Rapid alterations of gravitational stress during high-performance aircraft push-pull manoeuvres induce dramatic shifts in volume and pressure within the circulation system, which may result in loss of consciousness due to the rapid and significant reduction in cerebral perfusion. There are still no specific and effective countermeasures so far. r We found that lower body negative pressure (LBNP), applied prior to and during −Gz and released at the subsequent transition to +Gz, could effectively counteract gravitational haemodynamic stress induced by a simulated push-pull manoeuvre and improve cerebral diastolic perfusion in human subjects. r We developed a LBNP strategy that effectively protects cerebral perfusion at rapid −Gz to +Gz transitions via improving cerebral blood flow and blood pressure during push-pull manoeuvres and highlight the importance of the timing of the intervention. r Our findings provide a systemic link of integrated responses between the peripheral and cerebral haemodynamic changes during push-pull manoeuvres.

Background This study was designed to evaluate the clinical and radiographic outcomes of patients with nutcracker syndrome (NCS) who were treated with three-dimensional printing (3DP) extravascular titanium stents (EVTSs). The 3DP EVTS was expected to release the hypertension of the left renal vein (LRV) produced by its compression between the superior mesenteric artery (SMA) and the aorta without causing any complications. Method The pre-operative kidney model of each patient was printed out to enable surgical planning. After that, the EVTS was designed based on the LRV's primitive physiologic structure using computer-aided design software, and each stent was printed out with a precision setting of 20 μm. Seventeen patients who had been suffering from NCS underwent laparoscopic 3DP EVTS placement. The surgical procedure was designed for the placement of EVTS, taking great care in positioning and fixing the stent. Surgical data, which included patient demographic characteristics as well as pre- and post-operative test results, were collected and analyzed. Results The mean duration of surgery was 75 ± 9 min, and the mean blood loss was 20 ± 5 mL. Computed tomography examinations revealed that the pre- and post-operative angle between the SMA and the aorta ranged from 18.7° ± 4.3° to 48.0° ± 8.8° ( P < 0.05); in patients with left varicocele, the mean diameter of the left spermatic vein ranged from 3.7 ± 0.5 to 1.3 ± 0.2 mm ( P < 0.05). Moreover, Doppler ultrasound examinations showed that the peak velocity of blood flow at the hilar area ranged from 12.4 ± 3.3 to 18.5 ± 3.4 cm/s ( P < 0.05). No side effects were observed in the 24 to 42 months following surgery. Conclusion The findings after 2 years of follow-up suggest that the 3DP EVTS is a safe and effective minimally invasive alternative for the treatment of NCS.

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Background Efficient and topical delivery of drugs is essential for maximized efficacy and minimized toxicity. In this study, we aimed to design an exosome-based drug delivery platform endowed with the ability of escaping from phagocytosis at non-target organs and controllably releasing drugs at targeted location. Results The swtichable stealth coat CP05-TK-mPEG was synthesized and anchored onto exosomes through the interaction between peptide CP05 and exosomal surface marker CD63. Chlorin e6 (Ce6) was loaded into exosomes by direct incubation. Controllable removal of PEG could be achieved by breaking thioketal (TK) through reactive oxygen species (ROS), which was produced by Ce6 under ultrasound irradiation. The whole platform was called SmartExo. The stealth effects were analyzed in RAW264.7 cells and C57BL/6 mice via tracing the exosomes. To confirm the efficacy of the engineered smart exosomes, Bone morphogenetic protein 7 (Bmp7) mRNA was encapsulated into exosomes by transfection of overexpressing plasmid, followed by stealth coating, with the exosomes designated as SmartExo@Bmp7. Therapeutic advantages of SmartExo@Bmp7 were proved by targeted delivering Bmp7 mRNA to omental adipose tissue (OAT) of obese C57BL/6 mice for browning induction. SmartExo platform was successfully constructed without changing the basic characteristics of exosomes. The engineered exosomes effectively escaped from the phagocytosis by RAW264.7 and non-target organs. In addition, the SmartExo could be uptaken locally on-demand by ultrasound mediated removal of the stealth coat. Compared with control exosomes, SmartExo@Bmp7 effectively delivered Bmp7 mRNA into OAT upon ultrasound irradiation, and induced OAT browning, as evidenced by the histology of OAT and increased expression of uncoupling protein 1 (Ucp1). Conclusions The proposed SmartExo-based delivery platform, which minimizes side effects and maximizing drug efficacy, offers a novel safe and efficient approach for targeted drug delivery. As a proof, the SmartExo@Bmp7 induced local white adipose tissue browning, and it would be a promising strategy for anti-obesity therapy. Graphical Abstract

The cutaneous symptom of the paraneoplastic erythroderma can be the only symptom of a malignancy. Although many cases associated with malignancies have been reported, the pathogenesis of cancer related erythroderma is still unclear. Herein we presented a patient with large cell neuroendocrine carcinoma (LCNEC) of the lung and contemporary severe erythroderma. The patient suffered from skin erythema and scaling all over the body and the cutaneous lesions recovered completely after 3 weeks of surgery. Strong expression of neuron-specific enolase (NSE, 2+ positive) was found in both primary cancer and basal cells of the preoperative skin. Three months later, postoperative skin biopsy presented nearly normal skin tissues, accompanied with a negative expression of NSE. Nine months after surgery, cancer recurred in the liver and brain with the first symptom of skin erythema and scaling. The pathology of liver biopsy tissues illustrated the LCNEC and 3+ positive expression of NSE. The skin biopsy tissues showed 2+ positive stain of NSE. Evaluation after two cycles of chemotherapy showed marked improvement in erythroderma and reduction of tumor volume. However, the patient experienced recurrent worsening of erythroderma when chemotherapy was terminated due to severe myelosuppression. Eleven months after surgery, the patient died of cancer cachexia and multiple organ failure. To our knowledge, this was the first case of paraneoplastic erythroderma associated with LCNEC of lung. Furthermore, we firstly discovered that the deposition of NSE in basal cells might be a crucial pathogenic factor of erythroderma.