Eye Drop with Fas-Blocking Peptide Attenuates Age-Related Macular Degeneration.

Age-related macular degeneration (AMD), characterized by macular retinal degeneration, poses a significant health concern due to the lack of effective treatments for prevalent dry AMD. The progression of AMD is closely linked to reactive oxygen species and Fas signaling, emphasizing the need for targeted interventions. In this study, we utilized a NaIO3-induced retinal degeneration mouse model to assess the efficacy of Fas-blocking peptide (FBP). Intravitreal administration of FBP successfully suppressed Fas-mediated inflammation and apoptosis, effectively arresting AMD progression in mice. We developed a 6R-conjugated FBP (6R-FBP) for eye drop administration. 6R-FBP, administered as an eye drop, reached the retinal region, attenuating degeneration by modulating the expression of inflammatory cytokines and blocking Fas-mediated apoptosis in rodent and rabbit NaIO3-induced retinal degeneration models to address practical concerns. Intravitreal FBP and 6R-FBP eye drops effectively reduced retinal degeneration and improved retinal thickness in rodent and rabbit models. This study highlights the therapeutic potential of FBP, particularly 6R-FBP as an eye drop, in inhibiting Fas-mediated cell signaling and protecting against retinal cell death and inflammation in dry AMD. Future investigations should explore the translational prospects of this approach in primates with eye structures comparable to those of humans.

Intranasal Delivery of Anti-Apoptotic siRNA Complexed with Fas-Signaling Blocking Peptides Attenuates Cellular Apoptosis in Brain Ischemia.

Ischemic stroke-induced neuronal cell death leads to the permanent impairment of brain function. The Fas-mediating extrinsic apoptosis pathway and the cytochrome c-mediating intrinsic apoptosis pathway are two major molecular mechanisms contributing to neuronal injury in ischemic stroke. In this study, we employed a Fas-blocking peptide (FBP) coupled with a positively charged nona-arginine peptide (9R) to form a complex with negatively charged siRNA targeting Bax (FBP9R/siBax). This complex is specifically designed to deliver siRNA to Fas-expressing ischemic brain cells. This complex enables the targeted inhibition of Fas-mediating extrinsic apoptosis pathways and cytochrome c-mediating intrinsic apoptosis pathways. Specifically, the FBP targets the Fas/Fas ligand signaling, while siBax targets Bax involved in mitochondria disruption in the intrinsic pathway. The FBP9R carrier system enables the delivery of functional siRNA to hypoxic cells expressing the Fas receptor on their surface-a finding validated through qPCR and confocal microscopy analyses. Through intranasal (IN) administration of FBP9R/siCy5 to middle cerebral artery occlusion (MCAO) ischemic rat models, brain imaging revealed the complex specifically localized to the Fas-expressing infarcted region but did not localize in the non-infarcted region of the brain. A single IN administration of FBP9R/siBax demonstrated a significant reduction in neuronal cell death by effectively inhibiting Fas signaling and preventing the release of cytochrome c. The targeted delivery of FBP9R/siBax represents a promising alternative strategy for the treatment of brain ischemia.

Subtypes of Patients with Mild to Moderate Airflow Limitation as Predictors of Chronic Obstructive Pulmonary Disease Exacerbation.

COPD is a heterogeneous disease, and its acute exacerbation is a major prognostic factor. We used cluster analysis to predict COPD exacerbation due to subtypes of mild-moderate airflow limitation. In all, 924 patients from the Korea COPD Subgroup Study cohort, with a forced expiratory volume (FEV1) ≥ 50% and documented age, body mass index (BMI), smoking status, smoking pack-years, COPD assessment test (CAT) score, predicted post-bronchodilator FEV1, were enrolled. Four groups, putative chronic bronchitis (n = 224), emphysema (n = 235), young smokers (n = 248), and near normal (n = 217), were identified. The chronic bronchitis group had the highest BMI, and the one with emphysema had the oldest age, lowest BMI, and highest smoking pack-years. The young smokers group had the youngest age and the highest proportion of current smokers. The near-normal group had the highest proportion of never-smokers and near-normal lung function. When compared with the near-normal group, the emphysema group had a higher risk of acute exacerbation (OR: 1.93, 95% CI: 1.29-2.88). However, multiple logistic regression showed that chronic bronchitis (OR: 2.887, 95% CI: 1.065-8.192), predicted functional residual capacity (OR: 1.023, 95% CI: 1.007-1.040), fibrinogen (OR: 1.004, 95% CI: 1.001-1.008), and gastroesophageal reflux disease were independent predictors of exacerbation (OR: 2.646, 95% CI: 1.142-6.181). The exacerbation-susceptible subtypes require more aggressive prevention strategies.

Association of type 2 diabetes mellitus with lung cancer in patients with chronic obstructive pulmonary disease.

Background: Patients with chronic obstructive pulmonary disease (COPD) have an increased risk of developing lung cancer. Some studies have also suggested that diabetes mellitus (DM) may increase the risk of developing lung cancer. This study aimed to investigate whether type 2 DM (T2DM) is associated with an increased risk of lung cancer in patients with COPD. Materials and methods: We conducted a retrospective analysis on two cohorts: the National Health Insurance Service-National Sample Cohort (NHIS-NSC) of Korea and the Common Data Model (CDM) database of a university hospital. Among patients newly diagnosed with COPD in each cohort, those with a lung cancer diagnosis were included, and a control group was selected through propensity score matching. We used the Kaplan-Meier analysis and Cox proportional hazard models to compare lung cancer incidence between patients with COPD and T2DM and those without T2DM. Results: In the NHIS-NSC and CDM cohorts, we enrolled 3,474 and 858 patients with COPD, respectively. In both cohorts, T2DM was associated with an increased risk of lung cancer [NHIS-NSC: adjusted hazard ratio (aHR), 1.20; 95% confidence interval (CI), 1.02-1.41; and CDM: aHR, 1.45; 95% CI, 1.02-2.07). Furthermore, in the NHIS-NSC, among patients with COPD and T2DM, the risk of lung cancer was higher in current smokers than in never-smokers (aHR, 1.45; 95% CI, 1.09-1.91); in smokers with ≥30 pack-years than in never-smokers (aHR, 1.82; 95% CI, 1.49-2.25); and in rural residents than in metropolitan residents (aHR, 1.33; 95% CI, 1.06-1.68). Conclusion: Our findings suggest that patients with COPD and T2DM may have an increased risk of developing lung cancer compared to those without T2DM.

A modified method of measuring plasma volume with indocyanine green: reducing the frequency of blood sampling while maintaining accuracy.

Among various methods for measuring the plasma volume (PV), the indocyanine green (ICG) dilution technique is a relatively less invasive method. However, the ICG method is rather cumbersome because 10 blood samples need to be obtained within a short time after ICG administration. Thus, reducing the frequency of blood sampling while maintaining the accuracy would facilitate plasma volume measurement in clinical situations. We here developed a modified method to measure plasma volume using 2260 ICG plasma concentration data from 115 surgical patients. The mean relative error (MRE) and the percentage of cases with relative error (RE) greater than 5% in total (PRE) were used to quantify the difference between plasma volumes obtained by the original and modified methods. RE was determined as follows. RE(%) = (PV obtained by original method (PVoriginal)-PV obtained by modified method (PVmodified))/PVoriginal × 100. PVmodified was assumed to be equal to PVoriginal when the RE was < 5%. When the number of samples selected for the plasma volume estimation was 4 or less, the PRE was mostly 10% or more. Five out of the 10 blood samples (order: 1st, 2nd, 3rd, 9th, and 10th) showed similar accuracies with the plasma volume obtained by the original method (original: 2.72 ± 0.64 l, modified: 2.72 ± 0.65 l). This modified method may be able to aptly replace the original method and lead to a wider clinical application of the ICG dilution technique. Further validation is needed to determine if the results of this study may be applied in other populations.

Linezolid for treatment of chronic extensively drug-resistant tuberculosis.

BACKGROUND: Linezolid has antimycobacterial activity in vitro and is increasingly used for patients with highly drug-resistant tuberculosis. METHODS: We enrolled 41 patients who had sputum-culture-positive extensively drug-resistant (XDR) tuberculosis and who had not had a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their background regimen. The primary end point was the time to sputum-culture conversion on solid medium, with data censored 4 months after study entry. After confirmed sputum-smear conversion or 4 months (whichever came first), patients underwent a second randomization to continued linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 months, with careful toxicity monitoring. RESULTS: By 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had culture conversion (P=0.001). Most patients (34 of 39 [87%]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed. CONCLUSIONS: Linezolid is effective at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis, but patients must be monitored carefully for adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and the Ministry of Health and Welfare, South Korea; ClinicalTrials.gov number, NCT00727844.).