Search Results (97)

Background: Penetrating keratoplasty (PK) is a technically demanding corneal transplant procedure frequently performed in elderly patients with substantial systemic comorbidities. In this population, an anesthetic strategy that ensures hemodynamic stability, cooperative sedation, adequate analgesia, and preserved spontaneous ventilation is highly desirable. Dexmedetomidine, a highly selective alpha2-adrenergic agonist, provides “cooperative” sedation with minimal risk of respiratory depression and additional sympatholytic benefits. Methods: This single-center retrospective observational case series included 50 consecutive patients (American Society of Anesthesiologists [ASA] II–III, age 50–90 years) undergoing PK under sub-Tenon block combined with continuous dexmedetomidine infusion. Dexmedetomidine was administered without a loading bolus at 0.7 mcg/kg/h for 10–15 min, then reduced to 0.5 mcg/kg/h, targeting a Ramsay Sedation Scale (RSS) score of 2–3. The sub-Tenon block was performed using a mixture of levobupivacaine 0.5% and lidocaine 2% (3–5 mL). Heart rate (HR), mean arterial pressure (MAP), oxygen saturation (SpO₂) and RSS were recorded in nine predefined perioperative phases. Data were analyzed descriptively. Results: The mean age was 72 ± 9 years; 52% of patients were ASA III. Hypertension was present in all patients; 30% had cardiovascular disease, 28% diabetes mellitus type II, and 30% chronic obstructive pulmonary disease. Progressive, controlled bradycardia was observed (mean HR decreased from 76 to 57 beats/min during graft transplantation), while MAP gradually decreased from hypertensive baseline values (150–160 mmHg) to an optimal intraoperative range of 115–130 mmHg, without episodes of clinically significant hypotension. SpO₂ remained stable at 98–99% throughout all phases, with no episodes of desaturation or need for airway intervention or supplemental oxygen. Target sedation (RSS 2–3) was achieved in all patients (median RSS 3), with preserved spontaneous breathing and cooperation. Sub-Tenon block-related bulging occurred in 6% of cases. No episodes of clinically significant bradycardia, malignant arrhythmia, respiratory compromise, or need to discontinue dexmedetomidine were recorded. No opioids or non-steroidal analgesics were required intraoperatively or in the early postoperative period. Conclusions: The combination of sub-Tenon block and continuous dexmedetomidine sedation without a loading bolus represents a hemodynamically stable and respiratory-safe anesthetic strategy for PK in elderly, high-risk patients. These preliminary, hypothesis-generating findings suggest that the protocol provides stable surgical conditions and a favorable safety profile, justifying future prospective randomized controlled trials to establish its comparative efficacy against general anesthesia or standard sedative regimens. Full article

Pulmonary arterial hypertension (PAH) is a progressive, fatal disease of the pulmonary vasculature characterized by obliterative remodeling of small pulmonary arteries, leading to sustained elevation of pulmonary vascular resistance, right ventricular failure, and premature death. The diagnostic gold standard remains right heart catheterization, requiring a mean pulmonary artery pressure greater than 20 mmHg at rest, a pulmonary arterial wedge pressure of 15 mmHg or below, and a pulmonary vascular resistance exceeding 2 Wood units. PAH is an autosomal dominant disorder with markedly incomplete penetrance of approximately 20–30%, indicating that germline mutations alone are insufficient to cause disease. Disease manifestation requires additional “second hits”, including chronic hypoxia, systemic inflammation, hemodynamic stress, hormonal influences, and common genetic modifiers such as single-nucleotide polymorphisms (SNPs). This genetic and environmental complexity underpins the broad clinical heterogeneity observed across PAH subtypes, which include idiopathic PAH, heritable PAH, and disease associated with connective tissue disorders, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and drug or toxin exposure. This review provides a comprehensive and critical appraisal of the molecular-genetic architecture of PAH. Thirty genes have now been implicated in disease pathogenesis, spanning seven functional categories: receptors of the TGF-β/BMP signaling family (BMPR2, ACVRL1, ENG, BMPR1B); circulating BMP ligands (GDF2, BMP10); transcription factors (TBX4, SOX17, KLF4, FOXF1, SMAD1, SMAD4, SMAD9); membrane and polyamine transporters (ATP13A3, AQP1); potassium channel regulators (KCNA5, KCNK3, ABCC8); metabolic and mitochondrial genes (EIF2AK4, NFU1, GGCX); signaling receptors and structural proteins (NOTCH3, KDR, CAV1, PLEKHH2); vasoactive and extracellular matrix regulators (KLK1, CBLN2, CD248); and epigenetic regulators (TET2, TOPBP1). Among these, BMPR2 is the dominant contributor, accounting for 53–86% of heritable PAH and 14–35% of idiopathic cases. The remaining genes each account for fewer than 5% of cases individually, collectively reflecting a broad landscape of rare and ultra-rare genetic contributions. For each gene, we critically evaluate the strength of genetic evidence, pathogenic mechanisms, degree of mechanistic resolution, and clinical relevance. We further discuss the contribution of emerging technologies, including whole-genome sequencing, single-cell and spatial transcriptomics, multi-omics integration, iPSC-derived vascular models, and artificial intelligence, to expanding the PAH genetic architecture beyond single-gene discovery. A key theme across this landscape is convergence: despite mechanistic diversity at the gene level, most PAH-associated variants ultimately impair endothelial quiescence, promote smooth muscle proliferation, and drive apoptosis resistance through disruption of BMP signaling amplitude, transcriptional stability, ion channel homeostasis, metabolic integrity, or epigenetic regulation. This convergence supports both a unified therapeutic rationale and a precision medicine framework for genotype-stratified intervention in PAH. Full article

The global prevalence of pulmonary infections caused by non-tuberculous Mycobacteria (NTM), particularly the Mycobacterium avium complex (MAC), is increasing. Since NTM are ubiquitous in moist environments and resistant to standard disinfectants, this study evaluated the efficacy of chlorous acid water (CAW) against them. CAW demonstrated superior sanitizing effects compared to sodium hypochlorite (NaClO), efficiently inactivating NTM at 100 mg/L free available chlorine even in the presence of organic matter, where 1000 mg/L NaClO failed. Instead, subcellular fractionation and protein analysis revealed that CAW penetrates the cell to induce extensive aggregation of internal functional proteins, leading to the rapid collapse of membrane potential and ATP production. Furthermore, CAW exhibited significantly lower cytotoxicity toward human lung-derived A549 cells than NaClO. These results indicate that CAW inactivates NTM effectively by targeting internal protein stability and the respiratory chain, offering a potent and safer disinfection strategy for clinical and domestic environments. Full article

The lung represents a promising yet underexploited target for RNA therapeutics due to its large surface area and accessibility via non-invasive inhalation delivery. Despite rapid advances in RNA-based modalities, including small interfering RNA (siRNA), microRNA (miRNA), messenger RNA (mRNA), and CRISPR-Cas systems, efficient pulmonary delivery remains a major challenge. Multiple biological barriers, such as mucus and surfactant layers, mucociliary clearance, immune surveillance, and limited cellular uptake of negatively charged nucleic acids, significantly restrict therapeutic efficacy. In addition, aerosolization processes may introduce mechanical stress, compromising RNA integrity. Nanoparticle-based delivery systems have emerged as a central strategy to address these limitations. By protecting RNA cargo, enhancing mucus penetration, and promoting cellular internalization, engineered nanoparticles enable more effective pulmonary delivery. In this review, we adopt a barrier-centered perspective to examine the key biological obstacles to lung-targeted RNA delivery and highlight recent advances in nanoparticle-mediated strategies, with a focus on lipid nanoparticles, polymeric systems, and inorganic nanomaterials. We further discuss design principles that govern RNA stability, transport, and intracellular release and critically compare the strengths, limitations, and translational potential of each platform, including considerations of toxicity, biodegradability, and clinical readiness. Finally, we outline emerging clinical applications of RNA-loaded nanoparticles, using lung cancer as a representative disease model, and discuss remaining challenges and future directions. Continued innovation in nanoparticle engineering and delivery strategies is expected to accelerate the clinical translation of RNA therapeutics for pulmonary diseases. Full article

Peptide therapeutics occupy a unique chemical space between small molecules and biologics, combining high target specificity with structural programmability and favorable safety profiles. Recent regulatory approvals and expanding clinical pipelines underscore the growing therapeutic and commercial relevance of peptide-based drugs. This review outlines chemical modification approaches and contemporary design strategies, and evaluates their impact on proteolytic stability, pharmacokinetics, membrane permeability, and target engagement. We then highlight recent advances in artificial intelligence (AI)-guided peptide drug design, including machine learning models, protein language models, and generative architectures that enable high-throughput activity prediction, property optimization, and de novo sequence generation. These approaches collectively accelerate the traditional discovery–design–validation cycle while reducing experimental attrition through data-driven, structure-informed modeling frameworks. Among these applications, AI also enables the rational design of cell-penetrating peptides (CPPs) to enhance intracellular delivery and biological activity. Building on these methodological advances, we further examine their application to peptide therapeutics, with particular emphasis on AI-based predictive models for CPPs as well as on therapeutic applications within the central nervous and pulmonary systems. We conclude by outlining future perspectives and emphasize that the systematic integration of AI-enabled sequence design with rational chemical engineering and advanced delivery technologies, supported by rigorous experimental validation, will be critical for developing robust and clinically durable peptide-based medicines. Full article

The development of effective inhalable drugs remains a key challenge in the treatment of pulmonary diseases, due to the physiological barriers of the respiratory tract and the lack of predictive models that accurately reproduce the human lung environment. In this context, liposomes (LP) have emerged as promising nanocarriers for pulmonary drug delivery due to their high biocompatibility, surfactant-like composition, capacity to encapsulate both hydrophilic and lipophilic drugs, and potential to provide sustained drug release while reducing systemic toxicity. This study evaluates the influence of size and PEGylation on their physicochemical properties, cytotoxicity, interaction with the pulmonary mucus, and cellular internalisation. LP of 100 nm (LP 100), 200 nm (LP 200), and 600 nm (LP 600) were characterised physiochemically and evaluated in pulmonary cell lines (A549 and Calu-3) exposed in liquid–liquid interface (LLI) and air–liquid interface (ALI) by nebulisation. In addition, artificial pulmonary mucus (APM) was employed to analyse LP penetration through the pulmonary mucus barrier. Results indicate that LP 100 exhibits greater colloidal stability, lower cytotoxicity, and sustained migration through the APM over time with respect to larger particles. PEGylation of LP 100 (LP-PEG) further increases their stability and ability to penetrate the APM, although cellular internalisation is reduced due to the steric effect of the PEG coating. These findings highlight the importance of adjusting the size and surface modifications of LPs according to the therapeutic target of the drug, optimising their persistence on the epithelial surface or their cellular uptake. Full article

Background/Objectives: Levofloxacin (LVX) is a fluoroquinolone approved for the treatment of bacterial pneumonia, sinusitis, and prostatitis. Emerging in vitro and preclinical evidence suggests that efflux transporters are involved in LVX’s target tissue site distribution. Methods: The objective of this research was to characterize tissue exposure using a physiologically based pharmacokinetic (PBPK) model to be able to make more educated choices for optimal doses using target site pharmacokinetics data. Results: The final PBPK model in humans was applied to simulate free target site concentrations of LVX in lung and prostate, linking to minimum inhibitory concentrations (MIC) to assess appropriateness of currently approved dosing regimens for infections in both tissues. The clinical PBPK model was able to reproduce total plasma as well as free lung and prostate exposure of LVX in humans. Efflux transporters participate in LVX distribution to prostatic but not pulmonary tissue. Our results show a good penetration of LVX in both tissues with unbound partition coefficient (Kp,uu) equal to 0.79 and 0.72 for lung and prostate, respectively. Since LVX penetration in lung and prostate is similar, different sensitivities of the pathogens to LVX will dictate the effectiveness of the approved therapeutic regimen in the treatment of bacterial pneumonia, sinusitis, and prostatitis. Conclusions: Our research provides relevant insight into LVX’s target site exposure in lung and prostate. When integrated with pathogen-specific susceptibility data, these findings can be applied to refine current dosing regimens and help optimize the pharmacological treatment outcomes. Full article

Background and clinical significance. Penetrating cardiothoracic wounds require prompt treatment in order to decrease mortality and morbidity. Surgical therapy, aimed at bleeding control and removal of damaged tissue, varies widely from the direct suture of parenchymal lacerations to pneumonectomy, which is characterized by high mortality rates. We report our experience with a patient in hemorrhagic shock due to a gunshot wound to the chest, successfully treated by pneumorrhaphy under cardiopulmonary bypass (CPB). Case presentation. A 53-year-old man with a gunshot wound to the chest was admitted to our Emergency Department. A bedside ultrasonography revealed left pleural and pericardial effusion. He was hemodynamically instable, so he was immediately transferred to the operating room by the cardiac and Thoracic Surgery teams. Through a median sternotomy approximately 2 L of blood were evacuated and a deep laceration of the left upper lobe was discovered. The massive bleeding could not be controlled, leading to pleural cavity flooding. The surgical team decided to institute emergency CPB and perform lung repair by pneumorrhaphy, under circulatory support. The patient survived and was discharged on p.o. day 20. Conclusions. Clinical expertise, adequate instrumental equipment and a high level of interdisciplinary team-work favorably affected the patient’s outcome. Full article

Background/Objective: Postoperative dysphagia is a common cause of postoperative pulmonary complications (PPCs) following esophagectomy for esophageal cancer. Although the reclining posture is effective for general dysphagia, its effectiveness after esophagectomy remains unclear. Therefore, we aimed to explore effective approaches in the management of dysphagia after esophagectomy. Methods: This study included patients who underwent esophagectomy at the Department of Surgery, Hamamatsu University School of Medicine Hospital between January 2018 and March 2021. For the postoperative swallowing evaluation, the patients underwent a videofluoroscopic swallowing study by drinking 30 mL of liquid in two postures, a 45-degree reclining position (45°R) and a 90-degree upright position (90°U), and assessments were performed using the Penetration–Aspiration Scale. Results: Eighty-seven patients participated in the study. Laryngeal penetration and aspiration were, respectively, observed in 19 (21.8%) and 21 patients (24.1%) at 90°U, and in 14 (16.1%) and five patients (5.7%) at 45°R (p < 0.05). PPCs occurred in 10 patients (11.5%), and vocal cord paralysis occurred in 22 patients (25.3%). However, after adjusting the feeding conditions based on the results of the swallowing assessment, PPCs after meal initiation occurred in only five of these 10 patients (5.7%). Conclusions: Although dysphagia after esophagectomy is observed in approximately half of the patients, including those with minor dysphagia, the risk of aspiration can be reduced by changing the patient’s posture during food consumption. Thus, postural changes may be a useful approach for reducing the risk of PPCs. Full article

Acute pulmonary embolism (APE) remains a significant cause of mortality and morbidity despite increasing prophylaxis for deep venous thrombosis (DVT). The IVC filter is a temporary or permanent intravascular device that traps migrating thrombi from their origin in the pelvis or a lower limb into the pulmonary vasculature, thereby preventing significant APE. The current and longstanding indications for placing an IVC filter are in patients with documented lower extremity DVT and acute APE who also have absolute contraindications to anticoagulation or have experienced an acute, hemodynamically unstable APE requiring ventilatory and vasoactive support, with limited cardiovascular reserve. Updated guidelines have led to a significant rise in IVC filter placements for specific therapeutic indications of venous thromboembolism compared to prophylactic use. Meta-analyses show that IVC filter placement is associated with a lower risk of subsequent APE but an increased risk of DVT. However, there appears to be no significant reduction in APE-related mortality and no change in all-cause mortality. Early complications after IVC filter placement typically relate to procedural issues and include bleeding or infection at the venous access site, development of arteriovenous fistulas, accidental arterial puncture, and post-procedural access site hematoma or thrombosis. Additional early complications include IVC filter malposition, incomplete expansion, IVC penetration, or guidewire entrapment. Delayed complications may involve DVT below the filter, IVC occlusion due to the filter, IVC filter migration, fracture of one of the IVC filter components, IVC rupture, or IVC thrombosis. Retrieval of IVC filters by simple, advanced, or open techniques should be considered after weighing the risk-to-benefit for the individual patient. Deployment of the IVC filter remains an important component of interventional APE management within the narrow indications currently proposed. Current guidance recommends that an untethered temporary IVC filter should be placed and retrieved once the contraindication to anticoagulation is resolved. Full article

Background: Eravacycline exhibits potent activity against multidrug-resistant pathogens and holds promise for the management of hospital-acquired and ventilator-associated pneumonia (HAP/VAP). However, sensitive and robust bioanalytical methods to quantify eravacycline in human pulmonary epithelial lining fluid (ELF) for pharmacokinetic (PK) and pulmonary penetration studies in these infections remain limited. Methodology: A simple, rapid, and sensitive LC-MS/MS method was developed for the quantification of eravacycline in bronchoalveolar lavage fluid (BALF). Using urea as a volume normalizer, ELF concentrations were calculated from the eravacycline concentrations in BALF. This method was applied in a clinical study evaluating the pulmonary penetration after intravenous infusion in patients with HAP and VAP. Results: The developed LC-MS/MS method exhibited good linearity in the range of 1–200 ng/mL for quantifying eravacycline in BALF. In BALF, intra-day precision ranged from 1.4% to 6.0%, and inter-day precision from 1.6% to 9.9%, with accuracy between 98.0% and 102.4%. Matrix effects were within 97.4% to 107.6% for BALF samples from six different individuals, with extraction recoveries ranging from 103.5% to 107.2%. Stability studies demonstrated that eravacycline remained stable under various conditions, including storage at room temperature, freeze–thaw cycles, long-term (–70 °C) storage, and post-treatment handling. The method was successfully applied to clinical samples from four HAP or VAP patients, with measured eravacycline pulmonary penetration ratios of 4.29, 17.40, 5.22 and 4.70, indicating efficient pulmonary distribution. The measured eravacycline concentrations ranged from 0.0243 to 0.0436 μg/mL in BALF. The corresponding urea-corrected ELF concentrations ranged from 0.570 to 1.617 μg/mL. Conclusions: This study described a detailed and validated method for quantifying eravacycline concentrations in ELF from patients, providing a reliable analytical approach for investigating the pulmonary distribution of eravacycline. Full article

The ring finger protein 213 (RNF213) Arg4810Lys variant has been previously identified as a significant risk factor for Moyamoya disease (MMD), particularly in East Asian populations. This review explores the broader impact of the Arg4810Lys mutation on various cerebrovascular conditions, including Moyamoya syndrome (MMS), intracranial artery stenosis, quasi-Moyamoya syndromes, ischemic stroke, and intracranial atherosclerosis. Beyond the brain, it is also implicated in pulmonary arterial hypertension, coronary artery disease, and renal artery stenosis, emphasizing its systemic effects. Functional studies suggest that RNF213 Arg4810Lys alters angiogenic signaling, endothelial cell function, vascular remodeling, and immune response pathways, especially when influenced by environmental stressors, like hypoxia or inflammation. The gene dosage of Arg4810Lys significantly affects disease phenotypes, with homozygous carriers typically experiencing earlier onset with increased severe symptoms. The variant also exhibits incomplete penetrance and frequently co-occurs with additional genetic alterations, including trisomy, KIF1A, FLNA, and PCSK9 mutations, which complicates its pathogenicity. A comprehensive understanding of RNF213 Arg4810Lys’s systemic impact is essential to developing effective risk assessment strategies, personalized treatments, and targeted therapies for associated vascular diseases. Full article

The interaction between carbon nanoparticles (CNs) and Langmuir monolayers of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) as a model pulmonary surfactant (PS) film was studied to shed light on the physicochemical bases underlying the potential adverse effects associated with pollutant inhalation. The results indicated that the surface pressure–area isotherms of the DPPC monolayers shifted toward lower molecular areas, and the compression modulus was reduced in the presence of CNs, hindering the ability of the DPPC monolayers to reduce the surface tension. The relaxation process of the DPPC monolayers were influenced, and the surface morphology and the continuity of the monolayers were destroyed by the penetration of CNs into the DPPC monolayers. The molecular dynamics simulation revealed that particle incorporation into the DPPC monolayers reduced the packing density of the DPPC molecules, worsening the mechanical performance of the monolayers. This effect was attributed to the strong binding trend between the CNs and the DPPC molecules. These results demonstrated that CNs could alter the relaxation mechanisms of the PS film, and this may cause a modification of the inhaled particle transport at the PS film and contribute to adverse health effects in the respiratory system of workers involved in the CN production process. Full article

Cystic fibrosis produces viscous mucus in the lung that increases bacterial invasion, causing persistent infections and subsequent inflammation. Pseudomonas aeruginosa and Staphylococcus aureus are two of the most common infections in cystic fibrosis patients that are resistant to antibiotics. One antibiotic approved to treat these infections is levofloxacin (LVX), which functions to inhibit bacterial replication but can be further developed into tailorable particles. Nanoparticles are an emerging inhaled therapy due to enhanced targeting and delivery. The extracellular matrix (ECM) has been shown to possess pro-regenerative and non-toxic properties in vitro, making it a promising delivery agent. The combination of LVX and ECM formed into nanoparticles may overcome barriers to lung delivery to effectively treat cystic fibrosis bacterial infections. Our goal is to advance CF care by providing a combined treatment option that has the potential to address both bacterial infections and lung damage. Two hybrid formulations of a 10:1 and 1:1 ratio of LVX to ECM have shown neutral surface charges and an average size of ~525 nm and ~300 nm, respectively. The neutral charge and size of the particles may suggest their ability to attract toward and penetrate through the mucus barrier in order to target the bacteria. The NPs have also been shown to slow the drug dissolution, are non-toxic to human airway epithelial cells, and are effective in inhibiting Pseudomonas aeruginosa and Staphylococcus aureus. LVX-ECM NPs may be an effective treatment for pulmonary CF bacterial treatments. Full article

Background/Objectives: Pediatric asthma is a leading cause of emergency department visits, and air pollution is a known primary environmental trigger. Although worldwide air pollutants have been associated with asthma exacerbations, limited data have been reported in the Eastern Province of Saudi Arabia. This study aimed to investigate the relationship between air pollution and pediatric asthma admissions among children aged 2 to 14 years old at King Fahd Hospital of the University Hospital (KFHU). Methods: This is a retrospective cohort study, over 366 days, including 1750 pediatric asthma-related ER visits and daily concentrations of air pollutants (PM_2.5, PM₁₀, NO₂, SO₂, CO, and O₃) and meteorological factors (temperature and humidity). Various statistical models, such as Poisson regression and ARIMA, were applied to determine the association between pollutants levels and hospital ER visits. The data were visit-based in nature, and it was not possible to follow up with repeat visits or for admission status for individual patients. Results: Elevated levels of PM_2.5, NO₂, and CO were significantly associated with more pediatric asthma ER visits, mainly on the same day and with short lags. PM_2.5 displayed the strongest association, consistent with its deeper pulmonary penetration and greater toxicity. Also, PM₁₀ levels were inversely associated with ER visits, possibly due to particle size and deposition location differences. Significantly correlated with increased ER visits are lower ambient temperature and higher humidity. Conclusions: This study offers strong evidence on the relationship between air pollution and pediatric asthma events, in turn highlighting the vital importance of air quality regulation, public health policies, and clinical vigilance for environmental exposures. Full article