Recognition and management of idiopathic systemic capillary leak syndrome: an evidence-based review

Introduction: Idiopathic systemic capillary leak syndrome (SCLS) is a unique disorder characterized by episodes of massive systemic leak of intravascular fluid leading to volume depletion and shock. A typical attack of SCLS consists of prodromal, leak and post-leak phases. Complications, such as compartment syndrome and pulmonary edema, usually develop during the leak and post-leak phases respectively. Judicious intravenous hydration and early use of vasopressors is the cornerstone of management in such cases.

Areas covered: The purpose of the present review is to provide an up-to-date, evidence-based review of our understanding of SCLS and its management in the light of currently available evidence.

Commentary: Idiopathic SCLS was first described in 1960 and, since then, more than 250 cases have been reported. A large number of cases have been reported over the past one decade, most likely due to improved recognition. In the acute care setting, most patients with SCLS are managed as per the Surviving Sepsis guidelines and receive aggressive volume resuscitation – which is not the optimal management strategy for such patients. There is a need to raise awareness amongst physicians and clinicians in order to improve recognition of this disorder and ensure its appropriate management.     

Cell Labeling with Magneto-Endosymbionts and the Dissection of the Subcellular Location,Fate, and Host Cell Interactions

Purpose

The purposes of this study are to characterize magneto-endosymbiont (ME) labeling of mammalian cells and to discern the subcellular fate of these living contrast agents. MEs are novel magnetic resonance imaging (MRI) contrast agents that are being used for cell tracking studies. Understanding the fate of MEs in host cells is valuable for designing in vivo cell tracking experiments.

Procedures

The ME’s surface epitopes, contrast-producing paramagnetic magnetosomal iron, and genome were studied using immunocytochemistry (ICC), Fe and MRI contrast measurements, and quantitative polymerase chain reaction (qPCR), respectively. These assays, coupled with other common assays, enabled validation of ME cell labeling and dissection of ME subcellular processing.

Results

The assays mentioned above provide qualitative and quantitative assessments of cell labeling, the subcellular localization and the fate of MEs. ICC results, with an ME-specific antibody, qualitatively shows homogenous labeling with MEs. The ferrozine assay shows that MEs have an average of 7 fg Fe/ME, ～30 % of which contributes to MRI contrast and ME-labeled MDA-MB-231 (MDA-231) cells generally have 2.4 pg Fe/cell, implying ～350 MEs/cell. Adjusting the concentration of Fe in the ME growth media reduces the concentration of non-MRI contrast-producing Fe. Results from the qPCR assay, which quantifies ME genomes in labeled cells, shows that processing of MEs begins within 24 h in MDA-231 cells. ICC results suggest this intracellular digestion of MEs occurs by the lysosomal degradation pathway. MEs coated with listeriolysin O (LLO) are able to escape the primary phagosome, but subsequently co-localize with LC3, an autophagy-associated molecule, and are processed for digestion. In embryos, where autophagy is transiently suppressed, MEs show an increased capacity for survival and even replication. Finally, transmission electron microscopy (TEM) of ME-labeled MDA-231 cells confirms that the magnetosomes (the MRI contrast-producing particles) remain intact and enable in vivo cell tracking.

Conclusions

MEs are used to label mammalian cells for the purpose of cell tracking in vivo, with MRI. Various assays described herein (ICC, ferrozine, and qPCR) allow qualitative and quantitative assessments of labeling efficiency and provide a detailed understanding of subcellular processing of MEs. In some cell types, MEs are digested, but the MRI-producing particles remain. Coating with LLO allows MEs to escape the primary phagosome, enhances retention slightly, and confirms that MEs are ultimately processed by autophagy. Numerous intracellular bacteria and all endosymbiotically derived organelles have evolved molecular mechanisms to avoid intracellular clearance, and identification of the specific processes involved in ME clearance provides a framework on which to develop MEs with enhanced retention in mammalian cells.

     

Salbutamol in acute organophosphorus insecticide poisoning – a pilotdose-response phase II study

Background: Treatment of acute organophosphorus (OP) insecticide poisoning is difficult, with many patients dying despite best care. Pre-clinical studies have shown benefit from salbutamol, possibly due speeding alveolar fluid clearance or reducing bronchoconstriction. In this small pilot dose-response study, we aimed to explore whether addition of nebulized salbutamol to standard care might improve resuscitation.

Methods: We performed a single-blind phase II study comparing the effect of two different doses of nebulized salbutamol versus saline placebo, in addition to standard treatment. Primary outcome was oxygen saturations over the first 60?min of resuscitation; secondary outcomes included heart rate, incidence of dysrhythmias, time to ‘atropinization’, atropine dose required, and mortality.

Result: Seventy-five patients were randomized to receive 5?mg (Salb5, n?=?25) or 2.5mg (Salb2.5, n?=?25) of salbutamol, or saline placebo (NoSalb, n?=?25), by nebulizer. Oxygen saturations did not differ between groups over the first 60?min of resuscitation (median AUC NoSalb: 1376 [95% CI 1282 to 1470], Salb2.5: 1395 [1305 to 1486], Salb5: 1233 [1100 to 1367]; p?=?.9898). Heart rate was also similar across the three arms. Median time to full atropinization, and atropine dose required, were the same for all three arms (NoSalb 15.0 [10–16] min and 12.6 [8.0–13.4] mg, Salb2.5 15.0 [10–16] min and 12.6 [9.3–16.8] mg, and Salb5 15.0 [10–20] min and 12.6 [10.7–20.6] mg; p?=?.4805 and p?=?.1871, respectively). Three (12%) patients died in the Salb2.5 and Salb5 groups and two (8%) in the NoSalb group.

Conclusion: This pilot study, within the limitations of its small size and variation between patients, found no apparent evidence that administration of nebulized salbutamol improved resuscitation of patients with acute OP insecticide self-poisoning. The data obtained provides a basis to design further studies to ultimately test the role of salbutamol in OP insecticide poisoning.     

Shot by a Gun … Missed by a Provider

Background

Botulism is a paralytic disease caused by the neurotoxin produced by Clostridium botulinum. The majority of cases are due to ingestion or injection drug use. Wound botulism from traumatic injury is exceedingly rare, with only one to two cases reported each year in the United States.

Effect of VIPS fabrication parameters on the removal of acetic acid by supported liquid membrane using a PES–graphene membrane support

In this study, the removal of acetic acid by supported liquid membrane (SLM) using hybrid polyethersulfone (PES)–graphene membrane prepared by vapor induced phase separation (VIPS) was investigated. The effects of graphene loading, coagulation bath temperature, air exposure time, and air humidity on the morphology, mechanical strength, porosity, and contact angle of the membrane were analyzed. The performance and stability of the hybrid membrane as a SLM support for acetic acid removal were studied. The best PES–graphene membrane support was produced at a coagulation bath temperature of 50 °C, an air exposure time of 30 s and air humidity of 80%. The fabricated membrane has a symmetrical micropore cellular structure, high porosity and high contact angle. Under specific SLM conditions, almost 95% of acetic acid was successfully removed from 10 g L⁻¹ aqueous acetic acid solution. The hybrid membrane remains stable for more than 116 h without suffering any membrane breakage during the continuous SLM process.

In this study, the removal of acetic acid by supported liquid membrane (SLM) using hybrid polyethersulfone (PES)–graphene membrane prepared by vapor induced phase separation (VIPS) was investigated.     

Exposure–effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis

Aims

The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis.

Methods

Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C₀), maximum concentration (C_max) and area under the concentration–time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events.

Results

Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l^–1 h, P= 0.048) and C_max (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l^–1, P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l^–1 h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l^–1 h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l^–1 h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023).

Conclusions

This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis.