Perineuronal nets protect fast-spiking interneurons against oxidative stress

A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks. The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress. Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress. These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults. We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display. Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress. In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets. Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress. The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets. Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.     

Cyclooxygenase-2 expression during allergic inflammation in guinea-pig lungs

Prostaglandins and thromboxanes are important modulators of airway physiology. The synthesis of these mediators depends on two isoforms of cyclooxygenase (COX), constitutive COX-1 and inducible COX-2. COX-2 expression has been observed in various inflammatory diseases, but not all aspects of the expression and the role of COX-2 in conditions of allergic inflammation such as asthma are clear. In the present study, we examined the 72-h kinetics of the expression of COX-isoform mRNA in ovalbumin-sensitized and -challenged guinea-pig lungs. The sensitized animals showed a robust and transient induction of COX-2 mRNA expression within 1 h after ovalbumin challenge, whereas their COX-1 mRNA levels remained unchanged. Upregulation of the level and activity of COX-2 protein followed the induction of COX-2 mRNA. Lung slices harvested from ovalbumin-challenged animals released more prostaglandin D(2) and prostaglandin E(2) spontaneously or in response to A23187 (10 microM) ex vivo than did those from unchallenged animals. This response was significantly blocked by the COX-2 selective inhibitors, NS-398 and JTE-522. In vivo administration of NS-398 significantly inhibited the accumulation of eosinophils and neutrophils in the lungs. In conclusion, de novo COX-2 expression during allergic inflammation modifies prostanoid synthesis in the lung and airway pathophysiology.     

Chemotherapy for patients with advanced lung cancer receiving long-term oxygen therapy

Background

Long-term oxygen therapy (LTOT) is sometimes prescribed for patients with advanced lung cancer who are potential candidates for chemotherapy. The aim of this study was to assess the usefulness of chemotherapy for patients with this disease who require LTOT.

Methods

The medical records of 40 patients with advanced lung cancer who received LTOT while undergoing systemic chemotherapy at our institution between January 2009 and December 2014 were retrospectively reviewed. Chemotherapy consisted of cytotoxic or molecular-targeted agents.

Results

Twenty-four patients had adenocarcinoma, 6 had squamous cell carcinoma, and 10 had small cell lung cancer (SCLC). The median survival time from the date of the first chemotherapy cycle performed in conjunction with LTOT was 194 days. In a multivariate analysis, the only factor significantly associated with better prognosis was the line (first or second) of the first chemotherapy with LTOT (hazard ratio =0.42; 95% confidence interval, 0.18 to 0.94). Among the 40 patients, 10 (25%) received chemotherapy during the last 30 days of their lives, 2 of whom died of chemotherapy-related adverse events.

Conclusions

Chemotherapy for patients with advanced lung cancer who receive LTOT may be acceptable if it is the first- or second-line treatment. However, we should be mindful of the potential overuse of chemotherapy and its negative impact on quality of life.     

Evaluation of olfactory dysfunction to estimate the presence of eosinophilic chronic rhinosinusitis in patients with asthma

BackgroundEosinophilic chronic rhinosinusitis (ECRS) is often complicated by asthma and can be difficult to diagnose. This study aimed to clarify the usefulness of the self-administered odor questionnaire (SAOQ) and visual analog scale (VAS) to identify olfactory disorders in patients with asthma.MethodsThis retrospective study was conducted on patients with asthma who were referred to the Otolaryngology clinic between May and September 2018. The treatment step of asthma, asthma control test (ACT), pulmonary function test, peripheral blood eosinophils, and fractional exhaled nitric oxide (FeNO) were analyzed. ECRS was diagnosed based on the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis Study score. Olfactory dysfunction was evaluated using the SAOQ and VAS for olfactory disorders.ResultsThe study included 56 patients (18 males and 38 females), who were divided into two groups; those with ECRS (n = 18) and those without ECRS (n = 38). Age, sex, treatment step, ACT score, and pulmonary function were not significantly different between the groups. The ECRS group had a significantly higher FeNO value (89.1 ppb vs. 39.1 ppb) and a significantly lower SAOQ score (40.1% vs. 96.1%). The area under the receiver operating characteristic curve for the efficacy of ECRS diagnosis was 0.88, 0.889, 0.799, and 0.757 for SAOQ, VAS, blood eosinophil count, and FeNO, respectively.ConclusionThe SAOQ and VAS scores were useful tools that presented similar results to the blood eosinophil count and FeNO, and may help to improve the diagnosis of ECRS in patients with asthma.     

Daily exercise lowers blood pressure and reduces visceral adipose tissue areas in overweight Japanese men

OBJECTIVE: To investigate the link between a reduction in blood pressure (BP) and daily exercise. DESIGN: Cross-sectional and longitudinal clinical intervention study with exercise education. SUBJECTS: 43 overweight Japanese men aged 32-59 years (BMI, 29.0+/-2.3 kg/m2) at baseline. Among the participants, a randomly selected 23 overweight men (BMI, 28.5+/-1.7) were further enrolled into the 10 months exercise program. MEASUREMENTS: BP was measured every week and steps per day were also recorded every day throughout the observation period. Fat distribution was evaluated by visceral fat (V) and subcutaneous fat (S) areas measured with computed tomography (CT) scanning at umbilical level, at before, 5 months and after intervention. Anthropometric parameters were also measured at same point. Aerobic exercise level, muscle strength, flexibility and calorie intake and insulin resistance (HOMA index) were investigated at before and after the study. RESULTS: In a cross sectional analysis, systolic BP (SBP) and diastolic BP (DBP) were significantly correlated with body composition. In a second longitudinal analysis, SBP was significantly reduced at 2 months and DBP was also reduced at 3 months, and almost maintained until the end of the observation period. Increasing daily walking was observed in 3 months and maintained until 10 months. Body composition, aerobic exercise level, muscle strength, flexibility and insulin resistance were significantly improved. There was positive correlation between DeltaDBP and Deltavisceral fat area (1-5, 5-10, 1-10 months). By stepwise multiple regression analysis, only Deltavisceral fat area was independently related to DeltaDBP at a significant level (1-10 months: DeltaDBP=-0.608+0.105Deltavisceral fat area, r2=0.227, P=0.0334). CONCLUSION: The present study indicated daily exercise lowers BP and visceral fat area is the critical factor for BP change.     

Cyanotic congenital heart disease and coronary artery atherogenesis

Hypoxemic erythrocytotic residents of high altitudes lack coronary atherosclerosis and have low cholesterol levels. It was postulated that hypoxemic erythrocytotic adults with cyanotic congenital heart disease (CCHD) might be analogous. The incidence of coronary atherosclerosis in this patient population has not been established, and hypocholesterolemia has not previously been recognized. Accordingly, 279 patients were divided into 4 groups: group A: 143 cyanotic patients not operated on (54 men and 89 women, aged 18 to 69 years); group B: 47 cyanotic patients (28 men and 19 women rendered acyanotic by operation at age 22 to 69 years); group C: 41 acyanotic patients not operated on (22 men and 19 women, aged 22 to 75 years); and group D: 48 patients acyanotic before and after operation (24 men and 24 women, aged 21 to 70 years). Coronary arteries were studied angiographically in 59 patients and at necropsy in 5 subjects aged 37 to 56 years. Total cholesterol was <160 mg/dl in 58% of group A, 52% of group B, 10% of group C, and 12% of group D (p <0.000001, chi-square analysis). Angiograms disclosed dilated coronary arteries without obstruction. Necropsy disclosed ectatic coronary arteries with structural abnormalities of the media. In conclusion, this study provides the first quantitative and qualitative data on antiatherogenic changes in lipoproteins in adults with CCHD. The coronary arteries are atheroma free because hypocholesterolemia acts in concert with the antiatherogenic properties of upregulated nitric oxide, hyperbilirubinemia, hypoxemia, and low platelet counts. The persistence of hypocholesterolemia after the surgical elimination of cyanosis suggests a genetic determinant.