Effects of epidural compression on stellate neurons and thalamocortical afferent fibers in the rat primary somatosensory cortex

A number of neurological disorders such as epidural hematoma can cause compression of cerebral cortex. We here tested the hypothesis that sustained compression of primary somatosensory cortex may affect stellate neurons and thalamocortical afferent (TCA) fibers. A rat model with barrel cortex subjected to bead epidural compression was used. Golgi‑Cox staining analyses showed the shrinkage of dendritic arbors and the stripping of dendritic spines of stellate neurons for at least 3 months post‑lesion. Anterograde tracing analyses exhibited a progressive decline of TCA fiber density in barrel field for 6 months post‑lesion. Due to the abrupt decrease of TCA fiber density at 3 days after compression, we further used electron microscopy to investigate the ultrastructure of TCA fibers at this time. Some TCA fiber terminal profiles with dissolved or darkened mitochondria and fewer synaptic vesicles were distorted and broken. Furthermore, the disruption of mitochondria and myelin sheath was observed in some myelinated TCA fibers. In addition, expressions of oxidative markers 3‑nitrotyrosine and 4‑hydroxynonenal were elevated in barrel field post‑lesion. Treatment of antioxidant ascorbic acid or apocynin was able to reverse the increase of oxidative stress and the decline of TCA fiber density, rather than the shrinkage of dendrites and the stripping of dendritic spines of stellate neurons post‑lesion. Together, these results indicate that sustained epidural compression of primary somatosensory cortex affects the TCA fibers and the dendrites of stellate neurons for a prolonged period. In addition, oxidative stress is responsible for the reduction of TCA fiber density in barrels rather than the shrinkage of dendrites and the stripping of dendritic spines of stellate neurons

Dichlorido{N′-[(pyridin-2-yl)methyl­idene-κN]acetohydrazide-κ2 N′,O}copper(II)

In the title compound, [CuCl2(C8H9N3O)], the CuII atom has a distorted square-pyramidal CuCl2N2O coordination geometry. The tridentate acetohydrazide ligand occupies three basal positions, the fourth basal position being defined by a chloride anion at a distance of 2.2116 (6) Å. The second chloride anion is in the apical position and forms a longer Cu—Cl distance of 2.4655 (7) Å. Inter­molecular N—H⋯Cl hydrogen bonds are present in the crystal, leading to the formation of chains along [10]

Regulation of axon repulsion by MAX-1 SUMOylation and AP-3.

During neural development, growing axons express specific surface receptors in response to various environmental guidance cues. These axon guidance receptors are regulated through intracellular trafficking and degradation to enable navigating axons to reach their targets. In Caenorhabditis elegans, the UNC-5 receptor is necessary for dorsal migration of developing motor axons. We previously found that MAX-1 is required for UNC-5-mediated axon repulsion, but its mechanism of action remained unclear. Here, we demonstrate that UNC-5-mediated axon repulsion in C. elegans motor axons requires both max-1 SUMOylation and the AP-3 complex β subunit gene, apb-3 Genetic interaction studies show that max-1 is SUMOylated by gei-17/PIAS1 and acts upstream of apb-3 Biochemical analysis suggests that constitutive interaction of MAX-1 and UNC-5 receptor is weakened by MAX-1 SUMOylation and by the presence of APB-3, a competitive interactor with UNC-5. Overexpression of APB-3 reroutes the trafficking of UNC-5 receptor into the lysosome for protein degradation. In vivo fluorescence recovery after photobleaching experiments shows that MAX-1 SUMOylation and APB-3 are required for proper trafficking of UNC-5 receptor in the axon. Our results demonstrate that SUMOylation of MAX-1 plays an important role in regulating AP-3-mediated trafficking and degradation of UNC-5 receptors during axon guidance

Effects of phorbol myristate acetate and sivelestat on the lung injury caused by fat embolism in isolated lungs

<p>Abstract</p> <p>Background</p> <p>Fat embolism syndrome (FES) associated with acute lung injury (ALI) is a clinical condition following long bone fracture. We have reported 14 victims due to ALI with FES. Our laboratory has developed an animal model that produced fat emboli (FE). The major purpose of this study was to test whether neutrophil activation with phorbol myristate acetate (PMA) and inhibition with sivelestat (SVT) exert protection on the lung.</p> <p>Methods</p> <p>The lungs of Sprague-Dawley rats were isolated and perfused. FE was produced by addition of corn oil micelles into the lung perfusate. PMA and SVT were given simultaneously with FE. Parameters such as lung weight/body weight ratio, LW gain, exhaled nitric oxide (NO), protein concentration in bronchoalveolar lavage relating to ALI were measured. The neutrophil elastase (NE), myeloperoxidase, malondialdehyde and phopholipase A₂activity were determined. We also measured the nitrate/nitrite, methyl guanidine (MG), and cytokines. Pulmonary arterial pressure and microvascular permeability were assessed. Lung pathology was examined and scored. The inducible and endothelial NO synthase (iNOS and eNOS) were detected.</p> <p>Results</p> <p>FE caused ALI and increased biochemical factors. The challenge also resulted in pulmonary hypertension and increased microvascular permeability. The NE appeared to be the first to reach its peak at 1 hr, followed by other factors. Coadministration with PMA exacerbated the FE-induced changes, while SVT attenuated the effects of FE.</p> <p>Conclusions</p> <p>The FE-induced lung changes were enhanced by PMA, while SVT had the opposite effect. Sivelestat, a neutrophil inhibitor may be a therapeutic choice for patients with acute respiratory distress syndrome (ARDS) following fat embolism.</p

Mineral particles stimulate innate immunity through neutrophil extracellular traps containing HMGB1.

Calcium phosphate-based mineralo-organic particles form spontaneously in the body and may represent precursors of ectopic calcification. We have shown earlier that these particles induce activation of caspase-1 and secretion of IL-1β by macrophages. However, whether the particles may produce other effects on immune cells is unclear. Here, we show that these particles induce the release of neutrophil extracellular traps (NETs) in a size-dependent manner by human neutrophils. Intracellular production of reactive oxygen species is required for particle-induced NET release by neutrophils. NETs contain the high-mobility group protein B1 (HMGB1), a DNA-binding protein capable of inducing secretion of TNF-α by a monocyte/macrophage cell line and primary macrophages. HMGB1 functions as a ligand of Toll-like receptors 2 and 4 on macrophages, leading to activation of the MyD88 pathway and TNF-α production. Furthermore, HMGB1 is critical to activate the particle-induced pro-inflammatory cascade in the peritoneum of mice. These results indicate that mineral particles promote pro-inflammatory responses by engaging neutrophils and macrophages via signaling of danger signals through NETs

Characteristics, survival, and related factors of newly diagnosed colorectal cancer patients refusing cancer treatments under a universal health insurance program

BACKGROUND: Colorectal cancer is the third most commonly diagnosed cancer worldwide. Few studies have addressed the causes and risks of treatment refusal in a universal health insurance setting. METHODS: We examined the characteristics and survival associated with treatment refusal in patients with newly diagnosed colorectal cancer in Taiwan during 2004–2008. Treatment refusal was defined as not undergoing any cancer treatment within 4 months of confirmed cancer diagnosis. Patient data were extracted from four national databases. Factors associated with treatment refusal were identified through logistic regression using the generalized estimating equation method, and survival analysis was performed using the Cox proportional hazards model. RESULTS: Of the 41,340 new colorectal cancer cases diagnosed, 3,612 patients (8.74%) refused treatment. Treatment refusal rate was higher in patients with less urbanized areas of residence, lower incomes, preexisting catastrophic illnesses, cancer stages of 0 and IV, and diagnoses at regional and district hospitals. Logistic regression analysis revealed that patients aged >75 years were the most likely to refuse treatment (OR, 1.87); patients with catastrophic illnesses (OR, 1.66) and stage IV cancer (OR, 1.43) had significantly higher refusal rates. The treatment refusers had 2.66 times the risk of death of those who received treatment. Factors associated with an increased risk of death in refusers included age ≥75 years, insured monthly salary ≥22,801 NTD, low-income household or aboriginal status, and advanced cancer stage (especially stage IV; HR, 11.33). CONCLUSION: Our results show a lower 5-year survival for colorectal patients who refused treatment than for those who underwent treatment within 4 months. An age of 75 years or older, low-income household status, advanced stages of cancer, especially stage IV, were associated with higher risks of death for those who refused treatment

Immune reconstitution inflammatory syndrome of Kaposi’s sarcoma in an HIV-infected patient

We present a case of Kaposi’s sarcoma-related immune reconstitution inflammatory syndrome in an HIV-infected patient who developed fever, worsening pulmonary infiltrates with respiratory distress, and progression of skin tumors at the popliteal region and thigh that resulted in limitation on movement of the right knee joint at 3.5 months following a significant increase of CD4 count after combination antiretroviral therapy

Kinome-Wide siRNA Screening Identifies Src-Enhanced Resistance of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells

Background: Chemotherapy is the main treatment for triple-negative breast cancer (TNBC), which lack molecular markers for diagnosis and therapy. Cancer cells activate chemoresistant pathways and lead to therapeutic failure for patients with TNBC. Several kinases have been identified as chemoresistant genes. However, the involvement of kinases in the chemoresistance in TNBC cells is not fully understood.Methods: We employed a kinome siRNA library to screen whether targeting any kinases could increase the chemosensitivity of TNBC cell lines. The effects of kinase on cell viability in various breast cancer cells were validated with ATP level and colony formation. Protein expression and phosphorylation were determined by immunoblotting. The Cancer Genome Atlas (TCGA) dataset was collected to analyze the correlation of Src expression with prognosis of TNBC patients.Results: Primary screening and validation for the initial hits showed that Src kinase was a potential doxorubicin-resistant kinase in the TNBC cell lines MDA-MB-231 and Hs578T. Both siRNA against Src and the Src inhibitor dasatinib enhanced the cytotoxic effects of doxorubicin in TNBC cells. Moreover, phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3), downstream effectors of Src, were accordingly decreased in Src-silenced or -inhibited TNBC cells. Additionally, TCGA data analysis indicated that Src expression levels in tumor tissues were higher than those in tumor-adjacent normal tissues in patients with TNBC. High co-expression level of Src and STAT3 was also significantly correlated with poor prognosis in patients.Conclusion: Our results showed that Src-STAT3 axis might be involved in chemoresistance of TNBC cells