CRISPR-Cas9 mediated dsRNase knockout improves RNAi efficiency in the fall armyworm.

Lepidopteran insects are refractory to RNA interference (RNAi) response, especially to orally delivered double-stranded RNA (dsRNA). High nuclease activity in the midgut lumen is proposed as one of the major reasons for RNAi insensitivity. We identified three dsRNase genes highly expressed in the midgut of fall armyworm (FAW), Spodoptera frugiperda. The genomic region harboring those three dsRNase genes was deleted using the CRISPR-Cas9-mediated genome editing method. A homozygous line with deletion of three dsRNase genes was produced. dsRNA degradation by midgut lumen contents of mutant larvae was lower than in wild-type larvae. Feeding dsRNA targeting the inhibitor of apoptosis (IAP) gene increased knockdown of the target gene and mortality in mutants compared to wild-type larvae. These results suggest that dsRNases in the midgut contribute to RNAi inefficiency in FAW. Formulations that protect dsRNA from dsRNase degradation may improve RNAi efficiency in FAW and other lepidopteran insects.

Unlocking the mystery of the feeder organelle and versatile energy metabolism in Cryptosporidium parvum.

Xu and colleagues recently revealed the critical role of Cryptosporidium's feeder organelle in nutrient uptake, showcasing the parasite's ability to harness glucose and glucose-6-phosphate from host cells. This illuminates the sophisticated energy metabolism and survival strategies of the parasite, highlighting potential therapeutic targets.

Requirement of microtubules for secretion of a micronemal protein CpTSP4 in the invasive stage of the apicomplexan Cryptosporidium parvum.

The zoonotic Cryptosporidium parvum is a global contributor to infantile diarrheal diseases and opportunistic infections in immunocompromised or weakened individuals. Like other apicomplexans, it possesses several specialized secretory organelles, including micronemes, rhoptry, and dense granules. However, the understanding of cryptosporidial micronemal composition and secretory pathway remains limited. Here, we report a new micronemal protein in C. parvum, namely, thrombospondin (TSP)-repeat domain-containing protein-4 (CpTSP4), providing insights into these ambiguities. Immunostaining and enzyme-linked assays show that CpTSP4 is prestored in the micronemes of unexcysted sporozoites but secreted during sporozoite excystation, gliding, and invasion. In excysted sporozoites, CpTSP4 is also distributed on the two central microtubules unique to Cryptosporidium. The secretion and microtubular distribution could be completely blocked by the selective kinesin-5 inhibitors SB-743921 and SB-715992, resulting in the accumulation of CpTSP4 in micronemes. These support the kinesin-dependent microtubular trafficking of CpTSP4 for secretion. We also localize γ-tubulin, consistent with kinesin-dependent anterograde trafficking. Additionally, recombinant CpTSP4 displays nanomolar binding affinity to the host cell surface, for which heparin acts as one of the host ligands. A novel heparin-binding motif is identified and validated biochemically for its contribution to the adhesive property of CpTSP4 by peptide competition assays and site-directed mutagenesis. These findings shed light on the mechanisms of intracellular trafficking and secretion of a cryptosporidial micronemal protein and the interaction of a TSP-family protein with host cells.IMPORTANCECryptosporidium parvum is a globally distributed apicomplexan parasite infecting humans and/or animals. Like other apicomplexans, it possesses specialized secretory organelles in the zoites, in which micronemes discharge molecules to facilitate the movement and invasion of zoites. Although past and recent studies have identified several proteins in cryptosporidial micronemes, our understanding of the composition, secretory pathways, and domain-ligand interactions of micronemal proteins remains limited. This study identifies a new micronemal protein, namely, CpTSP4, that is discharged during excystation, gliding, and invasion of C. parvum sporozoites. The CpTSP4 secretion depends on the intracellular trafficking on the two Cryptosporidium-unique microtubes that could be blocked by kinesin-5/Eg5 inhibitors. Additionally, a novel heparin-binding motif is identified and biochemically validated, which contributes to the nanomolar binding affinity of CpTSP4 to host cells. These findings indicate that kinesin-dependent microtubular trafficking is critical to CpTSP4 secretion, and heparin/heparan sulfate is one of the ligands for this micronemal protein.

Effects of Different Mind-body Exercises in Managing Chronic Pain of Older Adults: A Network Meta-analysis of Randomized Trials.

INTRODUCTION: Mind-body exercises (MBEs) were shown to be effective in managing chronic pain among older adults in several recent studies. However, the differences in the effects of different MBEs remained unclear. OBJECTIVE: To compare the effects of different MBEs in managing chronic pain in older adults. METHODS: Eight databases were searched for studies published between 2012 and 2023, and 14 studies were included in this systematic review and network meta-analysis (NMA). The NMA was performed using R and Metainsight. RESULTS: Results showed that tai chi and yoga were effective in alleviating chronic pain, but their effects were not superior to traditional physical exercises and other MBEs. In addition, none of the MBEs were shown to be effective in mitigating chronic pain-related disabilities. CONCLUSION: Tai chi and yoga can be used for relieving chronic pain in older adults; however, MBE programs alone were not sufficient to mitigate chronic pain-related disabilities.

Dynamic biomechanical changes of clear aligners during extraction space closure: Finite element analysis.

INTRODUCTION: Clear aligners (CAs) have recently become popular and widely used orthodontic appliances. Research on CA biomechanics has become a focal point in orthodontics to improve the efficiency of CA treatment and address challenging issues, such as extraction. The biomechanical characteristics of CAs in space closure have been reported. However, previous studies have mainly focused on static biomechanical analysis that cannot demonstrate the dynamic biomechanical changes in CAs during space-closing. Given that these biomechanical changes can be significant and have considerable clinical value, this study aimed to investigate these characteristics. METHODS: Sequential extraction space-closing models were derived from included patient data and refined using modeling and CA design software. A finite element analysis was performed to obtain biomechanical raw data. This study introduced a dual coordinate system and space geometry analysis to demonstrate the biomechanical properties accurately. RESULTS: As space closure progressed, the instantaneous tooth displacements increased, indicating an enhanced space closure force because of the increased strain in the CA extraction area. Meanwhile, the central axis of rotation of the anterior teeth continuously moved toward the labial-apical direction, showing a gradually enhanced vertical and torque control effect. CONCLUSIONS: During space closure, CAs undergo specific biomechanical changes, including increased contraction and control forces on both sides of the gap. These biomechanical effects are beneficial to alleviate the roller coaster effect gradually. Meanwhile, more reasonable staging design strategies can be proposed on the basis of this biomechanical mechanism.

Azadirachtin Inhibits Nuclear Receptor HR3 in the Prothoracic Gland to Block Larval Ecdysis in the Fall Armyworm, Spodoptera frugiperda.

Azadirachtin has been used to control agricultural pests for a long time; however, the molecular mechanism of azadirachtin on lepidopterans is still not clear. In this study, the fourth instar larvae of fall armyworm were fed with azadirachtin, and then the ecdysis was blocked in the fourth instar larval stage (L4). The prothoracic glands (PGs) of the treated larvae were dissected for RNA sequencing to determine the effect of azadirachtin on ecdysis inhibition. Interestingly, one of the PG-enriched genes, the nuclear hormone receptor 3 (HR3), was decreased after azadirachtin treatment, which plays a critical role in the 20-hydroxyecdysone action during ecdysis. To deepen the understanding of azadirachtin on ecdysis, the HR3 was knocked out by using the CRISPR/Cas9 system, while the HR3 mutants displayed embryonic lethal phenotype; thus, the stage-specific function of HR3 during larval molting was not enabled to unfold. Hence, the siRNA was injected into the 24 h L4 larvae to knock down HR3. After 96 h, the injected larvae were blocked in the old cuticle during ecdysis which is consistent with the azadirachtin-treated larvae. Taken together, we envisioned that the inhibition of ecdysis in the fall armyworm after the azadirachtin treatment is due to an interference with the expression of HR3 in PG, resulting in larval mortality. The results in this study specified the understanding of azadirachtin on insect ecdysis and the function of HR3 in lepidopteran in vivo.

Comparing Different Stretching Exercises on Pain, Stiffness, and Physical Function Disability in Older Adults With Knee Osteoarthritis.

OBJECTIVE: To assess and compare the effects of different stretching exercise programs on pain, stiffness, and physical function disability in older adults with knee osteoarthritis (KOA). DATA SOURCES: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline for network meta-analysis (NMA). Relevant randomized controlled trials were identified by searching 7 databases up to December 2022. STUDY SELECTION: Inclusion criteria included (1) older adults with KOA; (2) intervention included stretching exercises; (3) control groups received no stretching exercise; and (4) outcome measurements included pain, stiffness, or physical function disability. Methodological quality was assessed using the Cochrane risk-of-bias tool for randomized trials version 2. DATA EXTRACTION: NMA was performed using R and MetaInsight, with results presented as a standardized mean difference (SMD) with 95% confidence interval (CI). DATA SYNTHESIS: We examined 17 studies, and NMA results indicated that proprioceptive neuromuscular facilitation (PNF) stretching, mind-body exercises, and multi-component exercise programs were effective in mitigating pain in older adults with KOA (SMD=2.54 [95% CI: 1.23; 3.84], SMD=1.09 [95% CI: 0.27; 1.92], SMD=0.57 [95% CI: 0.06; 1.09]). Moreover, mind-body exercises and multi-component exercises were the most effective programs in reducing stiffness (SMD=1.31 [95% CI: 0.12; 2.51]) and physical function disability (SMD=1.67 [95% CI: 0.01; 3.33]) in older adults with KOA, respectively. CONCLUSION: Findings suggest that PNF stretching, mind-body exercises, and multi-component exercises can be incorporated into exercise programs to better mitigate pain, stiffness, and physical function disability in older adults with KOA.

Cost-effective In Vivo and In Vitro Mouse Models for Evaluating Anticryptosporidial Drug Efficacy: Assessing Vorinostat, Docetaxel, and Baicalein.

BACKGROUND: Cryptosporidiosis is a significant diarrheal disease in humans and animals. Immunodeficient mice are the primary small animal models, but their high costs and specialized breeding/housing requirements limit in vivo drug testing. Numerous anticryptosporidial lead compounds identified in vitro remain untested in vivo. METHODS: Cryptosporidium tyzzeri, a natural mouse parasite closely related to Cryptosporidium parvum and Cryptosporidium hominis, was isolated to establish an infection model in immunocompetent mice. The model was validated using classic anticryptosporidial drugs (paromomycin and nitazoxanide) and then employed to assess the efficacy of 3 new leads (vorinostat, docetaxel, and baicalein). An in vitro culture of C. tyzzeri was also developed to complement the animal model. RESULTS: Chronic C. tyzzeri infection was established in chemically immunosuppressed wild-type mice. Paromomycin (1000 mg/kg/d) and nitazoxanide (100 mg/kg/d) demonstrated efficacy against C. tyzzeri. Vorinostat (30 mg/kg/d), docetaxel (25 mg/kg/d), and baicalein (50 mg/kg/d) were highly effective against C. tyzzeri infection. In vitro, nitazoxanide, vorinostat, docetaxel, and baicalein exhibited low to submicromolar efficacy against C. tyzzeri. CONCLUSIONS: Novel in vivo and in vitro models have been developed for cost-effective anticryptosporidial drug testing. Vorinostat, docetaxel, and baicalein show potential for repurposing and/or optimization for developing new anticryptosporidial drugs.

Swimming exercise attenuates mechanical hypersensitivity and mitigates peripheral nerve degeneration in rats with painful diabetic neuropathy (PDN).

BACKGROUND: This study aimed to assess the effectiveness of swimming exercise in alleviating mechanical hypersensitivity and peripheral nerve degeneration associated with a pre-clinical model of painful diabetic neuropathy (PDN). METHODS: This study is a pre-clinical study conducted using the streptozocin (STZ)-induced PDN rat model. Rats were randomly allocated to three groups: a vehicle group of non-diabetic rats (Vehicle, n = 9), a group of rats with PDN (PDN, n = 8), and a group of rats with PDN that performed a swimming exercise program (PDN-SW, n = 10). The swimming exercise program included daily 30-minute swimming exercise, 5 days per week for 4 weeks. Von Frey testing was used to monitor hindpaw mechanical sensitivity over 4 weeks. Assessment of cutaneous peripheral nerve fiber integrity was performed after the 4-week study period via immunohistochemistry for protein gene product 9.5-positive (PGP9.5+) intra-epidermal nerve fiber density (IENFD) in hind-paw skin biopsies by a blinded investigator. RESULTS: The results showed that swimming exercise mitigated but did not fully reverse mechanical hypersensitivity in rats with PDN. Immunohistochemical testing revealed that the rats in the PDN-SW group retained higher PGP9.5+ IENFD compared to the PDN group but did not reach normal levels of the Vehicle group. CONCLUSIONS: The results of this study indicate that swimming exercise can mitigate mechanical hypersensitivity and degeneration of peripheral nerve fibers in rats with experimental PDN.

Physical therapy for sleep apnea: a smartphone application for home-based physical therapy for patients with obstructive sleep apnea.

Purpose: In this study, we described "PT for Sleep Apnea", a smartphone application for home-based physical therapy of patients with Obstructive Sleep Apnea (OSA). Methods: The application was created in a joint program between the University of Medicine and Pharmacy at Ho Chi Minh City (UMP), Vietnam, and National Cheng Kung University (NCKU), Taiwan. Exercises maneuvers were derived from the exercise program previously published by the partner group at National Cheng Kung University. They included exercises for upper airway and respiratory muscle training and general endurance training. Results: The application provides video and in-text tutorials for users to follow at home and a schedule function to assist the user in organizing the training program, which may improve the efficacy of home-based physical therapy in patients with Obstructive Sleep Apnea. Conclusion: In the future, our group plans to conduct a user study and randomized-controlled trials to investigate whether our application can benefit patients with OSA.

Janus Metal-Organic Framework Membranes Boosting the Osmotic Energy Harvesting.

The unique ion-transport properties in nanoconfined pores enable nanofluidic devices with great potential in harvesting osmotic energy. The energy conversion performance could be significantly improved by the precise regulation of the "permeability-selectivity" trade-off and the ion concentration polarization effect. Here, we take the advantage of electrodeposition technique to fabricate a Janus metal-organic framework (J-MOF) membrane that possesses rapid ion-transport capability and impeccable ion selectivity. The asymmetric structure and asymmetric surface charge distribution of the J-MOF device can suppress the ion concentration polarization effect and enhance the ion charge separation, exhibiting an improved energy harvesting performance. An output power density of 3.44 W/m2 has been achieved with the J-MOF membrane at a 1000-fold concentration gradient. This work provides a new strategy for fabricating high-performance energy-harvesting devices.

On-target inhibition of Cryptosporidium parvum by nitazoxanide (NTZ) and paclitaxel (PTX) validated using a novel MDR1-transgenic host cell model and algorithms to quantify the effect on the parasite target.

Cryptosporidium parvum is a globally distributed zoonotic protozoan parasite that causes moderate to severe, sometime deadly, watery diarrhea in humans and animals, for which fully effective treatments are yet unavailable. In studying the mechanism of action of drugs against intracellular pathogens, it is important to validate whether the observed anti-infective activity is attributed to the drug action on the pathogen or host target. For the epicellular parasite Cryptosporidium, we have previously developed a concept that the host cells with significantly increased drug tolerance by transient overexpression of the multidrug resistance protein-1 (MDR1) could be utilized to evaluate whether and how much the observed anti-cryptosporidial activity of an inhibitor was attributed to the inhibitor's action on the parasite target. However, the transient transfection model was only applicable to evaluating native MDR1 substrates. Here we report an advanced model using stable MDR1-transgenic HCT-8 cells that allows rapid development of novel resistance to non-MDR1 substrates by multiple rounds of drug selection. Using the new model, we successfully validated that nitazoxanide, a non-MDR1 substrate and the only FDA-approved drug to treat human cryptosporidiosis, killed C. parvum by fully (100%) acting on the parasite target. We also confirmed that paclitaxel acted fully on the parasite target, while several other inhibitors including mitoxantrone, doxorubicin, vincristine and ivermectin acted partially on the parasite targets. Additionally, we developed mathematical models to quantify the proportional contribution of the on-parasite-target effect to the observed anti-cryptosporidial activity and to evaluate the relationships between several in vitro parameters, including antiparasitic efficacy (ECi), cytotoxicity (TCi), selectivity index (SI) and Hill slope (h). Owning to the promiscuity of the MDR1 efflux pump, the MDR1-transgenic host cell model could be applied to assess the on-parasite-target effects of newly identified hits/leads, either substrates or non-substrates of MDR1, against Cryptosporidium or other epicellular pathogens.

Different biomechanical effects of clear aligners in closing maxillary and mandibular extraction spaces: Finite element analysis.

INTRODUCTION: Compared with fixed treatments, clear aligners (CAs) have the advantages of comfort, esthetics, and hygiene, and are popular among patients and orthodontists. However, CAs exhibit control deficiencies in extraction patients because of insufficient root control and retention effects. These deficiencies can magnify biomechanical differences in bimaxillary dentition, further causing different orthodontic requirements between maxillary and mandibular dentition. This study aimed to elaborate on the biomechanical characteristics of bimaxillary dentition in extraction space closure and provided feasible biomechanical compensation strategies for use in clinical practice. METHODS: We constructed a 3-dimensional (3D) bimaxillary model based on patient data. Several 3D modeling-related software was used to generate a standard first premolar extraction model, CAs, and attachments. Subsequently, finite element analysis was performed to demonstrate the biomechanical effects. RESULTS: The maxillary and mandibular dentition showed a roller coaster effect during space closure. Compared with the maxillary dentition, the mandibular posterior teeth exhibited stronger relative anchorage causing greater anterior teeth retraction. The tipping and vertical movements of the anterior teeth were related to tooth length. The longer the anterior tooth, the less tipping and greater vertical displacement occurred. Generally, when having the same retraction distance, the mandibular dentition exhibited greater retroclination and fewer extrusions. Both mechanical and retention compensations should be considered to prevent these unwanted tipping movements. Adding specific attachments to bimaxillary dentitions compensated for the retention and root control deficiencies of CAs. CONCLUSIONS: When applying CAs to extraction patients, different biomechanical effects can present in the bimaxillary dentition because of specific dentition morphologies. To effectively treat these patients, mechanical compensation through overcorrection of the target position should be designed on the basis of bimaxillary control deficiencies, and retention compensation by adding specific attachments should also be considered according to the overcorrections.

Lactate Dehydrogenase and Risk of Readmission with Gastric Cancer: A Propensity Score Matching Analysis.

PURPOSE: Readmission is one of the measures of quality of care and potential costs. This study aimed to determine whether lactate dehydrogenase (LDH) is associated with an increased risk of 30-day readmission in gastric cancer. METHODS: We performed a retrospective study of patients who underwent radical gastrectomy for gastric cancer at our institution between July 2014 and May 2018. Balanced cohorts were created by propensity score matching (PSM) with a 1:1 ratio to generate the elevated LDH (ELDH) group (n = 151) and the low LDH group (Control) (n = 302). To determine the incidence, causes, and risk factors of 30-day readmission, subgroup analyzes were performed and used to develop an efficient prediction model. RESULTS: A total of 788 patients met the criteria to be included in the study. The cutoff value for serum LDH was 215.5. After PSM, a total of 302 patients were matched in pairs (ELDH group, n = 151, Control group, n = 151). ELDH levels had a higher risk of readmission (p = 0.005, Odds ratio 3.768, 95% confidence interval 1.493-9.510). The pre-match 30-day readmission rate was 7.2 percent, and common causes of post-match readmission included infection-related symptoms, gastrointestinal symptoms, and gastrointestinal bleeding. CONCLUSIONS: Patients with preoperative ELDH levels, postoperative complications, and high preoperative American Society of Anesthesiologists Scores had a higher risk of readmission 30 days after surgery.

Finite element analysis of the biomechanical effect of clear aligners in extraction space closure under different anchorage controls.

INTRODUCTION: Clear aligners (CAs) have attracted increasing attention from patients and orthodontists because of their excellent esthetics and comfort. However, treating tooth extraction patients with CAs is difficult because their biomechanical effects are more complicated than those of traditional appliances. This study aimed to analyze the biomechanical effect of CAs in extraction space closure under different anchorage controls, including moderate, direct strong, and indirect strong anchorage. It could provide several new cognitions for anchorage control with CAs through finite element analysis, further directing clinical practice. METHODS: A 3-dimensional maxillary model was generated by combining cone-beam computed tomography and intraoral scan data. Three-dimensional modeling software was used to construct a standard first premolar extraction model, temporary anchorage devices, and CAs. Subsequently, finite element analysis was performed to simulate space closure under different anchorage controls. RESULTS: Direct strong anchorage was beneficial for reducing the clockwise occlusal plane rotation, whereas indirect anchorage was conducive for anterior teeth inclination control. In the direct strong anchorage group, an increase in the retraction force would require more specific anterior teeth overcorrection to resist the tipping movement, mainly including lingual root control of the central incisor, followed by distal root control of the canine, lingual root control of the lateral incisor, distal root control of the lateral incisor, and distal root control of the central incisor. However, the retraction force could not eliminate the mesial movement of the posterior teeth, possibly causing a reciprocating motion during treatment. In indirect strong groups, when the button was close to the center of the crown, the second premolar presented less mesial and buccal tipping but more intrusion. CONCLUSIONS: The 3 anchorage groups showed significantly different biomechanical effects in both the anterior and posterior teeth. Specific overcorrection or compensation forces should be considered when using different anchorage types. The moderate and indirect strong anchorages have a more stable and single-force system and could be reliable models in investigating the precise control of future tooth extraction patients.

Efficacy and Safety of Maca (Lepidium meyenii) in Patients with Symptoms of Late-Onset Hypogonadism: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

PURPOSE: To evaluated the efficacy and safety of gelatinized Maca (Lepidium meyenii) for eugonadal patients with late onset hypogonadism symptoms (LOH). MATERIALS AND METHODS: Participants were instructed to receive 1,000 mg of Maca or placebo, two pills at a time, three times per day for 12 weeks before food intake. To evaluate the efficacy of the drug, Aging Males' Symptoms scale (AMS), Androgen Deficiency in the Aging Males (ADAM), International Prostate Symptom Score (IPSS), and International Index of Erectile Function (IIEF) questionnaires, serologic tests (total testosterone and free testosterone, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglyceride), body weight, and waist circumference were assessed at 4 and 12 weeks after treatment. RESULTS: A total of 80 participants were enrolled and randomly assigned to Maca treated group (n=41) or the placebo group (n=39). AMS, IIEF, and IPSS were significantly (p<0.05) improved in Maca treated group than in the placebo group. ADAM positive rate was also significantly (p<0.0001) decreased in Maca treated group. CONCLUSIONS: Maca may be considered an effective and safe treatment for eugonadal patients with late onset hypogonadism symptoms.

Quisqualis indica extract for men with lower urinary tract symptoms: A randomized, double-blind, placebo-controlled trial.

PURPOSE: To evaluate the efficacy and safety of Quisqualis indica in men with moderate lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: A total of 135 subjects with International Prostate Symptom Score (IPSS) of 8-19 were randomized in 2 centers from June 2018 to April 2019. Patients were assigned into one of the three groups: a low-dose group (LG, 1,000 mg Q. indica), a high-dose group (HG, 2,000 mg Q. indica) or a placebo group (PG). The primary endpoint was the change of IPSS at the end of treatment from baseline. Secondary end points included the changes of prostate specific antigen, testosterone, dihydrotestosterone, maximum urinary flow rate (Qmax), postvoid residual volume (PVR) and International Index of Erectile Function-5 (IIEF-5), with drug safety. RESULTS: 113 patients were able to finish the study. Compared to the PG, total IPSS in the LG and the HG was significantly improved at 6 weeks and 12 weeks. For IPSS subscores, LG showed improvements in all except for urgency and quality of life at 6 weeks. HG showed improvements in incomplete emptying and frequency at 6 weeks and 12 weeks along with improvements in intermittency, straining, and quality of life at 12 weeks. For IIEF-5 subscores, orgasmic function and overall satisfaction improved in HG when compared to PG at 12 weeks. Lastly, increase of Qmax and decrease of PVR was observed at 6 weeks in LG. CONCLUSIONS: 12-week treatment with Q. indica has a therapeutic effect and is well tolerated in patients with LUTS.

Sex modulates the outcome of subthalamic nucleus deep brain stimulation in patients with Parkinson's disease.

There are many documented sex differences in the clinical course, symptom expression profile, and treatment response of Parkinson's disease, creating additional challenges for patient management. Although subthalamic nucleus deep brain stimulation is an established therapy for Parkinson's disease, the effects of sex on treatment outcome are still unclear. The aim of this retrospective observational study, was to examine sex differences in motor symptoms, non-motor symptoms, and quality of life after subthalamic nucleus deep brain stimulation. Outcome measures were evaluated at 1 and 12 months post-operation in 90 patients with Parkinson's disease undergoing subthalamic nucleus deep brain stimulation aged 63.00 ± 8.01 years (55 men and 35 women). Outcomes of clinical evaluations were compared between sexes via a Student's t-test and within sex via a paired-sample t-test, and generalized linear models were established to identify factors associated with treatment efficacy and intensity for each sex. We found that subthalamic nucleus deep brain stimulation could improve motor symptoms in men but not women in the on-medication condition at 1 and 12 months post-operation. Restless legs syndrome was alleviated to a greater extent in men than in women. Women demonstrated poorer quality of life at baseline and achieved less improvement of quality of life than men after subthalamic nucleus deep brain stimulation. Furthermore, Hoehn-Yahr stage was positively correlated with the treatment response in men, while levodopa equivalent dose at 12 months post-operation was negatively correlated with motor improvement in women. In conclusion, women received less benefit from subthalamic nucleus deep brain stimulation than men in terms of motor symptoms, non-motor symptoms, and quality of life. We found sex-specific factors, i.e., Hoehn-Yahr stage and levodopa equivalent dose, that were related to motor improvements. These findings may help to guide subthalamic nucleus deep brain stimulation patient selection, prognosis, and stimulation programming for optimal therapeutic efficacy in Parkinson's disease.

Naphazoline and oxymetazoline are superior to epinephrine in enhancing the cutaneous analgesia of lidocaine in rats.

This study observed the cutaneous analgesic effect of adrenergic agonists when combined with lidocaine. We aimed at the usefulness of four adrenergic agonists and epinephrine as analgesics or as tools to prolong the effect of local anesthetics using a model of cutaneous trunci muscle reflex (pinprick pain) in rats. We showed that subcutaneous four adrenergic agonists and epinephrine, as well as the local anesthetic bupivacaine and lidocaine, developed a concentration-dependent cutaneous analgesia. The rank order of the efficacy of different compounds (ED50 ; median effective dose) was epinephrine [0.013 (0.012-0.014) µmol] > oxymetazoline [0.25 (0.22-0.28) µmol] > naphazoline [0.42 (0.34-0.53) µmol] = bupivacaine [0.43 (0.37-0.50) µmol] > xylometazoline [1.34 (1.25-1.45) µmol] > lidocaine [5.86 (5.11-6.72) µmol] > tetrahydrozoline [6.76 (6.21-7.36) µmol]. The duration of full recovery caused by tetrahydrozoline, oxymetazoline, or xylometazoline was greater (P < 0.01) than that induced via epinephrine, bupivacaine, lidocaine, or naphazoline at equianesthetic doses (ED25 , ED50 , and ED75 ). Co-administration of lidocaine (ED50 ) with four adrenergic agonists or epinephrine enhanced the cutaneous analgesic effect. We observed that four adrenergic agonists and epinephrine induce analgesia by themselves, and such an effect has a longer duration than local anesthetics. Co-administration of lidocaine with the adrenergic agonist enhances the analgesic effect, and the cutaneous analgesic effect of lidocaine plus naphazoline (or oxymetazoline) is greater than that of lidocaine plus epinephrine.

Synthesis and anti-HCC activity of full 2ʹ-F/OMe-siRNA encapsulated with neutral cytidinyl/cationic lipid / 药学学报

A variety of full 2ʹ-F/OMe-modified siRNAs were designed and synthesized, and the activity against hepatocellular carcinoma Huh-7 and HepG2 cells was evaluated. K&A DNA/RNA H-8 synthesizer was used to synthesize siRNAs, and neutral cytidinyl lipid DNCA mixed with cationic lipid CLD were used to transfect siRNA. By RT-qPCR and CCK-8 assay, the target gene silence and the proliferation of Huh-7 and HepG2 cells were detected. The siRNAs loading into Ago2 protein was detected by RNA-binding protein immunoprecipitation. Drug uptake and cell apoptosis were detected by flow cytometry, and the expression of PLK1 protein was detected by Western blot. Partial full 2ʹ-F/OMe modified siRNAs, especial siPLK1A3, increased the uptake of Huh-7 cells, enhanced their binding to Ago2 and gene silencing activity, down-regulated PLK1 protein, as well as induced more Huh-7 cell apoptosis and proliferation inhibition activity. It provides important data for the development of novel siRNA modification patterns and anti-HCC formulations.