Modulation of Tmem135 Leads to Retinal Pigmented Epithelium Pathologies in Mice.

Purpose: Aging is a critical risk factor for the development of retinal diseases, but how aging perturbs ocular homeostasis and contributes to disease is unknown. We identified transmembrane protein 135 (Tmem135) as a gene important for regulating retinal aging and mitochondrial dynamics in mice. Overexpression of Tmem135 causes mitochondrial fragmentation and pathologies in the hearts of mice. In this study, we examine the eyes of mice overexpressing wild-type Tmem135 (Tmem135 TG) and compare their phenotype to Tmem135 mutant mice. Methods: Eyes were collected for histology, immunohistochemistry, electron microscopy, quantitative PCR, and Western blot analysis. Before tissue collection, electroretinography (ERG) was performed to assess visual function. Mouse retinal pigmented epithelium (RPE) cultures were established to visualize mitochondria. Results: Pathologies were observed only in the RPE of Tmem135 TG mice, including degeneration, migratory cells, vacuolization, dysmorphogenesis, cell enlargement, and basal laminar deposit formation despite similar augmented levels of Tmem135 in the eyecup (RPE/choroid/sclera) and neural retina. We observed reduced mitochondria number and size in the Tmem135 TG RPE. ERG amplitudes were decreased in 365-day-old mice overexpressing Tmem135 that correlated with reduced expression of RPE cell markers. In Tmem135 mutant mice, RPE cells are thicker, smaller, and denser than their littermate controls without any signs of degeneration. Conclusions: Overexpression and mutation of Tmem135 cause contrasting RPE abnormalities in mice that correlate with changes in mitochondrial shape and size (overfragmented in TG vs. overfused in mutant). We conclude proper regulation of mitochondrial homeostasis by TMEM135 is critical for RPE health.

Capnography standards for outside the operating room.

PURPOSE OF REVIEW: Standards for capnography inside operating theatres in high and middle-income countries are well recognized and implemented. This review examines recent standards and recommendations for the use of capnography outside the operating room and their rationale and development. RECENT FINDINGS: The landmark publication of the Royal College of Anaesthetists and Difficult Airway Society's National Audit Project 4 report provided compelling evidence of airway deaths and a significant patient harm occurring outside the operating room, particularly in ICUs and to a lesser extent in emergency departments. Up to 74% of these ICU deaths could have been prevented by capnography. This provided a serious wake up call for relevant clinicians. As a result, there have recently been new standards published for the use of capnography in these and other areas of the hospital. Waveform capnography can also reflect cardiac output, as the 2015 resuscitation guidelines emphasized. Work still needs to be done on implementing all of these new standards. SUMMARY: Established standards for using capnography within the operating theatre have significantly improved patient safety and it is hoped that the recent publication of new but similar capnography standards for application outside the operating theatre will do the same there. The reasons for the current low levels of implementation of some of these standards outside the operating room are worthy of further research.

Protease-triggered siRNA delivery vehicles.

The safe and efficacious delivery of membrane impermeable therapeutics requires cytoplasmic access without the toxicity of nonspecific cytoplasmic membrane lysis. We have developed a mechanism for control of cytoplasmic release which utilizes endogenous proteases as a trigger and results in functional delivery of small interfering RNA (siRNA). The delivery approach is based on reversible inhibition of membrane disruptive polymers with protease-sensitive substrates. Proteolytic hydrolysis upon endocytosis restores the membrane destabilizing activity of the polymers thereby allowing cytoplasmic access of the co-delivered siRNA. Protease-sensitive polymer masking reagents derived from polyethylene glycol (PEG), which inhibit membrane interactions, and N-acetylgalactosamine, which targets asialoglycoprotein receptors on hepatocytes, were synthesized and used to formulate masked polymer-siRNA delivery vehicles. The size, charge and stability of the vehicles enable functional delivery of siRNA after subcutaneous administration and, with modification of the targeting ligand, have the potential for extrahepatic targeting.

Clinical relevance of intra-abdominal hypertension in patients with severe acute pancreatitis.

OBJECTIVES: Intra-abdominal hypertension (IAH) contributes to organ failure in patients with abdominal trauma and sepsis and leads to the development of abdominal compartment syndrome (ACS). This study aims to investigate the clinical significance of IAH in patients with severe acute pancreatitis (SAP). METHODS: Patients admitted to intensive care with SAP underwent daily measurement of intra-abdominal pressure (IAP), recording of the clinical data, and calculation of 4 organ dysfunction scores. RESULTS: Among 18 patients with SAP, 11 (61%) developed IAH (median, 20 mm Hg), whereas 10 (56%) developed ACS. The IAP correlated significantly with the 4 organ dysfunction scores; the scores were significantly higher when IAH existed than when it did not. The admission IAP correlated significantly with the duration of intensive care stay. Patients who developed IAH/ACS had significantly higher organ failure score and greater mortality compared with those who did not. Laparotomy and drainage reduced the IAP by a median of -11 mm Hg and relieved the IAH/ACS in all patients. CONCLUSIONS: Intra-abdominal hypertension and ACS are frequent findings in patients with SAP and are associated with deterioration in organ function. Intra-abdominal pressure correlates with the severity of organ failure, and a high admission IAP is associated with prolonged intensive care stay.