Targeted treatment for biofilm-based infections using PEGylated tobramycin.

Chronic infections often involve biofilm-based bacteria, in which the biofilm results in significant resistance against antimicrobial agents and prevents eradication of the infection. The physicochemical barrier presented by the biofilm matrix is a major impediment to the delivery of many antibiotics. Previously, PEGylation has been shown to improve antibiotic penetration into biofilms in vitro. In these studies, PEGylating tobramycin was investigated both in vitro and in vivo. Two distinct PEGylated tobramycin molecules were synthesized (mPEG-SA-Tob and mPEG-AA-Tob). Then, in a P. aeruginosa biofilm in vitro model, we found that mPEG-SA-Tob can operate as a prodrug and showed 7 times more effectiveness than tobramycin (MIC80: 14 µM vs.100 µM). This improved biofilm eradication is attributable to the fact that mPEG-SA-Tob can aid tobramycin to penetrate through the biofilm and overcome the alginate-mediated antibiotic resistance. Finally, we used an in vivo biofilm-based chronic pulmonary infection rat model to confirm the therapeutic impact of mPEG-SA-Tob on biofilm-based chronic lung infection. mPEG-SA-Tob has a better therapeutic impact than tobramycin in that it cannot only stop P. aeruginosa from multiplying in the lungs but can also reduce inflammation caused by infections and prevent a recurrence infection. Overall, our findings show that PEGylated tobramycin is an effective treatment for biofilm-based chronic lung infections.

Primary pituitary stalk mucosa-associated lymphoid tissue lymphoma: a case report and literature review.

Background: Primary extranodal mucosa-associated lymphoid tissue (MALT) lymphoma in the sellar region is a rare indolent B-cell lymphoma. Case presentation: A newly diagnosed patient with MALT lymphoma originating from the pituitary stalk is reported. A space-occupying lesion in the sellar region was found in a 24 year-old man who had no clinical symptoms except for those relating to a sex hormone disorder (rising estrogen and falling androgen) identified during a pre-employment physical examination. MALT lymphoma was diagnosed pathologically. Radiotherapy and chemotherapy were proposed after surgery. However, the patient selected androgen replacement therapy only rather than chemoradiotherapy. Over the next 3 months, no visual disturbance, headache, cranial nerve abnormality, or other symptoms occurred. Conclusion: Primary sellar region MALT lymphoma is an extremely rare disease. The differential diagnosis of sellar and parasellar masses should include primary sellar region MALT lymphoma. Early detection and treatment of this lymphoma can effectively improve the prognosis.

Pulmonary biofilm-based chronic infections and inhaled treatment strategies.

Certain pulmonary diseases, such as cystic fibrosis (CF), non-CF bronchiectasis, chronic obstructive pulmonary disease, and ventilator-associated pneumonia, are usually accompanied by respiratory tract infections due to the physiological alteration of the lung immunological defenses. Recurrent infections may lead to chronic infection through the formation of biofilms. Chronic biofilm-based infections are challenging to treat using antimicrobial agents. Therefore, effective ways to eradicate biofilms and thus relieve respiratory tract infection require the development of efficacious agents for biofilm destruction, the design of delivery carriers with biofilm-targeting and/or penetrating abilities for these agents, and the direct delivery of them into the lung. This review provides an in-depth description of biofilm-based infections caused by pulmonary diseases and focuses on current existing agents that are administered by inhalation into the lung to treat biofilm, which include i) inhalable antimicrobial agents and their combinations, ii) non-antimicrobial adjuvants such as matrix-targeting enzymes, mannitol, glutathione, cyclosporin A, and iii) liposomal formulations of anti-biofilm agents. Finally, novel agents that have shown promise against pulmonary biofilms as well as traditional and new devices for pulmonary delivery of anti-biofilm agents into the lung are also discussed.

A modified frozen elephant trunk technique for acute Stanford type A aortic dissection.

BACKGROUND: Acute Stanford type A aortic dissection is often fatal, with a high mortality rate and requiring emergency intervention. Salvage surgery aims to keep the patient alive by addressing severe aortic regurgitation, tamponade, primary tear, and organ malperfusion and, if possible, prevent the late dissection-related complications in the proximal and downstream aorta. Unfortunately, no optimal standard treatment or technique to treat this disease exists. Total arch replacement with frozen elephant trunk technique plays an important role in treating acute type A aortic dissection. We aim to describe a modified elephant trunk technique and report its short-term outcomes. METHODS: From February 2018 to August 2019, 16 patients diagnosed with acute Stanford type A aortic dissection underwent surgery with the modified frozen elephant trunk technique at Xiamen Heart Center (male/female: 9/7; average age: 56.1 ± 7.6 years). All perioperative variables were recorded and analyzed. We measured the diameters of the ascending aorta, aortic arch, and descending aorta on the bifurcation of the pulmonary and abdominal aortas and compared the diameters at admission, before discharge, and 3 months after discharge. RESULTS: Fifteen patients (93.8%) had hypertension. The primary tears were located in the lesser curvature of the aortic arch and ascending aorta in 5 (31.3%) and 9 patients (56.3%), respectively, and no entry was found in 2 patients (12.5%). The dissection extended to the iliac artery and distal descending aorta in 14 (87.6%) and 2 patients (12.5%), respectively. The duration of cardiopulmonary bypass (CPB), cross-clamping, and antegrade cerebral perfusion were 215.8 ± 40.5, 140.8 ± 32.3, and 55.1 ± 15.2 min, respectively. Aortic valve repair was performed in 15 patients (93.8%). Bentall procedure was performed in one patient (6.3%). Another patient received coronary artery repair (6.3%). The diameters at all levels were greater on discharge than those on admission, except the aortic arch. After 3 months, the true lumen diameter distal to the frozen elephant trunk increased, indicating false lumen thrombosis and/or aortic remodeling. CONCLUSIONS: The modified frozen elephant trunk technique for acute Stanford type A aortic dissection is safe and feasible and could be used for organ malperfusion. Short-term outcomes are encouraging, but long-term outcomes require further investigation.

FeCl2 monolayer on HOPG: art of growth and momentum filtering effect.

Magnetic layered transition metal halides have received intensive attention due to the potential magnetic properties in their monolayers. Following the recently reported success of trihalide monolayer ferromagnets, we have achieved the growth of a dihalide, FeCl2, monolayer system on graphite by molecular beam epitaxy. Scanning tunneling microscopy was used in the topographic and spectroscopic study of the monolayer islands at the atomic scale. Results show that the FeCl2 monolayer is an electronvolt-gaped insulator with various twist angles relative to the substrate. The tunneling probability on the monolayer islands is a function of the twist angle with a max/min ratio of ∼2.5. Our direct experimental evidence finds that the FeCl2 monolayer is an efficient momentum, perhaps spin, filtering insulating layer with subnanometer thickness.

Integrated analysis of immunocyte infiltration and differential gene expression in tricuspid aortic valve-associated thoracic aortic aneurysms.

BACKGROUND: Progressive dilatation is responsible for significant mortality and morbidity in patients with thoracic aortic aneurysms (TAAs). Studies have shown that the development and progression of TAAs are closely related to immune regulatory pathways and genes. Therefore, it is important to understand the immune regulatory mechanisms and biomarkers of TAA dilatation. METHODS: Systematic bioinformatics analysis was applied, including linear models for microarray data (LIMMA) differential expression analyses, principal component analysis (PCA), immunocyte identification, and genetic function enrichment analysis. RESULTS: Our results showed that both aortic intima-media (AMed) and outer aortic adventitia (AAdv) tissues were closely associated with T cell activation during the process of tricuspid aortic valve (TAV)-associated TAA dilation. Additionally, the degree of infiltration of resting memory CD4+ T cells was linked to both AAdv and AMed vascular dilation. The core regulators PPTRC, IL1B, CD4, CD3G, and IL2RA were also identified and are closely related to resting memory CD4+ T cell infiltration in this pathological process. CONCLUSIONS: The candidate genes PPTRC, IL1B, CD4, CD3G, and IL2RA were involved in the regulation of resting memory CD4 T cell tissue infiltration, which is closely related to the process of AAdv and AMed vascular dilation in TAV patients.

A Systematic Safety Evaluation of Nanoporous Mannitol Material as a Dry-Powder Inhalation Carrier System.

For carrier-based dry-powder inhaler (DPI) formulations, the adhesion between carrier particles and active pharmaceutical ingredients (API) particles have a significant influence on the aerosolization performance of the API-carrier complexes and the desired detachment of the API for efficient pulmonary delivery. In our previous study, nanoporous mannitol material was successfully fabricated as carriers by a one-step nonorganic solvent spray drying method with the thermal degradation of ammonium carbonate. These carriers were shown to achieve excellent aerosolization performance. In addition, no residue of ammonium carbonate was detected on the powder surface. However, the safety of nanoporous mannitol carriers (Nano-PMCs) during pulmonary administration/delivery was still unknown because the lung is vulnerable to the inhaled particles. To address this question, the present study was conducted to construct a systematic safety evaluation for DPIs carriers to investigate the safety of Nano-PMCs in the whole inhalation, which would make up for the lack of detailed and standardized method in this field. In vitro safety evaluation was carried out using respiratory and pulmonary cytotoxicity tests, hemolysis assay, and ciliotoxicity test. In vivo safety evaluation was studied by measuring inflammatory indicators in the bronchoalveolar lavage fluid, assessing the pulmonary function and observing pulmonary pathological changes. Nano-PMCs showed satisfactory biocompatibility on respiratory tracts and lungs in vitro and in vivo. It was suggested that Nano-PMCs were safe for intrapulmonary delivery and potential as DPI carriers.

"Aorta-clamp" technique for surgical repair of acute type A aortic dissection-5 min circulatory arrest at 30 °C.

BACKGROUND: Deep hypothermic circulatory arrest (HCA), which causes perioperative complications, is the foundation of surgical treatment for acute type A aortic dissection (AAAD). To extensively replace the dissected aorta and avoid the negative impacts of HCA, we developed an "aorta-clamp" technique and examined its efficacy in repairing AAAD. METHODS: From November 2014 to August 2016, we recruited 59 consecutive patients (51.3±10.9 years) with AAAD into this study. We performed total arch replacement combined with an elephant trunk implantation using the "aorta-clamp" technique under a 30 °C HCA with continual bilateral antegrade cerebral perfusion. RESULTS: The average HCA time was 4.9±1.0 min. Twenty-three patients had increased serum creatinine (sCr) before surgery, suggesting an AAAD-associated acute kidney injury (AKI). The sCr level returned to normal in five patients after operation and in 15 before discharge. Six patients (10.2%) with preoperative AKI required postoperative dialysis, and two of these patients (3.4%) died of multiple organ failure. Two patients (3.4%) required re-exploration due to bleeding. One patient (1.7%) exhibited temporary neurologic deficits. There were no late deaths. Computed tomography (CT) examination confirmed the patency of the anastomotic sites and thrombus obliteration of the residual false lumen. CONCLUSIONS: Using the "aorta-clamp" technique with continual bilateral antegrade cerebral perfusion, total arch replacement combined with an elephant trunk implantation can be performed under five minutes of mild (30 °C) HCA. Our data suggest that this technique for the surgical repair of AAAD is a safe, feasible and effective surgical approach with satisfactory early outcomes.

The application of different temperature during hypothermic circulatory arrest on aortic arch surgery / 中国胸心血管外科临床杂志

@#We conducted a detailed analysis of different hypothermic circulatory arrest techniques, from its evolution, application on aortic arch surgery and research, focusing on the application and advantages and disadvantage, which provides some guide for the future discussion on the optimal temperature of hypothermic circulatory arrest.

Moisture-Resistant Co-Spray-Dried Netilmicin with l-Leucine as Dry Powder Inhalation for the Treatment of Respiratory Infections.

Netilmicin (NTM) is one of the first-line drugs for lower respiratory tract infections (LRTI) therapy, but its nephrotoxicity and ototoxicity caused by intravenous injection restrict its clinical application. Dry powder inhalation (DPI) is a popular local drug delivery system that is introduced as a solution. Due to the nature of NTM hygroscopicity that hinders its direct use through DPI, in this study, L-leucine (LL) was added into NTM dry powder to reduce its moisture absorption rate and improve its aerosolization performance. NTM DPIs were prepared using spray-drying with different LL proportions. The particle size, density, morphology, crystallinity, water content, hygroscopicity, antibacterial activity, in vitro aerosolization performance, and stability of each formulation were characterized. NTM DPIs were suitable for inhalation and amorphous with a corrugated surface. The analysis indicated that the water content and hygroscopicity were decreased with the addition of LL, whilst the antibacterial activity of NTM was maintained. The optimal formulation ND2 (NTM:LL = 30:1) showed high fine particle fraction values (85.14 ± 8.97%), which was 2.78-fold those of ND0 (100% NTM). It was stable after storage at 40 ± 2 °C, 75 ± 5% relative humidity (RH). The additional LL in NTM DPI successfully reduced the hygroscopicity and improved the aerosolization performance. NTM DPIs were proved to be a feasible and desirable approach for the treatment of LRTI.

Clinical strategy of surgical management for Marfan syndrome in patients with severe left ventricular dysfunction / 中国胸心血管外科临床杂志

@#Objective     To retrospectively reviewed our experience of the surgical and perioperative treatment of patients suffering from critical Marfan syndrome with severe left ventricular dysfunction and to evaluate its therapeutic effect and prognosis. Methods     Between January 2012 and October 2016, 15 patients diagnosed with Marfan syndrome combined with severe left ventricular dysfunction (left ventricular ejection fraction≤40% or left ventricular end diastolic diameter≥75 mm) underwent operations for aortic root aneurysm in Zhujiang Hospital and Guangdong General Hospital. Among them, 11 were males and 4 were females with a mean age of 32.9±8.7 years ranging from 19 to 55 years. Five patients with aortic dissection underwent Bentall procedure and total arch reconstruction with stent graft implantation. Two patients underwent Bentall procedure and hemi-arch replacement, seven patients underwent Bentall procedure and one patient underwent Cabrol procedure. Concomitant procedures included mitral valve repair in 12 patients, mitral valve replacement in 3 patients and tricuspid valve repair in 12 patients. Results     There were 11 patients (73.3%) receiving intra-aortic balloon pumping implantation. One (6.7%) in-hospital death occurred. The left ventricular end diastolic diameter decreased from 80.5±7.4 mm to 58.3±6.0 mm (P<0.05) and the left ventricular ejection fraction improved from 37.3%±5.2% to 46.3%±4.4% 3 months postoperatively (P<0.05). The left ventricular end diastolic diameter decreased from 80.5±7.4 mm to 53.7±3.6 mm (P<0.05) and the left ventricular ejection fraction improved from 37.3%±5.2% to 57.7%±4.2% after one year (P<0.05). No death and reoperation occurred in the follow-up. Conclusion     Although the patients with Marfan syndrome and severe left ventricular dysfunction usually have a high surgical mortality, the key to satisfactory outcomes of severe Marfan syndrome is adequate preoperative preparation, complete correction of all vascular lesions during the operation, application of circulatory auxiliary device and perioperative strict and long-term ICU monitoring.

Modified total arch replacement for surgical repair of Stanford type A aortic dissection / 中国胸心血管外科临床杂志

@#Objective To evaluate the safety and effectiveness of modified total arch replacement by retrospectively analyzing the clinical outcome of surgical patients with Stanford type A aortic dissection (AAD). Methods From June 2015 to December 2016, 39 consecutive patients with AAD were recruited to this study. This modified technique was preformed under general anesthesia and a 30℃ hypothermia circulatory arrest (HCA) with continual bilateral antegrade cerebral perfusion. Different surgical approaches were applied according to the aortic root condition: Bentall procedure (4 patients), David procedure (2 patients), aortic valve plasty and ascending aortic replacement (25 patients) and Cabrol procedure (8 patients). Concomitant procedures included mitral valve plasty (1 patient) and tricuspid valve plasty (1 patient). Results The average cardiopulmonary bypass (CPB), aortic occlusion time (ACC), HCA and operation time was 218.5±42.2 min, 134.2±32.4 min, 4.9±2.3 min and 415.5±80.5 min respectively. Four patients required dialysis and 2 patients developed temporary neurological deficit. No permanent neurological deficit, postoperative paraplegia or in-hospital death occurred. Computed tomography examination was performed on all patients before discharge and 3 months after discharge. The follow-up result showed that 37 patients developed complete thrombosis in the false lumen and 2 patients developed partial thrombosis. Conclusion Modified total arch replacement is a safe and effective approach for AAD. It can greatly avoid postoperative complications and provide satisfactory short-term outcomes.