Single-dose of integrated bilayer microneedles for enhanced hypertrophic scar therapy with rapid anti-inflammatory and sustained inhibition of myofibroblasts.

Hypertrophic scar (HS) tends to raised above skin level with high inflammatory microenvironment and excessive proliferation of myofibroblasts. The HS therapy remains challenging due to dense scar tissue which makes it hard to penetrate, and the side effects resulting from intralesional corticosteroid injection which is the mainstay treatment in clinic. Herein, bilayer microneedle patches combined with dexamethasone and colchicine (DC-MNs) with differential dual-release pattern is designed. Two drugs loaded in commercially available materials HA and PLGA, respectively. Specifically, after administration, outer layer rapidly releases the anti-inflammatory drug dexamethasone, which inhibits macrophage polarization to pro-inflammatory phenotype in scar tissue. Subsequently, inner layer degrades sustainedly, releasing antimicrotubular agent colchicine, which suppresses the overproliferation of myofibroblasts with extremely narrow therapeutic window, and inhibits the overexpression of collagen, as well as promotes the regular arrangement of collagen. Only applied once, DC-MNs directly delivered drugs to the scar tissue. Compared to traditional treatment regimen, DC-MNs significantly suppressed HS at lower dosage and frequency by differential dual-release design. Therefore, this study put forward the idea of integrated DC-MNs accompany the development of HS, providing a non-invasive, self-applicable, more efficient and secure strategy for treatment of HS.

Platinum Nanozyme-Loaded Dissolving Microneedles Scavenge ROS and Promote Lineage Progression for Androgenetic Alopecia Treatment.

Androgenetic alopecia (AGA) is a prevalent issue affecting the physical and mental health of individuals but with fewer current treatments. Platinum nanozymes (PtNZs) are known for their excellent ability to reduce and modulate the high oxidative stress environment in AGA pathology. And microneedles are used to overcome the skin barrier due to the poor permeability of PtNZs. Herein, dissolving microneedles loaded with PtNZs (Pt-MNs) are designed and successfully induced hair regeneration in the AGA model. Pt-MNs possessed adequate mechanical strength to breach the skin barrier for effective PtNZs delivery. In vivo, PtNZs first reduced reactive oxygen species (ROS) to oxygen, which recovered the AGA pathological environment. And the oxygen then increased oxidative phosphorylation, promoting the differentiation of hair follicle stem cells to achieve hair regeneration. The group treated with Pt-MNs with a dosing frequency of once every three days achieved faster hair growth than the daily application of the positive drug minoxidil. Further safety experiments showed that the application of Pt-MNs locally opened temporary and recoverable skin channels, with no retention of Pt in major organs, indicating high safety. In conclusion, this study indicated the potential of Pt-MNs as an effective method for treating AGA.

Hair follicle-targeted delivery for hair recoloration using scalp-curvature-conforming microneedles based on sodium alginate and polyvinylpyrrolidone.

Hair-related disorders are currently widely concerned issues for not only the scientific society but also the public attentions. Microneedle-based drug delivery system has been regarded as a promise hair follicle-targeted drug delivery approach, largely because they can effectively penetrate the stratum corneum barrier and deliver drugs to hair follicles within dermis. However, the currently reported microneedles for treating hair-related disorders usually rely on rigid backings, showing poor adaptability to the curved scalp and thereby restricting their usability for hair follicles targeted drug delivery. To this end, this study utilized sodium alginate and polyvinylpyrrolidone to construct a scalp-curvature-conforming microneedle with flexible backing. Subsequently, Psoralea corylifolia extract (PE) was loaded into the microneedles to investigate its capability in delivering PE to the hair follicle site for treating leukotrichia associated with vitiligo. These PE-loaded microneedles can effectively conform to the curvature of skin, enhancing the efficiency of microneedle insertion and ensuring stable drug delivery. Moreover, animal studies demonstrate that the PE loaded microneedles can effectively penetrate the stratum corneum, benefiting the drug delivery to hair follicles located site, and consequently showing a successful inhibition of hair graying. In summary, the present study reports a design and preparation of scalp-curvature-conforming microneedle. This design may offer a potential solution for efficient drug delivery using microneedles to the curved skin.

Corrigendum: Hyperglycemia decreases epithelial cell proliferation and attenuates neutrophil activity by reducing ICAM-1 and LFA-1 expression levels.

[This corrects the article DOI: 10.3389/fgene.2020.616988.].

The left adrenal vein: An important direction for right adrenal venous sampling.

This study aimed to evaluate the guiding role of left adrenal vein (LAV) for right adrenal venous sampling (AVS). A total of 347 patients who were diagnosed with primary aldosteronism (PA) and underwent successful AVS procedures from January 2020 to July 2021 were retrospectively analyzed. According to the different quadrant position of the orifice of right adrenal vein (RAV), the area where the orifice of RAV is located is divided into three areas: A, B, and C and the area A is further subdivided into A1, A2, and A3 areas. By counting the area where the orifice of RAV is located, the guiding role of the LAV on the RAV is determined. Most of the orifice of RAV are located in area A, and the proportions of areas A, B, and C was 96.8%, 1.4%, and 1.7%, respectively. In area A, areas A1, A2, and A3 account for 80.9%, 17.0%, and 2.1%, respectively. High body mass index, female and smaller the angle between the LAV and horizontal line was associated with the closer positional relationship between the LAV on the RAV. These findings suggest that most of the horizontal position of the RAV orifice is close to the horizontal position of the most distal end of the LAV, which indicate that the LAV location can play an important role on the guiding for right AVS. Additionally, body mass index, sex, and the angle of the LAV was largely related to location of the orifice of the RAV.

PROTAC Degraders of Androgen Receptor-Integrated Dissolving Microneedles for Androgenetic Alopecia and Recrudescence Treatment via Single Topical Administration.

Androgenetic alopecia (AGA) is a transracial and cross-gender disease worldwide with a youth-oriented tendency, but it lacks effective treatment. The binding of androgen receptor (AR) and androgen plays an essential role in the occurrence and progression of AGA. Herein, novel proteolysis targeting chimera degrader of AR (AR-PROTAC) is synthesized and integrated with dissolving microneedles (PROTAC-MNs) to achieve AR destruction in hair follicles for AGA treatment. The PROTAC-MNs possess adequate mechanical capabilities for precise AR-PROTAC delivery into the hair follicle-residing regions for AR degradation. After applying only once topically, the PROTAC-MNs achieve an accelerated onset of hair regeneration as compared to the daily application of the first-line topical drug minoxidil. Intriguingly, PROTAC-MNs via single administration still realize superior hair regeneration in AGA recrudescence, which is the major drawback of minoxidil in clinical practice. With the degradation of AR, the PROTAC-MNs successfully regulate the signaling cascade related to hair growth and activate hair follicle stem cells. Furthermore, the PROTAC-MNs do not cause systemic toxicity or androgen deficiency-related chaos in vivo. Collectively, these AR-degrading dissolving microneedles with long-lasting efficacy, one-step administration, and high biocompatibility provide a great therapeutic potential for AGA treatment.

Investigation of the Correlation between Cuff Inflatable Hypertension and the Difference in Interarm Diastolic Pressure Induced by Single Arm Ischemia.

The correlation between cuff inflatable hypertension and the difference in interarm diastolic pressure induced by single arm ischemia is investigated. A total of 126 patients undergoing coronary angiography in our hospital from January 2020 to January 2021 are selected and divided into the non-pseudohypertension (non-PHT) group (64 cases) and the PHT group (62 cases) according to the difference between systolic blood pressure and diastolic blood pressure measured directly and indirectly. The patients are subjected to the beam arm ischemia test and blood pressure measurement. The diastolic pressure differences between the patients before and after the beam arm are analyzed, and endothelial function and imaging indicators are compared. The risk factors for PHT are analyzed by binary logistic regression, and the diagnostic efficacy of diastolic blood pressure difference interarms (DBPI-r) for PHT patients is analyzed by receiver operating characteristic (ROC) curve. The experimental results show that the diastolic pressure difference induced by single arm ischemia can be used in the diagnosis of cuff inflatable hypertension.

Pain management with transdermal drug administration: A review.

Pain management is an urgent issue to solve with complex mechanisms. Localized acute pain requires rapid and accurate delivery of drugs with less distribution in the blood circulation while chronic pain requires controlled release of drugs with long drug retention time. The transdermal route, a promising way with high patient compliance was known for painless delivery, long drug retention time, stable blood concentration, easily controlled dosage and release rate as well as the fewer side effects. This review presents transdermal route for pain management according to the different sites of action which drugs aim to reach, and illustrates different analgesic mechanisms, dosage forms, transdermal enhancements and clinical applications. In addition, the review concludes the difference of pain types and presents the future aims of pain management, thereby providing a reference for researches focusing on percutaneous analgesia.

Cellular Uptake and Transport Characteristics of FL118 Derivatives in Caco-2 Cell Monolayers.

In the evaluation of the druggability of candidate compounds, it was vital to predict the oral bioavailability of compounds from apparent permeability (Papp) across Caco-2 cell-culture model of intestinal epithelium cultured on commercial transwell plate inserts. The study was to investigate the transport characteristics and permeability of FL118 (10, 11-Methylenedioxy-20(S)-camptothecin) derivatives 7-Q6 (7-(4-Ethylphenyl)-10, 11-methylenedioxy-20(S)-camptothecin) and 7-Q20 (7-(4-Trifluoromethylphenyl)-10, 11-methylenedioxy-20(S)-camptothecin). Transport characteristics and permeability of the tested compounds to the small intestine were assessed at different concentrations (0.5, 1 µM) via Caco-2 cell monolayers model in vitro. Uptake studies based on Caco-2 cells, including temperatures, concentrations, and the influence of efflux transporters, were combined to confirm the transport characteristics of the tested compounds. Furthermore, cytotoxicity results showed that the concentrations used in the experiments were non-toxic and harmless to cells. In addition, The Papp of 7-Q6 was (3.69 ± 1.07) × 10-6 cm/s with efflux ratio (ER) 0.98, while the Papp of 7-Q20 was (7.78 ± 0.89) × 10-6 cm/s with ER 1.05 for apical-to-basolateral (AP→BL) at 0.5 µM, suggesting that 7-Q20 might possess higher oral bioavailability in vivo. Furthermore, P-glycoprotein (P-gp) was proved to slightly affect the accumulations of 7-Q20, while the absorption of 7-Q6 was irrelevant with P-gp and breast cancer resistant protein (BCRP) based on the cellular uptake assays. Accordingly, 7-Q6 was completely absorbed by passive diffusion, and 7-Q20 was mainly dependent on passive diffusion with being effluxed by P-gp slightly. Meanwhile, both 7-Q6 and 7-Q20 were potential antitumor drugs that might exhibit high oral bioavailability in the body.

Differences in oscillometric blood pressure readings between unsupported and supported back conditions.

Appropriate body posture is important for accurate blood pressure (BP) measurement. However, the impact of an unsupported back on BP readings is currently controversial. This study included 224 subjects (18-86 years old, 54.5 ± 15.5 years old, 105 males). BP was measured with an oscillometric BP device randomly following one of two protocols for back support conditions: (1) supported-unsupported-supported-unsupported, or (2) unsupported-supported-unsupported-supported. The average of the two systolic BP (SBP) and diastolic BP (DBP) readings in the same position was recorded as the final BP value. The differences in BP between the unsupported and supported back conditions were calculated as delta BP. Moreover, the percentage variation in BP (PV) was calculated with the formula delta BP/BP with an unsupported back. Multivariable regression analysis evaluated the impact of age, sex, hypertension history and supported BP level on PV. The SBP/DBP levels measured with an unsupported back were slightly higher than those when the back was supported (132.7 ± 19.5/79.6 ± 12.9 mmHg vs. 130.3 ± 20.0/78.5 ± 14.3 mmHg), and the delta SBP (2.3 mmHg) was statistically significant. The multivariable regression analysis showed that age was a positive factor but supported SBP level as a negative factor for systolic PV, while age and supported DBP level were positive factors, but hypertension history was a negative factor for diastolic PV. For a group participant, the mean difference in oscillometric SBP/DBP in the unsupported back position was 2.3/1.0 mmHg higher than that in the supported back position.

Is the blood pressure of right arm measured with synchronous four-limb method is equal to that with single arm method?

OBJECTIVE: Synchronous four-limb blood pressure (BP) measurement (four-limb method) is widely used for diagnosing peripheral artery diseases in clinical practise, but it is unclear whether the BP of right arm measured with this method is similar to that measured with single arm method. METHODS: This study included 198 in-patients (aged 18-89, mean age 60.1± 13.9 years old, 109 males). They were divided into four groups on the therapy as renin-angiotensin system inhibitor (46 patients), calcium channel blocker (43 patients), beta receptor blocker (27 patients), and combination (Com, 82 patients) groups. The patients were randomly instructed to follow one of two BP measurement proposals designed to avoid the bias induced by BP measurement order. The result with single arm method was recorded as RA-1 and that with four-limb method as RA-4. The difference between RA-4 and RA-1 was calculated as Dif-RA. The percentage increase (PI) was also calculated on the formula: (RA-4 - RA-1)/RA-1. RESULTS: The mean Dif-RA on SBP and DBP were 1.9/1.5 mmHg. Although the levels of SBP, DBP and pulse pressure of RA-1 were different, the PI of these parameters were comparable among four treatment groups. Multivariate regression analyses showed that age and SBP of RA-1 were positive independent factors for Dif-RA on SBP. CONCLUSION: The SBP and DBP of right arm measured with synchronous four-limb method are 1.9/1.5 mmHg higher against the single arm method in treated hypertensives, and the increase extent of BP is not associated with the used drugs.

Hyperglycemia Decreases Epithelial Cell Proliferation and Attenuates Neutrophil Activity by Reducing ICAM-1 and LFA-1 Expression Levels.

Delayed repair is a serious public health concern for diabetic populations. Intercellular adhesion molecule 1 (ICAM-1) and Lymphocyte function-associated antigen 1 (LFA-1) play important roles in orchestrating the repair process. However, little is known about their effects on endothelial cell (EC) proliferation and neutrophil activity in subjects with hyperglycemia (HG). We cultured ECs and performed a scratch-closure assay to determine the relationship between ICAM-1 and EC proliferation. Specific internally labeled bacteria were used to clarify the effects of ICAM-1 and LFA-1 on neutrophil phagocytosis. Transwell assay and fluorescence-activated cell sorting analysis evaluated the roles of ICAM-1 and LFA-1 in neutrophil recruitment. ICAM-1+/+ and ICAM-1-/- mice were used to confirm the findings in vivo. The results demonstrated that HG decreased the expression of ICAM-1, which lead to the low proliferation of ECs. HG also attenuated neutrophil recruitment and phagocytosis by reducing the expression of ICAM-1 and LFA-1, which were strongly associated with the delayed repair.

Preparation and Characterization of Antioxidative and UV-Protective Larch Bark Tannin/PVA Composite Membranes.

In order to prepare functional materials for antioxidant and ultraviolet (UV)-protective green food packaging, condensed tannin, previously extracted from larch bark, was mixed with polyvinyl alcohol (PVA), and then the mixture was used to cast composite membranes. An antioxidative assay using 1,1-diphenyl-2-picrylhydrazyl (DPPH)-a free radical scavenger-and starch⁻potassium iodide oxidation⁻discoloration analyses showed that the composite membranes have good antioxidative activities. The low UV transmission and protective effect of the composite films on vitamin E indicated the UV protection ability of the composite membranes. Both larch bark tannin and PVA are rich in hydroxyl groups; scanning electron microscopy analysis demonstrated their compatibility. Also, the mechanical and crystallization properties of the composite membranes did not significantly decrease with the addition of larch bark tannin.

Distinguishing Computer-Generated Graphics from Natural Images Based on Sensor Pattern Noise and Deep Learning.

Computer-generated graphics (CGs) are images generated by computer software. The rapid development of computer graphics technologies has made it easier to generate photorealistic computer graphics, and these graphics are quite difficult to distinguish from natural images (NIs) with the naked eye. In this paper, we propose a method based on sensor pattern noise (SPN) and deep learning to distinguish CGs from NIs. Before being fed into our convolutional neural network (CNN)-based model, these images—CGs and NIs—are clipped into image patches. Furthermore, three high-pass filters (HPFs) are used to remove low-frequency signals, which represent the image content. These filters are also used to reveal the residual signal as well as SPN introduced by the digital camera device. Different from the traditional methods of distinguishing CGs from NIs, the proposed method utilizes a five-layer CNN to classify the input image patches. Based on the classification results of the image patches, we deploy a majority vote scheme to obtain the classification results for the full-size images. The experiments have demonstrated that (1) the proposed method with three HPFs can achieve better results than that with only one HPF or no HPF and that (2) the proposed method with three HPFs achieves 100% accuracy, although the NIs undergo a JPEG compression with a quality factor of 75.

A Cyber-Physical System for Girder Hoisting Monitoring Based on Smartphones.

Offshore design and construction is much more difficult than land-based design and construction, particularly due to hoisting operations. Real-time monitoring of the orientation and movement of a hoisted structure is thus required for operators' safety. In recent years, rapid development of the smart-phone commercial market has offered the possibility that everyone can carry a mini personal computer that is integrated with sensors, an operating system and communication system that can act as an effective aid for cyber-physical systems (CPS) research. In this paper, a CPS for hoisting monitoring using smartphones was proposed, including a phone collector, a controller and a server. This system uses smartphones equipped with internal sensors to obtain girder movement information, which will be uploaded to a server, then returned to controller users. An alarming system will be provided on the controller phone once the returned data exceeds a threshold. The proposed monitoring system is used to monitor the movement and orientation of a girder during hoisting on a cross-sea bridge in real time. The results show the convenience and feasibility of the proposed system.

Impact of glucose load in an oral glucose tolerance test on urinary albumin excretion varies with 2-h glucose levels.

BACKGROUND: The aim of the present study was to investigate whether an oral glucose load can induce an increase in urinary albumin excretion (UAE). METHODS: One hundred and thirty subjects without macroalbuminuria or increased fasting serum glucose (≥7.0 mmol/L) were included in the study. At 0600 hours, subjects were asked to empty their bladder and drink 300 mL water. At 0800 hours, venous blood and 2-h urine were collected for fasting examination. Subjects were then asked to drink 300 mL solution containing 75 g glucose and, at 1000 hours, samples were collected again for post-challenge examination. Concentrations of serum glucose, urinary glucose, albumin, N-acetyl-ß-D-glucosaminidase and retinol-binding protein were measured. RESULTS: Based on the results of the oral glucose tolerance test, subjects were divided into three groups: (i) normal glucose tolerance (NGT; n = 55); (ii) impaired glucose tolerance (IGT; n = 39); and (iii) newly diagnosed diabetes mellitus (NDM; n = 36). In the NDM group, post-challenge urinary excretion of glucose and albumin was 14- and 1.6-fold greater than fasting values, respectively. In the IGT and NGT groups, although post-challenge urinary glucose excretion was 2.6- and 1.6-fold greater than fasting values, UAE did not increase. There was a positive correlation between post-challenge serum glucose and the UAE rate (UAER; r = 0.24, P < 0.01) and the UAER increment (ΔUAER; r = 0.19, P < 0.05), as well as between the serum glucose increment and post-challenge UAER (r = 0.23, P < 0.01) and ΔUAER (r = 0.18, P < 0.05). Post-challenge serum glucose levels were independently correlated with logarithmically converted post-challenge UAER (ß = 0.322, P = 0.008). CONCLUSIONS: Oral glucose load can induce a significant increase in UAE in NDM subjects. The main mechanism may be glomerular hyperfiltration.

Bioleached sludge composting drastically reducing ammonia volatilization as well as decreasing bulking agent dosage and improving compost quality: A case study.

Sludge bioleaching technology with Acidithiobacillus species has been commercially adopted for improving advanced dewatering of sludge in China since 2010. However, up to now, little information on bioleached dewatered sludge (BS) composting is available. Here, we report the changes of physicochemical and biological properties in BS composting and evaluate compost product quality compared to conventional dewatered sludge (CS) composting in an engineering scale composting facility. The results showed that the amount of bulking agents required in BS composting was only about 10% of CS composting to obtain optimum moisture content, reducing about 700 kg bulking agents per ton fresh sludge. pH of BS composting mixture was slightly lower consistently by about 0.2-0.3 pH units than that in CS mixture in the first 30 days. Organic matter biodegradation in BS system mainly occurred in the first 9 days of composting. In spite of higher content of NH4(+)-N was found in BS mixture in related to CS mixture; unexpectedly the cumulative ammonia volatilization in the former was only 51% of the latter, indicating that BS composting drastically reduced nitrogen loss. Compared to CS composting system, the relative lower pH, the higher intensity of microbial assimilation, and the presence of water soluble Fe in BS system might jointly reduce ammonia volatilization. Consequently, BS compost product exhibited higher fertilizer values (N+P2O5+K2O=8.38%) as well as lower heavy metal levels due to the solubilization of sludge-borne heavy metals during bioleaching process. Therefore, composting of BS possesses more advantages over the CS composting process.

Bridge displacement monitoring method based on laser projection-sensing technology.

Bridge displacement is the most basic evaluation index of the health status of a bridge structure. The existing measurement methods for bridge displacement basically fail to realize long-term and real-time dynamic monitoring of bridge structures, because of the low degree of automation and the insufficient precision, causing bottlenecks and restriction. To solve this problem, we proposed a bridge displacement monitoring system based on laser projection-sensing technology. First, the laser spot recognition method was studied. Second, the software for the displacement monitoring system was developed. Finally, a series of experiments using this system were conducted, and the results show that such a system has high measurement accuracy and speed. We aim to develop a low-cost, high-accuracy and long-term monitoring method for bridge displacement based on these preliminary efforts.

Association of an inter-arm systolic blood pressure difference with all-cause and cardiovascular mortality: An updated meta-analysis of cohort studies.

OBJECTIVE: To evaluate whether an association exists between an inter-arm systolic blood pressure difference (sIAD) and all-cause and cardiovascular mortality. METHODS: We searched for cohort studies that evaluated the association of a sIAD and all-cause or cardiovascular mortality in the electronic databases Medline/PubMed and Embase (August 2014). Random effects models were used to calculate pooled hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Nine cohort studies (4 prospective and 5 retrospective) enrolling 15,617 participants were included. The pooled HR of all-cause mortality for a sIAD of ≥ 10 mm Hg was 1.53 (95% CI 1.14-2.06), and that for a sIAD of ≥ 15 mm Hg was 1.46 (1.13-1.88). Pooled HRs of cardiovascular mortality were 2.21 (95% CI 1.52-3.21) for a sIAD of ≥ 10mm Hg, and 1.89 (1.32-2.69) for a sIAD of ≥ 15 mm Hg. In the patient-based cohorts including hospital- and diabetes-based cohorts, both sIADs of ≥ 10 and ≥ 15 mm Hg were associated with increased all-cause (pooled HR 1.95, 95% CI 1.01-3.78 and 1.59, 1.06-2.38, respectively) and cardiovascular mortality (pooled HR 2.98, 95% CI 1.88-4.72 and 2.10, 1.07-4.13, respectively). In the community-based cohorts, however, only a sIAD of ≥ 15 mm Hg was associated with increased cardiovascular mortality (pooled HR 1.94, 95 % CI 1.12-3.35). CONCLUSIONS: In the patient populations, a sIAD of ≥ 10 or of ≥ 15 mm Hg could be a useful indictor for increased all-cause and cardiovascular mortality, and a sIAD of ≥ 15 mm Hg might help to predict increased cardiovascular mortality in the community populations.