Sharp needle reconstructs peripheral outflow for patients with malfunctional arteriovenous fistula.

OBJECTIVE: To investigate the feasibility and efficacy of combining ultrasound-guided sharp needle technique with percutaneous transluminal angioplasty (PTA) for treating outflow stenosis or dysfunction in arteriovenous fistula (AVF) among hemodialysis patients. METHODS: From October 2021 to March 2023, patients with occluded or malfunctional fistula veins not amenable to regularly angioplasty were retrospectively enrolled in the study. They underwent ultrasound-guided sharp needle intervention followed by PTA. Data on the location and length between the two veins, technical success, clinical outcomes, and complications were collected. Patency rates post-angioplasty were calculated through Kaplan-Meier analysis. RESULTS: A total of 23 patients were included. The mean length of the reconstructed extraluminal segment was 3.18 cm. The sharp needle opening was performed on the basilic vein (60.9%), brachial vein (26.1%), or upper arm cephalic vein (13%) to create outflow channels. Postoperatively, all cases presented with mild subcutaneous hematomas around the tunneling site and minor diffuse bleeding. The immediate patency rate for the internal fistulas was 100%, with 3-month, 6-month, and 12-month patency rates at 91.3%, 78.3%, and 43.5%, respectively. CONCLUSION: Sharp needle technology merged with PTA presents an effective and secure minimally invasive method for reconstructing the outflow tract, offering a new solution for recanalizing high-pressure or occluded fistulas.

Engineering Escherichia coli for high-yielding 2,5-Dimethylpyrazine synthesis from L-Threonine by reconstructing metabolic pathways and enhancing cofactors regeneration.

2,5-Dimethylpyrazine (2,5-DMP) is important pharmaceutical raw material and food flavoring agent. Recently, engineering microbes to produce 2,5-DMP has become an attractive alternative to chemical synthesis approach. In this study, metabolic engineering strategies were used to optimize the modified Escherichia coli BL21 (DE3) strain for efficient synthesis of 2,5-DMP using L-threonine dehydrogenase (EcTDH) from Escherichia coli BL21, NADH oxidase (EhNOX) from Enterococcus hirae, aminoacetone oxidase (ScAAO) from Streptococcus cristatus and L-threonine transporter protein (EcSstT) from Escherichia coli BL21, respectively. We further optimized the reaction conditions for synthesizing 2,5-DMP. In optimized conditions, the modified strain can convert L-threonine to obtain 2,5-DMP with a yield of 2897.30 mg/L. Therefore, the strategies used in this study contribute to the development of high-level cell factories for 2,5-DMP.

The effect of China's birth policy changes on birth defects-A large hospital-based cross-sectional study.

A retrospective analysis of birth data hospital-based obtained from 14 monitoring areas in the Huaihe River Basin from 2009 to 2019 was conducted. Trend in the total prevalence of birth defects (BDs) and subgroups were analyzed using the Joinpoint Regression model. The incidence of BDs increased gradually from 118.87 per 10,000 in 2009 to 241.18 per 10,000 in 2019 (AAPC = 5.91, P < 0.001). Congenital heart diseases were the most common subtype of BDs. The proportion of maternal age younger than 25 decreased but the age 25-40 years increased significantly (AAPC<20=-5.58; AAPC20-24=-6.38; AAPC25-29 = 5.15; AAPC30-35 = 7.07; AAPC35-40 = 8.27; All P < 0.05). Compared with the one-child policy period, the risk of BDs was greater for groups among maternal age younger than 40 years during the partial and universal two-child policy period (P < 0.001). The incidence of BDs and the proportion of women with advanced maternal age in Huaihe River Basin is increasing. There was an interaction between changes in birth policy and the mother's age on the risk of BDs.

Risk factors for severe low anterior resection syndrome in patients with rectal cancer undergoing sphincter­preserving resection: A systematic review and meta­analysis.

The present study aimed to evaluate the incidence and risk factors of severe low anterior resection syndrome (LARS) in patients with rectal cancer undergoing sphincter-preserving resection, and to provide the clinical basis and reference for the treatment of rectal cancer and the prevention of LARS. Studies on the incidence and risk factors for severe LARS in patients with rectal cancer undergoing sphincter-preserving resection were searched using PubMed, Embase, Cochrane Library, Scopus and Web of Science, according to the inclusion and exclusion criteria. After evaluating the study quality and extracting relevant data, RevMan 5.2 and STATA software were used to conduct a meta-analysis. A total of 12 articles were considered eligible for the present meta-analysis. Within these articles, there were 3,877 cases of sphincter-preserving resection for rectal cancer and 1,589 cases of severe LARS; the incidence of severe LARS was 40.99%. The results of the meta-analysis revealed that sex [female; odds ratio (OR), 6.54; 95% CI, 3.63-11.76; Z, 6.27; P<0.00001], radiotherapy and chemotherapy (OR, 3.45; 95% CI, 2.29-5.21; Z, 5.91; P<0.00001), total mesorectal excision (TME; OR, 4.39; 95% CI, 3.32-5.79; Z, 10.41; P<0.00001), and distance between tumor and anal margin (OR, 2.74; 95% CI, 0.86-8.72; Z, 1.70; P<0.00001) may be the risk factors for severe LARS.

Small bowel diverticulum with enterolith causing intestinal obstruction: A case report.

BACKGROUND: Small bowel diverticula are rare in clinics, and small intestinal obstruction caused by coprolites is rarer and difficult to diagnose early. The true incidence of these diverticula may be underestimated due to their clinical symptoms not differing from those of small bowel obstruction resulting from other causes. It is common in the elderly, although it can occur at any age. CASE SUMMARY: This is a case report of a 78-year-old man with epigastric pain for 5 d. Conservative treatment does not effectively relieve pain, inflammatory indicators are elevated, and computed tomography suggests jejunal intussusception and mild ischemic changes in the intestinal wall. Laparoscopic exploration showed that the left upper abdominal loop was slightly edematous, the jejunum mass at the near Flex ligament was palpable, the size was about 7 cm × 8 cm, the local movement was slight, and the diverticulum was seen 10 cm downward, and the local small intestine was dilated and edema. Segmentectomy was performed. After the short parenteral nutrition after surgery, the fluid and enteral nutrition solution were pumped through the jejunostomy tube, and the patient was discharged after the treatment was stable, and the jejunostomy tube was removed in an outpatient clinic one month after the operation. Postoperative pathology: Jejunectomy specimen: (1) Small intestinal diverticulum with chronic inflammation, ulcer with full-thickness activity, and necrosis of the intestinal wall in some areas; (2) also see that the hard object is consistent with stone changes; and (3) the incision margin on both sides shows chronic inflammation of mucosal tissue. CONCLUSION: Clinically, the diagnosis of small bowel diverticulum is difficult to distinguish from jejunal intussusception. Combined with the patient's condition, rule out other possibilities after a timely disease diagnosis. According to the patient's body tolerance adopt personalized surgical methods to achieve better recovery after surgery.

High level expression of nicotinamide nucleoside kinase from Saccharomyces cerevisiae and its purification and immobilization by one-step method.

Nicotinamide riboside kinase (NRK) plays an important role in the synthesis of ß -nicotinamide nucleotide (NMN). NMN is a key intermediate of NAD+ synthesis, and it actually contribute to the well-being of our health. In this study, gene mining technology was used to clone nicotinamide nucleoside kinase gene fragments from S. cerevisiae, and the ScNRK1 was achieved a high level of soluble expression in E. coli BL21. Then, the reScNRK1 was immobilized by metal affinity label to optimize the enzyme performance. The results showed that the enzyme activity in the fermentation broth was 14.75 IU/mL, and the specific enzyme activity after purification was 2252.59 IU/mg. After immobilization, the optimum temperature of the immobilized enzyme was increased by 10°C compared with the free enzyme, and the temperature stability was improved with little change in pH. Moreover, the activity of the immobilized enzyme remained above 80% after four cycles of immobilized reScNRK1, which makes the enzyme more advantageous in the enzymatic synthesis of NMN.

Multiple Photoisomerization Pathways of the Green Fluorescent Protein Chromophore in a Reversibly Photoswitchable Fluorescent Protein: Insights from Quantum Mechanics/Molecular Mechanics Simulations.

Herein, we have employed a combined CASPT2//CASSCF approach within the quantum mechanics/molecular mechanics (QM/MM) framework to explore the early time photoisomerization of rsEGFP2 starting from its two OFF trans states, i.e., Trans1 and Trans2. The results show similar vertical excitation energies to the S1 state in their Franck-Condon regions. Considering the clockwise and counterclockwise rotations of the C11-C9 bond, four pairs of the S1 excited-state minima and low-lying S1/S0 conical intersections were optimized, based on which we determined four S1 photoisomerization paths that are essentially barrierless to the relevant S1/S0 conical intersections leading to efficient excited-state deactivation to the S0 state. Most importantly, our work first identified multiple photoisomerization and excited-state decay paths, which must be seriously considered in the future. This work not only sheds significant light on the primary trans-cis photoisomerization of rsEGFP2 but also aids in the understanding of the microscopic mechanism of GFP-like RSFPs and the design of novel GFP-like fluorescent proteins.

Aromatic Amides: A Smart Backbone toward Isolated Ultralong Bright Blue-Phosphorescence in Confined Polymeric Films.

We describe an aromatic amide skeleton for manipulation of triplet excited states toward bright long-lived blue phosphorescence. Spectroscopic studies and theoretical calculations demonstrated that the aromatic amides can promote strong spin-orbit coupling between (π,π*) and the bridged (n,π*) states, and enable multiple channels to populate the emissive 3 (π,π*), as well as facilitate robust hydrogen bonding with polyvinyl alcohol to suppress non-radiative relaxations. Isolated inherent deep-blue (0.155, 0.056) to sky-blue (0.175, 0.232) phosphorescence with high quantum yields (up to 34.7 %) in confined films are achieved. The blue afterglow of the films can last for several seconds and are showcased in information display, anti-counterfeiting, and white light afterglow. Owing to the high population of 3 (π,π*) states, the smart aromatic amide skeleton provides an important molecular design prototype to manipulate triplet excited states for ultralong phosphorescence with various colors.

Transcutaneous Electrical Acupoint Stimulation Improves Postoperative Sleep Quality in Patients Undergoing Laparoscopic Gastrointestinal Tumor Surgery: A Prospective, Randomized Controlled Trial.

INTRODUCTION: This study was conducted to observe the effect of transcutaneous electrical acupoint stimulation (TEAS) on the postoperative sleep quality of patients undergoing gastrointestinal tumor surgery and to verify the possible mechanism. METHODS: Eighty-three patients were allocated to the TEAS or Sham group. Patients in the TEAS group received TEAS treatment (disperse-dense waves; frequency, 2/100 Hz) on bilateral Shenmen (HT7), Neiguan (PC6) and Zusanli (ST36) points for 30 min each time, total three times in the perioperative period. In the Sham group, electrodes were placed; however, no current was given. Sleep quality was assessed on the day before surgery (P1) and the first and third days after surgery (D1 and D3) using the Pittsburgh Sleep Quality Index (PSQI) and Athens Insomnia Scale (AIS). Postoperative pain was assessed using visual analog scale (VAS) 72 h postoperatively. The incidences of abdominal distension, dizziness, postoperative nausea and vomiting (PONV) and pulmonary complications were recorded. Serum levels of inflammatory cytokines and the expression of key factors of oxidative stress and key molecules of the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signal pathway were measured. RESULTS: TEAS ameliorated sleep quality at D1 and D3 (PSQI P < 0.05, AIS P < 0.05) and decreased postoperative pain as demonstrated by lower VAS scores compared to the Sham group (P < 0.05). The incidences of abdominal distension and PONV were also lower in the TEAS group. Markers of oxidative stress were increased (P < 0.05), and the serum concentration of interleukin-6 (IL-6) was significantly lower in the TEAS group. The key mediators of the Nrf2/ARE pathway were enhanced after TEAS. CONCLUSION: Perioperative TEAS improved postoperative sleep quality, reduced postoperative pain and alleviated postoperative adverse effects in patients undergoing laparoscopic gastrointestinal tumor surgery resection. This may be associated with activating Nrf2/ARE signal pathway and decreasing its inflammatory actions. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( http://www.chictr.org.cn/index.aspx ), ChiCTR2100054971.

Improving ocular bioavailability of hydrophilic drugs through dynamic covalent complexation.

The clinical benefits of diquafosol tetrasodium (DQS), a hydrophilic P2Y2 receptor agonist for dry eye, have been hindered by a demanding dosing regimen. Nevertheless, it is challenging to achieve sustained release of DQS with conventional drug delivery vehicles which are mainly designed for hydrophobic small molecule drugs. To address this, we developed an affinity hydrogel for DQS by taking advantage of borate-mediated dynamic covalent complexation between DQS and hydroxypropyl guar. The resultant formulation (3% DQS Gel) was characterized by sustained release, low corneal permeation, and extended ocular retention, which were desirable attributes for ocular surface drug delivery. Both in vitro and in vivo studies had been carried out to verify the biocompatibility of 3% DQS Gel. Using corneal fluorescein staining, the Schirmer's test, PAS staining, quantitative PCR and immunohistological analyses as outcome measures, the superior therapeutic effects of 3% DQS Gel over PBS, the hydrogel vehicle and free DQS were demonstrated in a mouse dry eye model. Our DQS delivery strategy reported herein is readily applicable to other hydrophilic small molecule drugs with cis-diol moieties, thus providing a general solution to improve clinical outcomes of numerous diseases.

Effects of vegetation type differences induced by human disturbance on the nutrition strategy and gut microbiota of Siberian roe deer.

The Siberian roe deer (Capreolus pygargus) is a widely distributed ungulate in northeast China. Due to a series of human disturbance activities such as large-scale forest cutting, deforestation and reclamation, road construction in the past, the appearance and internal structure of forest vegetation in the habitat of Siberian roe have changed significantly. At the same time, Siberian roe population had a series of ecological adaptation responses in the face of such habitat changes. Therefore, two typical vegetation types with differences were selected in the Muling Forest, China. We used nutritional ecology and microbial metagenomic analysis techniques to compare the nutritional selection strategy and the structure and functional characteristics of faecal microbiota of Siberian roe groups in two vegetation types. The results showed that the α diversity of dietary and gut microbes of deer in Natural Forest was higher than that in Plantation Forest. However, the gut microbes of the Plantation Forest group contained more unique enzymes in the functional pathways of carbon metabolism and biosynthesis of amino acids. This study suggests that habitat type is associated with plant community composition, and contributes to changes in the intake proportions of major macronutrients by altering the availability, quality, and composition of certain edible plants. Feeding behaviour may be an important regulatory factor of gut microbiota structure and function of deer. The metabolic function of gut microbiota to different nutrients may affect the microbial community structure. Therefore, our results suggest that the gut microbes of Siberian roe may have coevolved with their diets, and reflect the adaptability of deer populations to environmental changes (e.g., vegetation type). Our study provides new insights into how spatial heterogeneity affects nutrition and microecosystems by describing the interactions among the environment, diet, and symbiotic gut microbes in wild ungulates.

The adverse impact of ecotropic viral integration site-1 (EVI1) overexpression on the prognosis of acute myeloid leukemia with KMT2A gene rearrangement in different risk stratification subtypes.

INTRODUCTION: AML patients with KMT2A-MLLT3 and other 11q23 abnormalities belong to the intermediate and high-risk level groups, respectively. Whether the poor prognostic value of Ecotropic Viral Integration site-1 (EVI1) overexpression suits either the subtypes of KMT2A-MLLT3 or Non-KMT2A-MLLT3 AML patients (intermediate and high risk group) needs to be further investigated. METHODS: We retrospectively analyzed the clinical characteristics of 166 KMT2A-r and KMT2A-PTD AML patients. RESULTS: For the Non-KMT2A-MLLT3 group, patients in the EVI1-high subgroup had shorter OS and DFS and higher CIR than those in the EVI1-low subgroup (p = .027, p = .018, and p = .020, respectively). Additionally, both KMT2A-MLLT3 and Non-KMT2A-MLLT3 patients who received chemotherapy alone had poorer prognosis than patients who also received allogeneic hematopoietic stem cell transplant (allo-HSCT) regardless of their EVI1 expression level (all p < .001). For transplanted patients with KMT2A-MLLT3 or Non-KMT2A-MLLT3 rearrangement, the EVI1-high subgroup had worse prognosis than the EVI1-low subgroup (all p < .05). The 2-year CIR of the KMT2A-MLLT3 and Non-KMT2A-MLLT3 groups with high EVI1 expression was high (52% and 49.6%, respectively). However, for patients with low EVI1 expression, the 2-year CIR of transplanted patients with KMT2A-MLLT3 and Non-KMT2A-MLLT3 was relatively low. CONCLUSIONS: Our study showed that for the Non-KMT2A-MLLT3 group, the EVI1-high group had shorter OS and DFS than the EVI1-low group. High EVI1 expression showed an adverse effect in AML with KMT2A rearrangement in different risk stratification subtypes. For the EVI1-high patients with non-KMT2A-MLLT3 rearrangement, other novel regimens towards relapse should be taken into consideration.

Application of electroacupuncture in the prevention of low anterior resection syndrome after rectal cancer surgery.

BACKGROUND: Low anterior resection syndrome (LARS) is one of the common postoperative complications in patients with rectal cancer, which seriously affects their postoperative recovery and quality of life (QoL). Electroacupuncture therapy is one of the characteristic therapies of traditional Chinese medicine. There are few reports on the prevention and treatment of LARS by electroacupuncture therapy. AIM: To explore the clinical effectiveness of electroacupuncture in managing rectal cancer patients with postoperative LARS. METHODS: A total of 50 patients with LARS after rectal cancer surgery were retrospectively selected as the research subjects. According to the treatment methods, they were divided into an observation group (n = 25) and a control group (n = 25). During the four-week treatment period, the control group received standard defecation function training, while the observation group received electroacupuncture care and traditional defecation function training. The anal pressure index (which includes anal resting pressure, anal systolic pressure, and maximum tolerable volume), European Organization of Research and Treatment of Cancer (EORTC) QoL C30 (QLQ-C30) score, LARS Scale (LARSS) score, Wexner anal incontinence scale score, Xu Zhongfa five-item 10-point scale score, and the occurrence of adverse reactions were compared between the two groups before and after treatment. RESULTS: The experimental group showed considerably enhanced LARSS scores compared to those in the control group after four weeks of treatment. In the first week, second week, and fourth week, the LARSS score and Wexner anal incontinence scale score decreased, and the Xu Zhong method five-item 10-point scale score increased, with significant differences (P < 0.05). The experimental group showed substantial improvements in anal resting pressure, anal systolic pressure, and maximum tolerance volume after undergoing 4 wk of therapy in the untreated group (P < 0.05). The experimental group's QLQ-C30 score on the EORTC QoL questionnaire was higher than that of the control group during the 1st, 2nd, and 4th wk (P < 0.05). No significant variation between the groups in the frequency of adverse reactions (P > 0.05) was observed. CONCLUSION: Electroacupuncture positively impacted LARS following rectal cancer surgery, effectively improving clinical symptoms and anal pressure indicators and patients' standard of life.

Effect of astragaloside IV and salvianolic acid B on antioxidant stress and vascular endothelial protection in the treatment of atherosclerosis based on metabonomics.

Vascular endothelial cells and oxidation reduction system play an important role in the pathogenesis of atherosclerosis (AS). If these conditions are disordered, it will inevitably lead to plaque formation and even rupture. Astragaloside IV (AsIV) and salvianolic acid B (Sal B) are the main active ingredients of Astragalus membranaceus and Salvia miltiorrhiza, respectively, and found to ameliorate vascular endothelial dysfunction and protect against oxidative stress in recent studies. However, it is still unknown if the combination of AsIV and Sal B (AsIV + Sal B) can inhibit the development of plaque through amplifying the protective effect of vascular endothelial cells and anti-oxidative stress effect. To clarify the role of AsIV + Sal B in AS, we observed the efficacy of each group (Control, Model, AsIV, Sal B, and AsIV + Sal B) by biomolecular assays, such as observing the pathological morphology of the aorta by oil red O staining, evaluating the level of oxidative stress and endothelial cells in the serum by the Elisa test, and analyzing the changes of all small molecule metabolites in liver tissue by UPLC-QTOF-MS. Results showed that AsIV, Sal B and AsIV + Sal B decreased the deposition of lipid in the arterial wall, so as to exert the effect of anti-oxidant stress and vascular endothelial protection, where the inhibitory effect of AsIV + Sal B was the most obvious. Metabonomics analysis showed that Sal B regulated the metabolic pathways of arginine and proline. AsIV regulated glycerol metabolism and saturated fatty acid biosynthesis metabolism. AsIV + Sal B is mainly related to the regulation of the citrate cycle (TCA cycle), alanine, aspartic acid, and glutamate metabolism, cysteine, and methionine metabolism. Succinic acid and methionine are synergistic metabolites that exert an enhancing effect when AsIV and Sal B were used in combination. In conclusion, we demonstrated that AsIV acompanied with Sal B can be successfully used for anti-oxidative stress and vascular endothelial protection of AS, and succinic acid and methionine are the synergistic metabolites.

The Arginine Repressor ArgR2 Controls Conjugated Linoleic Acid Biosynthesis by Activating the cla Operon in Lactiplantibacillus plantarum.

CLA (conjugated linoleic acid) has attracted substantial attention due to its physiological functions, including regulating immunity, reducing obesity, and contributing to cancer suppression. In Lactiplantibacillus plantarum, CLA oleate hydratase (CLA-HY), CLA short-chain dehydrogenase (CLA-DH), and CLA acetoacetate decarboxylase (CLA-DC) catalyze the biotransformation of linoleic acid (LA) to CLA. However, the underlying transcriptional regulation mechanism of this pathway remains largely unknown. In this study, the potential transcriptional regulators that might bind to the cla promoter of L. plantarum AR195 were investigated by DNA pulldown. Interestingly, ArgR2, the transcriptional regulator of arginine metabolism, was identified as a potential regulator involved in the regulation of CLA biotransformation. Electrophoretic mobility shift assay (EMSA) and molecular interaction results demonstrated the specific binding of ArgR2 to the regulatory region of the cla operon. The knockout of argR2 led to the downregulation of cla-dh and cla-dc by 91% and 34%, respectively, resulting in a decline in the CLA yield by 14%. A segmental EMSA revealed that ArgR2 bound to three distinct sites in the cla regulatory region, and these binding sites were highly conserved and rich in AT. The regulatory mechanism of ArgR2 on CLA biosynthesis further expanded our knowledge of the regulatory mechanism of CLA biosynthesis in L. plantarum and laid the theoretical foundation for the production and application of CLA. IMPORTANCE CLA (conjugated linoleic acid) has received extensive attention owing to its important physiological functions. CLA from natural sources is far from meeting people's demands. Lactic acid bacteria can efficiently synthesize cis-9,trans-11-CLA and trans-10,cis-12-CLA, which possess physiological activities. However, little is known about the regulatory mechanism. In this study, we identified that the biosynthesis of CLA in L. plantarum AR195 was transcriptionally regulated by the arginine biosynthesis regulatory protein ArgR2. The regulation mechanism of ArgR2 on CLA biosynthesis lays a theoretical foundation for the regulation of CLA synthesis and industrial production.

Determination of the regulatory network and function of the lysR-type transcriptional regulator of Lactiplantibacillus plantarum, LpLttR.

BACKGROUND: Lactiplantibacillus plantarum has various healthcare functions including the regulation of immunity and inflammation, reduction of serum cholesterol levels, anti-tumor activity, and maintenance of the balance of intestinal flora. However, the underlying metabolic and regulatory mechanisms of these processes remain unclear. Our previous studies have shown that the LysR type transcriptional regulator of L. plantarum (LpLttR) regulates the biotransformation of conjugated linoleic acids (CLAs) through the transcriptional activation of cla-dh (coding gene for CLA short-chain dehydrogenase) and cla-dc (coding gene for CLA acetoacetate decarboxylase). However, the regulatory network and function of LpLttR have not yet been characterized in L. plantarum. RESULTS: In this study, the regulatory role of LpLttR in various cellular processes was assessed using transcriptome analysis. The deletion of LpLttR had no evident influence on the bacterial growth. The transcriptome data showed that the expression of nine genes were positively regulated by LpLttR, and the expression of only two genes were negatively regulated. Through binding motif analysis and molecular interaction, we demonstrated that the regulatory region of the directly regulated genes contained a highly conserved sequence, consisting of a 15-base long box and rich in AT. CONCLUSION: This study revealed that LpLttR of L. plantarum did not play a global regulatory role similar to that of the other transcriptional regulators in this family. This study broadens our knowledge of LpLttR and provides a theoretical basis for the utilization of L. plantarum.

A topical fluorometholone nanoformulation fabricated under aqueous condition for the treatment of dry eye.

Fluorometholone (FMT) is a frequently prescribed drug for the alleviation of dry eye. However, due to low aqueous solubility, it has been routinely used as an ophthalmic suspension, which is characterized by low bioavailability, inconvenience of administration, and difficulty in delivering accurate dose. Furthermore, the opaque appearance of the ophthalmic suspension is not desirable for optical purpose. In the present study, a transparent FMT nanoformulation (FMT-CD NPs) was fabricated by the cyclodextrin (CD) nanoparticle technology without organic solvents. It was demonstrated that FMT was encapsulated in an amorphous form, which was associated with increased release rate and enhanced corneal penetration efficiency. The biocompatibility of FMT-CD NPs was confirmed by the Live/Dead assay, CCK-8 assay and the wound healing assay. Most importantly, FMT-CD NPs alleviated dry eye signs more efficiently than the commercial eye drop, with one-fifth the dosage of FMT in the latter. Collectively, our study provides a promising FMT formulation for improved management of dry eye while reducing drug related side effects.

Efficacy and safety of mesenchymal stem cells treatment for multidrug-resistant graft-versus-host disease after haploidentical allogeneic hematopoietic stem cell transplantation.

PURPOSE: Graft-versus-host disease (GVHD) is an important complication after human leukocyte antigen (HLA) haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT), which may lead to poor prognosis. Our study intends to identify the efficacy and safety of mesenchymal stem cells (MSCs) for multidrug-resistant (MDR)-GVHD after HID HSCT. METHODS: MDR-GVHD was referring to GVHD remaining no response to at least two types of therapy, and hUCB-MSCs were given at the dose of (1.0-2.0) × 106/kg once a week. RESULTS: A total of 21 patients were enrolled in this retrospective study (acute GVHD (aGVHD): n = 14, chronic GVHD (cGVHD): n = 7). The median dose of MSCs was 1.2 × 106 cells/kg (range, 0.8-1.8 × 106) cells/kg, and the median numbers of infusion were 2 (range, 1-7) and 3 (range, 2-12) for MDR-aGVHD and MDR-cGVHD patients, respectively. In MDR-aGVHD patients, the overall response rate (ORR) was 57.1%, including 50.0% complete response (CR) and 7.1% partial response (PR), and the median time to response was 49.5 days (range, 16-118) days. The 2-year probability of overall survival after MSCs was 64.3%. Five patients (35.7%) developed infections after MSCs, and no obvious hematologic toxicities were observed. Five MDR-aGVHD patients died after MSCs treatments because of GVHD progression (n = 1), severe infection (bacterial central nervous system infection: n = 1; fungal pneumonia: n = 2), and poor graft function (n = 1). In MDR-cGVHD patients, three patients (42.9%) achieved PR after MSCs and the median time to response was 56 days (22-84) days. The ORRs for moderate and severe cGVHD were 50.0% and 33.3%, respectively. Four MDR-cGVHD patients died after MSCs treatments because of GVHD progression (n = 2), severe fungal pneumonia (n = 1), and relapse (n = 1). CONCLUSION: MSCs treatment may be safe and effective for MDR-GVHD after HID HSCT.

Engineering Advanced Drug Delivery Systems for Dry Eye: A Review.

Dry eye disease (DED) is a widespread and frequently reported multifactorial ocular disease that not only causes ocular discomfort but also damages the cornea and conjunctiva. At present, topical administration is the most common treatment modality for DED. Due to the existence of multiple biological barriers, instilled drugs generally exhibit short action times and poor penetration on the ocular surface. To resolve these issues, several advanced drug delivery systems have been proposed. This review discusses new dosage forms of drugs for the treatment of DED in terms of their characteristics and advantages. Innovative formulations that are currently available in the market and under clinical investigation are elaborated. Meanwhile, their deficiencies are discussed. It is envisioned that the flourishing of advanced drug delivery systems will lead to improved management of DED in the near future.