Early detection of kidney disease is of vital importance due to its current prevalence worldwide. Fluorescence imaging, especially in the second near‐infrared window (NIR‐II) has been regarded as a ...promising technique for the early diagnosis of kidney disease due to the superior resolution and sensitivity. However, the reported NIR‐II organic renal‐clearable probes are hampered by their low brightness (ϵmaxΦf>1000 nm<10 M−1 cm−1) and limited blood circulation time (t1/2<2 h), which impede the targeted imaging performance. Herein, we develop the aza‐boron‐dipyrromethene (aza‐BODIPY) brush macromolecular probes (Fudan BDIPY Probes (FBP 912)) with high brightness (ϵmaxΦf>1000 nm≈60 M−1 cm−1), which is about 10‐fold higher than that of previously reported NIR‐II renal‐clearable organic probes. FBP 912 exhibits an average diameter of ≈4 nm and high renal clearance efficiency (≈65 % excretion through the kidney within 12 h), showing superior performance for non‐invasively diagnosis of renal ischemia‐reperfusion injury (RIR) earlier than clinical serum‐based protocols. Additionally, the high molecular weight polymer brush enables FBP 912 with prolonged circulation time (t1/2≈6.1 h) and higher brightness than traditional PEGylated renal‐clearable control fluorophores (t1/2<2 h), facilitating for 4T1 tumor passive targeted imaging and renal cell carcinoma active targeted imaging with higher signal‐to‐noise ratio and extended retention time.
A series of bright NIR‐II brush macromolecular fluorophores (FBP) with high renal‐clearance efficiency and long‐blood circulation time has been developed. These achieve real‐time in vivo NIR‐II imaging of renal ischemia‐reperfusion injury, tumor passive targeted imaging and renal cell carcinoma active targeted imaging with higher signal‐to‐noise ratio and extended retention time.
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Recently, zwitterionic materials have been developed as alternatives to PEG for prolonging the circulation time of nanoparticles without triggering immune responses. However, ...zwitterionic coatings also hindered the interactions between nanoparticles and tumor cells, leading to less efficient uptake of nanoparticles by cancer cells. Such effect significantly limited the applications of zwitterionic materials for the purposes of drug delivery and the development to novel therapeutic agents. To overcome these issues, surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(β-amino ester) (PAE) heterogeneous surfaces were constructed. Owing to the synergistic effect of zwitterionic coatings and micro-phase-separated surfaces, PMPC mixed-shell micelles exhibited the improved blood circulation time compared to single-PEG-shell micelles (PEGSMs) and single-PMPC-shell micelles (PMPCSMs). Moreover, such MSMs can convert their surface to positively charged ones in response to the acidic tumor microenvironment, leading to a significant enhancement in cellular uptake of MSMs by tumor cells. This strategy demonstrated a general approach to enhance the cellular uptake of zwitterionic nanoparticles without compromising their long circulating capability, providing a practical method for improving the tumor-targeting efficiency of particulate drug delivery systems.
Herein we demonstrate a general strategy to integrate non-fouling zwitterionic surface on the nanoparticles without compromising their capability of tumor accumulation, by constructing a surface-adaptive mixed-shell micelles (MSMs) with poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)/poly(β-amino ester) (PAE) heterogeneous surfaces. At the blood pH (7.4), PAE chains collapsed to the inner of the shell due to the deprotonation, and the forming micro-phase separation structure was synergistic with zwitterionic surface to prolong the circulation time of MSMs in the blood. While at the tumor sites, PAE was protonated, and the positively charged surface of MSMs enhanced cellular uptake. This self-assembly-based strategy is compatible to other zwitterionic materials, endowing a great flexibility for the construction of responsive drug delivery systems particularly to the novel chemotherapeutic agents.
Adrenaline and vasopressin are widely used to treat people with cardiac arrest, but there is uncertainty about the safety, effectiveness and the optimal dose.
To determine whether adrenaline or ...vasopressin, or both, administered during cardiac arrest, afford any survival benefit.
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase and DARE from their inception to 8 May 2018, and the International Liaison Committee on Resuscitation 2015 Advanced Life Support Consensus on Science and Treatment Recommendations. We also searched four trial registers on 5 September 2018 and checked the reference lists of the included studies and review papers to identify potential papers for review.
Any randomised controlled trial comparing: standard-dose adrenaline versus placebo; standard-dose adrenaline versus high-dose adrenaline; and adrenaline versus vasopressin, in any setting, due to any cause of cardiac arrest, in adults and children. There were no language restrictions.
Two review authors independently identified trials for review, assessed risks of bias and extracted data, resolving disagreements through re-examination of the trial reports and by discussion. We used risk ratios (RRs) with 95% confidence intervals (CIs) to compare dichotomous outcomes for clinical events. There were no continuous outcomes reported. We examined groups of trials for heterogeneity. We report the quality of evidence for each outcome, using the GRADE approach.
We included 26 studies (21,704 participants).Moderate-quality evidence found that adrenaline increased survival to hospital discharge compared to placebo (RR 1.44, 95% CI 1.11 to 1.86; 2 studies, 8538 participants; an increase from 23 to 32 per 1000, 95% CI 25 to 42). We are uncertain about survival to hospital discharge for high-dose compared to standard-dose adrenaline (RR 1.10, 95% CI 0.75 to 1.62; participants = 6274; studies = 10); an increase from 33 to 36 per 1000, 95% CI 24 to 53); standard-dose adrenaline versus vasopressin (RR 1.25, 95% CI 0.84 to 1.85; 6 studies; 2511 participants; an increase from 72 to 90 per 1000, 95% CI 60 to 133); and standard-dose adrenaline versus vasopressin plus adrenaline (RR 0.76, 95% CI 0.47 to 1.22; 3 studies; 3242 participants; a possible decrease from 24 to 18 per 1000, 95% CI 11 to 29), due to very low-quality evidence.Moderate-quality evidence found that adrenaline compared with placebo increased survival to hospital admission (RR 2.51, 95% CI 1.67 to 3.76; 2 studies, 8489 participants; an increase from 83 to 209 per 1000, 95% CI 139 to 313). We are uncertain about survival to hospital admission when comparing standard-dose with high-dose adrenaline, due to very low-quality evidence. Vasopressin may improve survival to hospital admission when compared with standard-dose adrenaline (RR 1.27, 95% CI 1.04 to 1.54; 3 studies, 1953 participants; low-quality evidence; an increase from 260 to 330 per 1000, 95% CI 270 to 400), and may make little or no difference when compared to standard-dose adrenaline plus vasopressin (RR 0.95, 95% CI 0.83 to 1.08; 3 studies; 3249 participants; low-quality evidence; a decrease from 218 to 207 per 1000 (95% CI 181 to 236).There was no evidence that adrenaline (any dose) or vasopressin improved neurological outcomes.The rate of return of spontaneous circulation (ROSC) was higher for standard-dose adrenaline versus placebo (RR 2.86, 95% CI 2.21 to 3.71; participants = 8663; studies = 3); moderate-quality evidence; an increase from 115 to 329 per 1000, 95% CI 254 to 427). We are uncertain about the effect on ROSC for the comparison of standard-dose versus high-dose adrenaline and standard-does adrenaline compared to vasopressin, due to very low-quality evidence. Standard-dose adrenaline may make little or no difference to ROSC when compared to standard-dose adrenaline plus vasopressin (RR 0.97, 95% CI 0.87 to 1.08; 3 studies, 3249 participants; low-quality evidence; a possible decrease from 299 to 290 per 1000, 95% CI 260 to 323).The source of funding was not stated in 11 of the 26 studies. The study drugs were provided by the manufacturer in four of the 26 studies, but neither drug represents a profitable commercial option. The other 11 studies were funded by organisations such as research foundations and government funding bodies.
This review provides moderate-quality evidence that standard-dose adrenaline compared to placebo improves return of spontaneous circulation, survival to hospital admission and survival to hospital discharge, but low-quality evidence that it did not affect survival with a favourable neurological outcome. Very low -quality evidence found that high-dose adrenaline compared to standard-dose adrenaline improved return of spontaneous circulation and survival to admission. Vasopressin compared to standard dose adrenaline improved survival to admission but not return of spontaneous circulation, whilst the combination of adrenaline and vasopressin compared with adrenaline alone had no effect on these outcomes. Neither standard dose adrenaline, high-dose adrenaline,vasopressin nor a combination of adrenaline and vasopressin improved survival with a favourable neurological outcome. Many of these studies were conducted more than 20 years ago. Treatment has changed in recent years, so the findings from older studies may not reflect current practice.
Whereas medical practice stems from Hippocrates, cardiovascular science originates with Aristotle. The Hippocratic philosophy was championed by Galen (129-216 CE), whose advocacy of a tripartite soul ...found favor in the early Christian Church. In contrast, Aristotle’s works were banned as heresy by ecclesiastical authority, only to survive and prosper in the Islamic Golden Age (775-1258 CE). Galen theorized that the circulation consisted of separate venous and arterial systems. Blood was produced in the liver and traveled centrifugally through veins. When arriving in the right ventricle, venous blood passed through tiny pores in the ventricular septum into the left ventricle, where it became aerated by air passing from the lungs through the pulmonary veins to the left side of the heart. Following arrival at distal sites, arterial blood disappeared, being consumed by the tissues, requiring that the liver needed to continually synthesize new blood. The heart was viewed as a sucking organ, and the peripheral pulse was deemed to result from changes in arterial tone, rather than cardiac systole. Galen’s framework remained undisputed and dominated medical thought for 1,300 years, but the reintroduction of Aristotelian principles from the Islamic world into Europe (through the efforts of the Toledo School of Translators) were nurtured by the academic freedom and iconoclastic environment uniquely cultivated at the University of Padua, made possible by Venetian rebellion against papal authority. At Padua, the work of Andreas Vesalius, Realdo Colombo, Hieronymus Fabricius ab Acquapendente, and William Harvey (1543-1628) methodically destroyed Galen’s model, leading to the modern concept of a closed-ended circulation. Yet, due to political forces, Harvey was ridiculed, as was James Lind, who performed the first prospective controlled trial, involving citrus fruits for scurvy (1747); it took nearly 50 years for his work to be accepted. Even the work of William Withering (1785), the father of cardiovascular pharmacology, was tarnished by professional jealously and the marketing campaign of a pharmaceutical company. Today’s cardiovascular investigators should understand that major advances are routinely derided by the medical establishment for political or personal reasons; and it may take decades or centuries for important work to be accepted.
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•Medical practice stems from Hippocrates; cardiovascular science originates with Aristotle.•Galen’s theory of separate venous and arterial systems—dominant for 1,300 years—was destroyed by scholars at the University of Padua (1500-1650 CE).•Landmark works by Harvey, Lind, and Withering were derided and tarnished by political and personal reasons.•Young investigators must challenge the status quo; if they do not rebel, nothing will change.
In water, amphiphilic block copolymers (BCPs) can self-assemble into various micelle structures depicting curved liquid/liquid interface. Crystallization, which is incommensurate with this curved ...space, often leads to defect accumulation and renders the structures leaky, undermining their potential biomedical applications. Herein we report using an emulsion-solution crystallization method to control the crystallization of an amphiphilic BCP, poly (L-lactide acid)-b-poly (ethylene glycol) (PLLA-b-PEG), at curved liquid/liquid interface. The resultant BCP crystalsomes (BCCs) structurally mimic the classical polymersomes and liposomes yet mechanically are more robust thanks to the single crystal-like crystalline PLLA shell. In blood circulation and biodistribution experiments, fluorophore-loaded BCCs show a 24 h circulation half-life and a 8% particle retention in the blood even at 96 h post injection. We further demonstrate that this good performance can be attributed to controlled polymer crystallization and the unique BCC nanostructure.
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