Gamma-polyglutamic acid-coated vectors for effective and safe gene therapy.

In the present study, we developed some novel gene delivery vectors, coated cationic complexes with gamma-polyglutamic acid (gamma-PGA) for effective and safe gene therapy. Cationic complexes were constructed with pDNA and cationic vectors, such as poly-L-arginine hydrochloride (PLA), poly-L-lysine hydrobromide (PLL), N-[1-(2, 3-dioleyloxy) propyl]-N, N, N-trimethylammonium chloride (DOTMA)-cholesterol (Chol) liposomes, and DOTMA-dioleylphosphatidylethanolamine (DOPE) liposomes. The cationic complexes showed high gene expression with strong cytotoxicity in melanoma B16-F10 cells. The cationic complexes were also strongly toxic to erythrocytes. On the other hand, the gamma-PGA was able to coat all cationic complexes and form stable nano-sized particles with negative charges. These gamma-PGA-coated complexes had high gene expression without cytotoxicity and toxicities to the erythrocytes. In in vivo transfection experiments, polyplexes showed high transfection efficiency over 10(5) RLU/g in the lung tissue after intravenous injection, although gamma-PGA-coated polyplexes showed a high value in the spleen. High transfection efficiency in lipoplexes and gamma-PGA-coated lipoplexes was observed in the spleen and lung. Thus, gamma-PGA-coated vectors are useful for clinical gene therapy

Development of anionic bubble lipopolyplexes for efficient and safe gene transfection with ultrasound exposure in mice

Anionic bubble lipopolyplexes have been developed as anionic ultrasound (US)-responsive gene delivery carriers with biocompatible compounds for efficient and safe transfection in mice. The particles of the anionic bubble lipopolyplexes were approximately 450-600 nm with an anionic surface charge. In the absence of US exposure, the bubble lipopolyplexes showed extremely low gene expression in the human vascular endothelial cell line EAhy926. The anionic bubble lipopolyplexes, however, delivered pDNA into cells without endocytosis and showed markedly high gene expression following US exposure. The anionic bubble lipopolyplexes showed little cytotoxicity in EAhy926 cells and little aggregation with erythrocytes. Following intravenous administration into mice, the anionic bubble lipopolyplexes showed high levels of gene expression in the liver, kidney, and spleen only after US exposure to the abdominal area. The level of gene expression in liver non-parenchymal cells was significantly higher than that in parenchymal cells. In addition, the anionic bubble lipopolyplexes did not show any severe hepatic toxicity and did not enhance the production of proinflammatory cytokines. Overall, we have succeeded in preparing anionic bubble lipopolyplexes for efficient and safe transfection with US exposure in mice

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome: insights from the LUNG SAFE study

Contains fulltext : 218568.pdf (publisher's version ) (Open Access)BACKGROUND: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. METHODS: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 >/= 0.60 during hyperoxemia). RESULTS: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). CONCLUSIONS: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. TRIAL REGISTRATION: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073

Posterior reversible encephalopathy syndrome (PRES) of the brainstem

A 71-year-old man had disordered consciousness whose Glasgow Coma Scale was E4V1M5. His blood pressure was high, but there was no abnormality in the cerebrospinal fluid examination. The MRI finding reveals a high-intensity area at the pons without the blood flow interruption. Thus, he has diagnosed with brainstem PRES</jats:p

Case Report: Lifesaving Hemostasis With Resuscitative Endovascular Balloon Occlusion of the Aorta in a Patient With Cardiac Arrest Caused by Upper Gastrointestinal Hemorrhage

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is performed to treat hemorrhagic shock, whose cause is located below the diaphragm. However, its use in patients with gastrointestinal hemorrhage is relatively rare. The 45-year-old man with a history of dilated cardiomyopathy had experienced epigastric discomfort and had an episode of presyncope. On his presentation, the patient's blood pressure was 82/64 mmHg, heart rate 140/min, and consciousness level GCS E4V5M6. Hemodynamics stabilized rapidly with a transfusion that was administered on an emergency basis, and a blood sample only showed mild anemia (Hb, 11.5 g/dL). The patient was admitted to investigating the presyncope episode, and the planned endoscopy was scheduled the following day. The patient had an episode of presyncope soon and was found in hemorrhagic shock resulting from a duodenal ulcer rapidly deteriorated to cardiac arrest. Although a spontaneous heartbeat was restored with cardiopulmonary resuscitation, the patient's hemodynamics were unstable despite the emergency blood transfusion administered by pumping. Consequently, a REBOA device was placed, resuscitation was continued, and hemostasis was achieved by vascular embolization for the gastroduodenal artery. The patient was subsequently discharged without complications. However, there is no established evidence regarding the REBOA use in upper gastrointestinal hemorrhage, and the investigations that have been reported have been limited. Further, one recent research suggests that appropriate patient selection and early use may improve survival in these life-threatening cases. As was seen in the present case, REBOA can effectively treat upper gastrointestinal hemorrhage by temporarily stabilizing hemodynamics and enabling a hemostatic procedure to be quickly performed during that time. This report also demonstrated the hemodynamics during the combination of intermittent and partial REBOA to avoid the complications of ischemic or reperfusion injury of the intestines or lower extremities.</jats:p