptor with Jo2 reduces phospho-Akt and increases apoptosis in WT cells and WT mice but not in Arrb2-deficient cells and Arrb2-deficient mice. Consistent with direct interaction of Arrb2 with and regulating Akt phosphorylation, the expression of a full-length or N terminus but not the C terminus of Arrb2 reduces Akt phosphorylation and coimmunoprecipates with Akt. These results reveal that the protective effect of deficiency of Arrb2 is due to loss of negative regulation of Akt due to BDL and decreased downstream GSK3β and p38 MAPK signaling pathways.

Isolated ventricular noncompaction (IVNC) occurs because of interruption of trabecular morphogenesis in the myocardium leading to ventricular noncompaction. Patients present with heart failure or with systemic complications secondary to thromboembolism or arrhythmias. High index of suspicion is necessary for early diagnosis. We present a case of 48-year-old male with unexplained recurrent syncope who was eventually diagnosed with IVNC.

Noncardiac causes should be kept in the differential while evaluating ST elevation on EKG. Rarely abdominal pathologies like acute pancreatitis can present with ST elevation in the inferior leads. Once acute coronary syndrome is ruled out by emergent cardiac catheterization alternative diagnosis should be sorted. Abdominal pathologies, like acute pancreatitis and acute cholecystitis, can present with ST elevation in the inferior leads. Treating the underlying condition would result in resolution of these EKG changes.

Air embolism is an infrequent but potentially catastrophic complication. It could be a complication of invasive procedures including surgery, central line placement, positive pressure ventilation, trauma, hemodialysis, pacemaker placement, cardiac ablation, and decompression sickness. Usually, it does not cause any hemodynamic complication. In rare cases, it could lodge in the heart and cause cardiac arrest. We present a case of an 82-year-old white female who underwent computed tomography (CT) guided biopsy of right lung pulmonary nodule. When she was turned over after the lung biopsy, she became unresponsive and developed cardiopulmonary arrest. She underwent successful resuscitation and ultimately was intubated. CT chest was performed immediately after resuscitation which showed frothy air dense material in the left atrium and one of the right pulmonary veins suggesting a Broncho venous fistula with air embolism. Although very rare, air embolism could be catastrophic resulting in cardiac arrest. Supportive care including mechanical ventilation, vasopressors, volume resuscitation, and supplemental oxygen is the initial management. Patients with cardiac, neurological, or respiratory complications benefit from hyperbaric oxygen therapy.

The publisher regrets that the paper was published without Figures 1, 2 and 3. The publisher would like to apologise for any inconvenience caused.

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A young otherwise healthy 27-year-old male who has been using anabolic steroids for a long time developed Type I aortic dissection associated with heavy weightlifting. The patient did not have a recent history of trauma to the chest, no history of hypertension, and no illicit drug use. He presented with severe chest pain radiating to back and syncopal event with exertion. Initial vitals were significant for blood pressure of 80/50 mmHg, pulse of 80 beats per minute, respirations of 24 per minute, and oxygen saturation of 92% on room air. Physical exam was significant for elevated jugular venous pressure, muffled heart sounds, and cold extremities with diminished pulses in upper and absent pulses in lower extremities. Bedside echocardiogram showed aortic root dilatation and cardiac tamponade. STAT computed tomography (CT) scan of chest revealed dissection of ascending aorta. Cardiothoracic surgery was consulted and patient underwent successful repair of ascending aorta. Hemodynamic stress of weightlifting can predispose to aortic dissection. Aortic dissection is a rare but often catastrophic condition if not diagnosed and managed acutely. Although rare, aortic dissection needs to be in the differential when a young weightlifter presents with chest pain as a delay in diagnosis may be fatal.

T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) is a newly identified negative immunomodulator that is up-regulated on dysfunctional T cells during viral infections. The expression and function of Tim-3 on human innate immune responses during HCV infection, however, remains poorly characterized. In this study, we report that Tim-3 is constitutively expressed on human resting CD14+ monocyte/macrophages (M/MØ) and functions as a cap to block IL-12, a key pro-inflammatory cytokine linking innate and adaptive immune responses. Tim-3 expression is significantly reduced and IL-12 expression increased upon stimulation with Toll-like receptor 4 (TLR4) ligand - lipopolysaccharide (LPS) and TLR7/8 ligand - R848. Notably, Tim-3 is over-expressed on un-stimulated as well as TLR-stimulated M/MØ, which is inversely associated with the diminished IL-12 expression in chronically HCV-infected individuals when compared to healthy subjects. Up-regulation of Tim-3 and inhibition of IL-12 are also observed in M/MØ incubated with HCV-expressing hepatocytes, as well as in primary M/MØ or monocytic THP-1 cells incubated with HCV core protein, an effect that mimics the function of complement C1q and is reversible by blocking the HCV core/gC1qR interaction. Importantly, blockade of Tim-3 signaling significantly rescues HCV-mediated inhibition of IL-12, which is primarily expressed by Tim-3 negative M/MØ. Tim-3 blockade reduces HCV core-mediated expression of the negative immunoregulators PD-1 and SOCS-1 and increases STAT-1 phosphorylation. Conversely, blocking PD-1 or silencing SOCS-1 gene expression also decreases Tim-3 expression and enhances IL-12 secretion and STAT-1 phosphorylation. These findings suggest that Tim-3 plays a crucial role in negative regulation of innate immune responses, through crosstalk with PD-1 and SOCS-1 and limiting STAT-1 phosphorylation, and may be a novel target for immunotherapy to HCV infection.