Matrix Metalloproteinase-3 Causes Dopaminergic Neuronal Death through Nox1-Regenerated Oxidative Stress

In the present study we investigated the interplay between matrix metalloproteinase 3 (MMP3) and NADPH oxidase 1 (Nox1) in the process of dopamine (DA) neuronal death. We found that MMP3 activation causes the induction of Nox1 via mitochondrial reactive oxygen species (ROS) production and subsequently Rac1 activation, eventually leading to Nox1-derived superoxide generation in a rat DA neuronal N27 cells exposed to 6-OHDA. While a MMP3 inhibitor, NNGH, largely attenuated mitochondrial ROS and subsequent Nox1 induction, both apocynin, a putative Nox inhibitor and GKT137831, a Nox1 selective inhibitor failed to reduce 6-OHDA-induced mitochondrial ROS. However, both inhibitors for MMP3 and Nox1 similarly attenuated 6-OHDA-induced N27 cell death. RNAi-mediated selective inhibition of MMP3 or Nox1 showed that knockdown of either MMP3 or Nox1 significantly reduced 6-OHDA-induced ROS generation in N27 cells. While 6-OHDA-induced Nox1 was abolished by MMP3 knockdown, Nox1 knockdown did not alter MMP3 expression. Direct overexpression of autoactivated MMP3 (actMMP3) in N27 cells or in rat substantia nigra (SN) increased expression of Nox1. Selective knockdown of Nox1 in the SN achieved by adeno-associated virus-mediated overexpression of Nox1-specific shRNA largely attenuated the actMMP3-mediated dopaminergic neuronal loss. Furthermore, Nox1 expression was significantly attenuated in Mmp3 null mice treated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Together we established novel molecular mechanisms underlying oxidative stress-mediated dopaminergic neuronal death in which MMP3 activation is a key upstream event that leads to mitochondrial ROS, Nox1 induction and eventual dopaminergic neuronal death. Our findings may lead to the development of novel therapeutic approach

Matrix Metalloproteinase-3 Causes Dopaminergic Neuronal Death through Nox1-Regenerated Oxidative Stress

In the present study we investigated the interplay between matrix metalloproteinase 3 (MMP3) and NADPH oxidase 1 (Nox1) in the process of dopamine (DA) neuronal death. We found that MMP3 activation causes the induction of Nox1 via mitochondrial reactive oxygen species (ROS) production and subsequently Rac1 activation, eventually leading to Nox1-derived superoxide generation in a rat DA neuronal N27 cells exposed to 6-OHDA. While a MMP3 inhibitor, NNGH, largely attenuated mitochondrial ROS and subsequent Nox1 induction, both apocynin, a putative Nox inhibitor and GKT137831, a Nox1 selective inhibitor failed to reduce 6-OHDA-induced mitochondrial ROS. However, both inhibitors for MMP3 and Nox1 similarly attenuated 6-OHDA-induced N27 cell death. RNAi-mediated selective inhibition of MMP3 or Nox1 showed that knockdown of either MMP3 or Nox1 significantly reduced 6-OHDA-induced ROS generation in N27 cells. While 6-OHDA-induced Nox1 was abolished by MMP3 knockdown, Nox1 knockdown did not alter MMP3 expression. Direct overexpression of autoactivated MMP3 (actMMP3) in N27 cells or in rat substantia nigra (SN) increased expression of Nox1. Selective knockdown of Nox1 in the SN achieved by adeno-associated virus-mediated overexpression of Nox1-specific shRNA largely attenuated the actMMP3-mediated dopaminergic neuronal loss. Furthermore, Nox1 expression was significantly attenuated in Mmp3 null mice treated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Together we established novel molecular mechanisms underlying oxidative stress-mediated dopaminergic neuronal death in which MMP3 activation is a key upstream event that leads to mitochondrial ROS, Nox1 induction and eventual dopaminergic neuronal death. Our findings may lead to the development of novel therapeutic approach

Bilateral iliac and popliteal arterial thrombosis in a child with focal segmental glomerulosclerosis

Thromboembolic complications (TECs) are clinically important sequelae of nephrotic syndrome (NS). The incidence of TECs in children is approximately 2%–5%. The veins are the most commonly affected sites, particularly the deep veins in the legs, the inferior vena cava, the superior vena cava, and the renal veins. Arterial thrombosis, which is less common, typically occurs in the cerebral, pulmonary, and femoral arteries, and is associated with the use of steroids and diuretics. Popliteal artery thrombosis in children has been described in cases of traumatic dissection, osteochondroma, Mycoplasma pneumoniae infection, and fibromuscular dysplasia. We report of a 33-month-old girl with bilateral iliac and popliteal arterial thrombosis associated with steroid-resistant NS due to focal segmental glomerulosclerosis. Her treatment involved thrombectomy and intravenous heparinization, followed by oral warfarin for 8 months. Herein, we report a rare case of spontaneous iliac and popliteal arterial thrombosis in a young child with NS

Factors Associated With the Appropriate Use of Ultra-Broad Spectrum Antibiotics, Meropenem, for Suspected Healthcare-Associated Pneumonia

ABSTRACT: Pneumonia is a common disease-causing hospitalization. When a healthcare-associated infection is suspected, antibiotics that provide coverage for multi-drug resistant (MDR) or extended-spectrum beta-lactamase (ESBL) bacteria are frequently prescribed. Limited data is available for guidance on using meropenem as a first-line empiric antimicrobial in hospitalized patients with risk factors for MDR/ESBL bacterial infections. This was a single-center, retrospective study designed and conducted to identify factors associated with positive cultures for MDR/ESBL pathogens in hospitalized patients with suspected healthcare-associated pneumonia.Of the 246 patients, 103 patients (41%) received meropenem. Among patients prescribed meropenem, MDR/ESBL pathogens were detected in only 20 patients (13%). Patients admitted from a skilled nursing facility/long-term acute care (SNF/LTAC) or with a history of a positive culture for MDR/ESBL pathogens were significantly associated with positive cultures of MDR/ESBL pathogens during the hospitalization (odds ratio [95% confidence intervals], 31.40 [5.20-189.6] in SNF/LTAC and 18.50 [2.98-115.1] in history of culture-positive MDR/ESBL pathogen). There was no significant difference in mortality between the 3 antibiotic groups.Admission from a SNF/LTAC or having a history of cultures positive for MDR/ESBL pathogens were significantly associated with a positive culture for MDR/ESBL pathogens during the subsequent admission. We did not detect significant association between meropenem use as a first-line drug and morbidity and mortality for patients admitted to the hospital with suspected healthcare-associated pneumonia, and further prospective studies with larger sample size are needed to confirm our findings

Favorable response to doxorubicin combination chemotherapy does not yield good clinical outcome in patients with metastatic breast cancer with triple-negative phenotype

<p>Abstract</p> <p>Background</p> <p>We analyzed the responses to first line treatment and clinical outcomes of metastatic breast cancer patients treated with palliative doxorubicin/cyclophosphamide (AC) according to molecular cancer subtype.</p> <p>Methods</p> <p>A retrospective analysis was performed for 110 metastatic breast cancer patients selected on the basis of palliative AC treatment and the availability of immunohistochemical data for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2/neu) status.</p> <p>Results</p> <p>Of the 110 patients analyzed, 71 (64.5%) were hormone receptor positive (HR+), 14 (12.7%) were HER2+, and 25 (22.7%) were triple negative (TN). There were no differences in age, stage at diagnosis, total number of cycles of palliative chemotherapy, incidence of visceral metastasis, and metastatic sites with the exception of liver among breast cancer subtypes. The overall response rates to AC were 55.9% for the HR+ subgroup, 42.9% for the HER2+ subgroup, and 56.5% for the TN subgroup. The progression-free survival (PFS) in patients with HER2+ and TN were significantly shorter than in the HR+ (median PFS, 9.1 <it>vs </it>8.1 <it>vs </it>11.5 months, respectively; p = 0.0002). The overall survival (OS) was 25.4 months in the TN subgroup and 27.3 months in HER2+ subgroup. The median OS for these two groups was significantly shorter than for patients in the HR+ subgroup (median, 38.5 months; 95% CI, 30.1-46.9 months; p < 0.0001).</p> <p>Conclusions</p> <p>The response to palliative AC chemotherapy did not differ among breast cancer subtypes. Despite chemosensitivity for palliative AC, the TN subtype has a shorter overall survival than non-TN subtypes. Innovative treatment strategies should be developed to slow the course of disease.</p

Optimization of ultrasound-assisted extraction conditions for extraction of bioactive compounds from purple carrot (Daucus carota L.) using response surface methodology

Abstract Statically-based optimization was employed to maximize the total phenol content, total flavonoid content, and radical scavenging activity from purple carrot (Daucus carota L.) using ultrasound-assisted extraction. To enhance the extraction of bioactive components, key variables of ultrasound-assisted extraction including extraction time (5.0 ~ 55.0 min), extraction temperature (26.0 ~ 94.5 °C), and ethanol concentration (0.0 ~ 99.5%) were chosen as independent variables and optimized using Response surface methodology. The optimal extraction conditions were predicted as 41.9 °C, 46.1 min, and 26.0% ethanol, under these conditions, total phenol content, total flavonoid content, and radical scavenging activity were found to be 16.1 mg GAE/g DM, 0.86 QE/g DM, and 25.6%, respectively, similar to the experimental values of the validation experiment. When the purple carrot extract was analyzed using HPLC, chlorogenic acid was identified as a main substance. Therefore, ultrasound-assisted extraction can effectively increase the anti-oxidant production of purple carrot, and purple carrot extract has high potential as functional food and cosmetic raw material

Posterior reversible encephalopathy syndrome in an untreated hypertensive patient after spinal surgery under general anesthesia -A case report-

Posterior reversible encephalopathy syndrome (PRES) is an unfamiliar term to anesthesiologists, and this is characterized by neurologic symptoms that include mental change, headache, seizure and visual disturbance and also abnormal neuroimaging finding. A 71-year-old female patient was operated on for posterior decompression and total laminectomy under general anesthesia for the spinal stenosis. After the operation, she developed generalized tonic-clonic seizure and a stuporous mentality in the recovery room. The magnetic resonance imaging (MRI) revealed swelling and increased signal intensity at the deep gray nuclei, cerebral cortex and cerebellum. After one week, she returned to an alert mentality and then she was diagnosed with PRES. She was discharged without any neurologic deficit on postoperative day 20. This report describes our experience with PRES after spinal surgery was performed under general anesthesia on a suspected untreated hypertensive patient

Impact of Chronic Cough on Health-Related Quality of Life in the Korean Adult General Population: The Korean National Health and Nutrition Examination Survey 2010–2016

PurposeChronic cough is a prevalent condition in the community and may pose considerable impairment to quality of life (QoL). However, its disease burden remains largely undefined in the general population. The present study investigated the relationship between chronic cough and health-related QoL in a Korean nationwide population database, with an emphasis on clinical conditions which may confound the impact of cough.MethodsThis study analyzed cross-sectional datasets of adults (aged ≥ 40 years) in the Korean National Health and Nutrition Examination Survey 2010–2016. Health-related QoL was assessed using the 3-level EuroQoL 5-dimension component (EQ-5D-3L) index score. The presence of chronic cough and other conditions were defined using structured questionnaires.ResultsThe prevalence of chronic cough was 3.48% ± 0.17% among adults aged ≥ 40 years. The overall EQ-5D-3L index score was significantly lower in subjects with than without chronic cough (0.79 ± 0.01 vs. 0.86 ± 0.00, P < 0.001). In subgroup analyses by age and sex, chronic cough had a notably large impact on QoL in women aged ≥ 65 years (vs. those without chronic cough: 0.55 ± 0.04 vs. 0.70 ± 0.01, P < 0.001), although the mean difference in the scores exceeded the minimally important difference score of 0.05 in all subgroups. In multivariate analyses, chronic cough was significantly associated with QoL, independent of confounders including depression, arthritis, asthma, and chronic obstructive pulmonary disease. In dimension analyses, chronic cough was more associated with anxiety/depression, pain/discomfort, and usual activities than with self-care or mobility in the EQ-5D.ConclusionsThe present study demonstrated significant associations between chronic cough and health-related QoL in a nationwide large general adult population aged ≥ 40 years, which were independent of clinical confounders. The impact of chronic cough was greater in women aged ≥ 65 years. These findings indicate a considerable burden of chronic cough in the general population and warrant further investigations to assess the disease burden of chronic cough in a global scale