Embarking on life's blueprint: investigating the crucial involvement of extracellular vesicles in embryo development.

Extracellular vesicles (EVs) contain biological molecules, such as proteins, lipids, and diverse nucleic acids, which alter various physiological and pathological processes in recipient cells. This review examines the current understanding of EVs in terms of their biological characteristics, effects on embryonic development, and potential therapeutic value in treating reproductive disorders. EVs play a crucial role in early embryonic development, from fertilization to the pre-implantation stage, as well as during gastrulation, cell differentiation, and organogenesis. In the pre-implantation period, EVs interact with maternal reproductive tissue and promote implantation receptivity, whereas during gastrulation, they regulate cell differentiation and contribute to tissue formation and maintenance. Abnormal bioactive molecules in EVs are associated with developmental disorders; therefore, EVs can serve as biomarkers. In addition, EVs are potential therapeutic agents that can deliver genetic material to targeted tissues or organs. The findings of this review highlight the potential role of EVs in intercellular signaling during embryonic development. This will help advance assisted reproductive technologies and therapies to overcome infertility and developmental disorders.

Increased alertness and moderate ingroup cohesion in bonobos' response to outgroup cues.

In a number of species, including humans, perceived outgroup threat can promote ingroup cohesion. However, the distribution and selection history of this association across species with varied intergroup relations remains unclear. Using a sample of 8 captive groups (N = 43 individuals), we here tested whether bonobos, like chimpanzees, show more affiliative ingroup behaviour following perception of outgroup cues (unfamiliar male long-distance vocalisations). We used comparable methods to our previous study of captive chimpanzees, and found that, although weaker, there was an association for more frequent social grooming in response to the outgroup condition than the control condition, alongside more alert posture and increased self-directed behaviour. This provides preliminary evidence for an ancestral origin to the proximate association between outgroup cues and ingroup cohesion, at least prior to the Pan-Homo split, and suggests the presence of intergroup competition in our last common ancestor.

Discovery of novel disease-causing mutation in SSBP1 and its correction using adenine base editor to improve mitochondrial function.

Mutations in nuclear genes regulating mitochondrial DNA (mtDNA) replication are associated with mtDNA depletion syndromes. Using whole-genome sequencing, we identified a heterozygous mutation (c.272G>A:p.Arg91Gln) in single-stranded DNA-binding protein 1 (SSBP1), a crucial protein involved in mtDNA replisome. The proband manifested symptoms including sensorineural deafness, congenital cataract, optic atrophy, macular dystrophy, and myopathy. This mutation impeded multimer formation and DNA-binding affinity, leading to reduced efficiency of mtDNA replication, altered mitochondria dynamics, and compromised mitochondrial function. To correct this mutation, we tested two adenine base editor (ABE) variants on patient-derived fibroblasts. One variant, NG-Cas9-based ABE8e (NG-ABE8e), showed higher editing efficacy (≤30%) and enhanced mitochondrial replication and function, despite off-target editing frequencies; however, risks from bystander editing were limited due to silent mutations and off-target sites in non-translated regions. The other variant, NG-Cas9-based ABE8eWQ (NG-ABE8eWQ), had a safer therapeutic profile with very few off-target effects, but this came at the cost of lower editing efficacy (≤10% editing). Despite this, NG-ABE8eWQ-edited cells still restored replication and improved mtDNA copy number, which in turn recovery of compromised mitochondrial function. Taken together, base editing-based gene therapies may be a promising treatment for mitochondrial diseases, including those associated with SSBP1 mutations.

Momordica cochinchinensis extract alleviates oxidative stress and skin damage caused by fine particulate matter.

Momordica cochinchinensis (MC), commonly known as gac fruit, is a tropical fruit rich in antioxidants and bioactive compounds. This research aimed to elucidate the effect of MC on apoptosis induced by fine particulate matter with a diameter of less than 10 µm (< PM10) in epidermal keratinocyte HaCaT cells. We found that PM10 significantly diminish the viability of HaCaT cells through cytotoxic mechanisms. However, the treatment with MC at a concentration of 10 µg/mL notably restored the cellular viability decreased by PM10. MC reduced the activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) by mainly preventing the generation of reactive oxygen species (ROS) in HaCaT cells subjected to PM10. Furthermore, MC exhibited a regulatory effect on the expression of genes associated with apoptosis, including B-Cell Lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), and cleaved caspase-3 by inhibiting the activation of the transcription factor nuclear factor-kappa B (NF-κB). These findings demonstrate that MC aids in neutralizing the apoptotic signaling pathway of free radicals produced by environmental pollutants such as PM10, which have the potential to damage skin cells and accelerate the aging process.

Mechanisms of sensory adaptation and inhibition of the cold and menthol receptor TRPM8.

Our sensory adaptation to cold and chemically induced coolness is mediated by the intrinsic property of TRPM8 channels to desensitize. TRPM8 is also implicated in cold-evoked pain disorders and migraine, highlighting its inhibitors as an avenue for pain relief. Despite the importance, the mechanisms of TRPM8 desensitization and inhibition remained unclear. We found, using cryo-electron microscopy, electrophysiology, and molecular dynamics simulations, that TRPM8 inhibitors bind selectively to the desensitized state of the channel. These inhibitors were used to reveal the overlapping mechanisms of desensitization and inhibition and that cold and cooling agonists share a common desensitization pathway. Furthermore, we identified the structural determinants crucial for the conformational change in TRPM8 desensitization. Our study illustrates how receptor-level conformational changes alter cold sensation, providing insights into therapeutic development.

Risk of Cardiovascular Events Associated with Chronic Obstructive Pulmonary Disease and/or Metabolic Syndrome: A Large-Scale Nationwide Population-Based Cohort Study.

Purpose: Chronic obstructive pulmonary disease (COPD) and metabolic syndrome (MetS) are among the most prevalent conditions that might predispose individuals to life-threatening events. We aimed to examine their associations with cardiovascular (CV) events and mortality using a large-scale population dataset from the National Health Information Database in Korea. Patients and Methods: This population-based cohort study enrolled adults aged ≥40 years who had undergone more than two health examinations between 2009 and 2011. They were divided into four groups based on the presence of COPD and MetS. Analysis of the outcomes and CV events or deaths was performed from 2014 to 2019. We compared CV event incidence and mortality rates using a multivariate Cox proportional hazards model and Kaplan-Meier curves. Results: Totally, 5,101,810 individuals were included, among whom 3,738,458 (73.3%) had neither COPD nor MetS, 1,193,014 (23.4%) had only MetS, 125,976 (2.5%) had only COPD, and 44,362 (0.9%) had both. The risk of CV events was significantly higher in individuals with both COPD and MetS than in those with either COPD or MetS alone (HRs: 2.4 vs 1.6 and 1.8, respectively; all P <0.001). Similarly, among those with both COPD and MetS, all-cause and CV mortality risks were also elevated (HRs, 2.9 and 3.0, respectively) compared to the risks in those with either COPD (HRs, 2.6 and 2.1, respectively) or MetS (HRs, 1.7 and 2.1, respectively; all P <0.001). Conclusion: The comorbidity of MetS in patients with COPD increases the incidence of CV events and all-cause and cardiovascular mortality rates.

Combined clinical, structural, and cellular studies discriminate pathogenic and benign TRPV4 variants.

Dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) cause diverse and largely distinct channelopathies, including inherited forms of neuromuscular disease, skeletal dysplasias, and arthropathy. Pathogenic TRPV4 mutations cause gain of ion channel function and toxicity that can be rescued by small molecule TRPV4 antagonists in cellular and animal models, suggesting that TRPV4 antagonism could be therapeutic for patients. Numerous variants in TRPV4 have been detected with targeted and whole exome/genome sequencing, but for the vast majority, their pathogenicity remains unclear. Here, we used a combination of clinical information and experimental structure-function analyses to evaluate 30 TRPV4 variants across various functional protein domains. We report clinical features of seven patients with TRPV4 variants of unknown significance and provide extensive functional characterization of these and an additional 17 variants, including structural position, ion channel function, subcellular localization, expression level, cytotoxicity, and protein-protein interactions. We find that gain-of-function mutations within the TRPV4 intracellular ankyrin repeat domain target charged amino acid residues important for RhoA interaction, whereas ankyrin repeat domain residues outside of the RhoA interface have normal or reduced ion channel activity. We further identify a cluster of gain-of-function variants within the intracellular intrinsically disordered region that may cause toxicity via altered interactions with membrane lipids. In contrast, assessed variants in the transmembrane domain and other regions of the intrinsically disordered region do not cause gain of function and are likely benign. Clinical features associated with gain of function and cytotoxicity include congenital onset of disease, vocal cord weakness, and motor predominant disease, whereas patients with likely benign variants often demonstrated late-onset and sensory-predominant disease. These results provide a framework for assessing additional TRPV4 variants with respect to likely pathogenicity, which will yield critical information to inform patient selection for future clinical trials for TRPV4 channelopathies.

Comparative analysis of reduced toxicity conditioning regimens between fludarabine plus melphalan and fludarabine plus busulfex in adult patients with acute lymphoblastic leukemia.

Reduced-toxicity conditioning (RTC) regimens aim to mitigate regimen-related toxicity while maintaining anti-leukemic efficacy in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We assessed outcomes of RTC regimens utilizing melphalan versus intravenous busulfan combined with fludarabine in adult acute lymphoblastic leukemia (ALL) patients. A retrospective analysis was conducted with 149 consecutive adult ALL patients (median age 51, range 18-60) in remission undergoing allo-HSCT. Patients received either fludarabine 150 mg/BSA plus 2 days of melphalan 70 mg/BSA (FM140, n = 76) from 2009 to 2015 or fludarabine plus 3 days of busulfan 3.2 mg/kg (FB9.6, n = 73) from 2016 to 2021. At 5 years post-HSCT, FM140 demonstrated superior disease-free survival (53.4% vs. 30.5%, p = 0.007) and lower cumulative relapse (27.4% vs. 46.8%, p = 0.026) than FB9.6. Five-year overall survival and non-relapse mortality did not significantly differ. FM140 exhibited a higher incidence of acute graft-versus-host disease (GVHD) grades II-IV (49.3% vs. 30.3%, p = 0.016), though rates of acute GVHD grades III-IV and chronic GVHD were similar. Multivariate analysis identified Philadelphia chromosome and minimal residual disease positive status, and FB9.6 conditioning as predictors of increased relapse and poorer disease-free survival. FM140 RTC regimen displayed significantly reduced relapse and superior disease-free survival compared to FB9.6 in ALL patients undergoing allo-HSCT, highlighting its current clinical utility.

Enhanced efficacy of glycoengineered rice cell-produced trastuzumab.

For several decades, a plant-based expression system has been proposed as an alternative platform for the production of biopharmaceuticals including therapeutic monoclonal antibodies (mAbs), but the immunogenicity concerns associated with plant-specific N-glycans attached in plant-based biopharmaceuticals has not been completely solved. To eliminate all plant-specific N-glycan structure, eight genes involved in plant-specific N-glycosylation were mutated in rice (Oryza sativa) using the CRISPR/Cas9 system. The glycoengineered cell lines, PhytoRice®, contained a predominant GnGn (G0) glycoform. The gene for codon-optimized trastuzumab (TMab) was then introduced into PhytoRice® through Agrobacterium co-cultivation. Selected cell lines were suspension cultured, and TMab secreted from cells was purified from the cultured media. The amino acid sequence of the TMab produced by PhytoRice® (P-TMab) was identical to that of TMab. The inhibitory effect of P-TMab on the proliferation of the BT-474 cancer cell line was significantly enhanced at concentrations above 1 µg/mL (****P < 0.0001). P-TMab bound to a FcγRIIIa variant, FcγRIIIa-F158, more than 2.7 times more effectively than TMab. The ADCC efficacy of P-TMab against Jurkat cells was 2.6 times higher than that of TMab in an in vitro ADCC assay. Furthermore, P-TMab demonstrated efficient tumour uptake with less liver uptake compared to TMab in a xenograft assay using the BT-474 mouse model. These results suggest that the glycoengineered PhytoRice® could be an alternative platform for mAb production compared to current CHO cells, and P-TMab has a novel and enhanced efficacy compared to TMab.

Population pharmacokinetic modeling of sufentanil in adult Korean patients undergoing cardiopulmonary bypass surgery.

Sufentanil is frequently used as an anesthetic agent in cardiac surgery owing to its cardiovascular safety and favorable pharmacokinetics. However, the pharmacokinetics profiles of sufentanil in patients undergoing cardiopulmonary bypass (CPB) surgery remain less understood, which is crucial for achieving the desired level of anesthesia and mitigating surgical complications. Therefore, this study aimed to develop a population pharmacokinetic model of sufentanil in patients undergoing CPB surgery and elucidate the clinical factors affecting its pharmacokinetic profile. Adult patients who underwent cardiac surgery with CPB and were administered sufentanil for anesthesia were enrolled. Arterial blood samples were collected to quantify plasma concentrations of sufentanil and clinical laboratory parameters, including inflammatory cytokines. A population pharmacokinetic model was established using nonlinear mixed-effects modeling. Simulations were performed using the pharmacokinetic parameters of the final model. Overall, 20 patients were included in the final analysis. Sufentanil pharmacokinetics were modeled using a two-compartment model, accounting for CPB effects. Sufentanil clearance increased 2.80-fold during CPB and warming phases, while the central compartment volume increased 2.74-fold during CPB. CPB was a significant covariate affecting drug clearance and distribution volume. No other significant covariates were identified despite increased levels of the inflammatory cytokines, including IL-6, IL-8, and TNF-α during CPB. The simulation indicated a 30 µg loading dose and 40 µg/h maintenance infusion for target-controlled infusion. Additionally, a bolus dose of 60 µg was added at CPB initiation to adjust for exposure changes during this phase. Considering the target sufentanil concentrations, a uniform dosing regimen was acceptable for effective analgesia.

Receptor mediated biological activities of phytoestrogens.

Phytoestrogens are plant-derived compounds that have chemical structures and functions similar to estrogen. Phytoestrogens act as ligand-inducible transcription factors involved in cellular growth by binding to estrogen receptors (ERs), specifically ER alpha (ERα) and beta (ERß). Through this mechanism, phytoestrogens have a physiological function similar to that of the female hormone 17ß-estradiol (E2), which can be useful in treating osteoporosis, cardiovascular disease, and cancer. Furthermore, phytoestrogens have been found to elicit various cellular responses depending on their affinity for ERs; in particular, they show a greater affinity with for ERß. This study aimed to comprehensively analyze the mode of action of eight phytoestrogens, namely kaempferol, coumestrol, glycitein, apigenin, daidzein, genistein, equol, and resveratrol, by evaluating their estrogenic activity as ER ligands. Based on the bioluminescence resonance energy transfer (BRET)-based ER dimerization and transactivation assay results, all the phytoestrogens tested were identified as estrogen agonists by mediating ERα and ERß dimerization. The specific binding and functions of ERα and ERß were distinguished by differentiating between their dimerization activity. In addition, this study contributes to advancing our understanding of the overall mechanism of action involving both ERs.

A clinical application for arterial coupling and histomorphometric comparison of internal mammary and thoracodorsal arteries for safe use.

BACKGROUND: In breast reconstruction, arterial coupling has been reported to be more favorable in the thoracodorsal artery (TDA) than the internal mammary artery (IMA). This technique may help overcome anastomosis in a small, deep space. Understanding the arteries' mechanical properties is crucial for breast reconstruction's safety and success. METHODS: Abdominal-based free flap breast reconstructions performed by a single surgeon between 2020 and 2022 were retrospectively analyzed. The patients were classified by microanastomosis technique (handsewn and coupler device) to compare the rate of vascular revision. Histomorphometric analysis of arterial coupling in TDA and IMA was performed in 10 fresh cadavers for comparing wall thickness and composition, including densities of elastic fiber, smooth muscle, and collagen. RESULTS: A total of 309 patients (339 reconstructed breasts) were included. There were 29 patients in the TDA handsewn group (A), 38 patients in the TDA coupler group (B), and 242 patients in the IMA handsewn group (C). The rates of arterial revision in groups A, B, and C were 0.00% (95%CI: 0.00%-11.03%), 2.5% (95%CI: 0.44%-12.88%), and 1.49% (95%CI: 0.58%-3.77%), respectively, with no statistically significant differences (p-value = .694). Histologically, the thickness of the tunica media and adventitia between IMA and TDA showed no significant difference. The density of elastic fiber was significantly higher in IMA (16.70%) than in TDA (0.79%) (p-value <.001). CONCLUSION: The histologic characteristics of TDA are more favorable for arterial coupling than those of IMA. Arterial coupling is a safe option in situations where TDA anastomosis must be performed through a narrow and deep incision.

Risk of lung diseases in patients with previous carbon monoxide poisoning: a nationwide population-based cohort study in the Republic of Korea.

INTRODUCTION: Carbon monoxide poisoning is associated with severe damage to various organs. In this study, we aimed to determine if previous carbon monoxide poisoning was associated with an increased risk of lung diseases. METHODS: The study population was derived from the National Health Insurance Service database of Korea between 1 January 2002 and 31 December 2021. Adults with carbon monoxide poisoning, with at least one visit to medical facilities between 2002 and 2021, were included. For comparison, an equal number of matched controls with the same index date were selected from the database. RESULTS: A total of 28,618 patients with carbon monoxide poisoning and 28,618 matched controls were included in this study. Approximately 42.8 per cent of the patient and control groups were female, with a mean age of 51.3 years. In patients with carbon monoxide poisoning, there was a significant increase in the risk of lung cancer (adjusted hazard ratio, 1.84; 95 per cent confidence interval, 1.42-2.39; P < 0.001), chronic obstructive pulmonary disease (adjusted hazard ratio, 1.60; 95 per cent confidence interval, 1.36-1.89; P < 0.001), pulmonary tuberculosis (adjusted hazard ratio, 1.46; 95 per cent confidence interval, 1.13-1.88; P = 0.003), and non-tuberculous mycobacterial infection (adjusted hazard ratio, 1.54; 95 per cent confidence interval, 1.01-2.36; P = 0.047). DISCUSSION: In this retrospective cohort study, previous carbon monoxide poisoning was associated with an increased risk of lung cancer, chronic obstructive pulmonary disease, pulmonary tuberculosis, and non-tuberculous mycobacterial infection. Further studies are needed to confirm such an association in other populations and the risk of lung diseases due to the toxic effect of carbon monoxide from different sources. CONCLUSIONS: Previous carbon monoxide poisoning was associated with an increased risk of lung diseases, but the relative importance of the causes and sources of exposure was not known. The long-term management of survivors of acute carbon monoxide poisoning should include monitoring for lung cancer, chronic obstructive pulmonary disease, pulmonary tuberculosis, and non-tuberculous mycobacterial infection.

Cinnamaldehyde-Treated Bone Marrow Mesenchymal-Stem-Cell-Derived Exosomes via Aqueous Two-Phase System Attenuate IL-1ß-Induced Inflammation and Catabolism via Modulation of Proinflammatory Signaling Pathways.

Osteoarthritis (OA) is a degenerative joint disorder that is distinguished by inflammation and chronic cartilage damage. Interleukin-1ß (IL-1ß) is a proinflammatory cytokine that plays an important role in the catabolic processes that underlie the pathogenesis of OA. In this study, we investigate the therapeutic efficacy of exosomes derived from untreated bone-marrow-derived mesenchymal stem cells (BMMSC-Exo) and those treated with cinnamaldehyde (BMMSC-CA-Exo) for preventing the in vitro catabolic effects of IL-1ß on chondrocytes. We stimulated chondrocytes with IL-1ß to mimic the inflammatory microenvironment of OA. We then treated these chondrocytes with BMMSC-Exo and BMMSC-CA-Exo isolated via an aqueous two-phase system and evaluated their effects on the key cellular processes using molecular techniques. Our findings revealed that treatment with BMMSC-Exo reduces the catabolic effects of IL-1ß on chondrocytes and alleviates inflammation. However, further studies directly comparing treatments with BMMSC-Exo and BMMSC-CA-Exo are needed to determine if CA preconditioning can provide additional anti-inflammatory benefits to the exosomes beyond those of CA preconditioning or treatment with regular BMMSC-Exo. Through a comprehensive molecular analysis, we elucidated the regulatory mechanisms underlying this protective effect. We found a significant downregulation of proinflammatory signaling pathways in exosome-infected chondrocytes, suggesting the potential modulation of the NF-κB and MAPK signaling cascades. Furthermore, our study identified the molecular cargo of BMMSC-Exo and BMMSC-CA-Exo, determining the key molecules, such as anti-inflammatory cytokines and cartilage-associated factors, that may contribute to their acquisition of chondroprotective properties. In summary, BMMSC-Exo and BMMSC-CA-Exo exhibit the potential as therapeutic agents for OA by antagonizing the in vitro catabolic effects of IL-1ß on chondrocytes. The regulation of the proinflammatory signaling pathways and bioactive molecules delivered by the exosomes suggests a multifaceted mechanism of action. These findings highlight the need for further investigation into exosome-based therapies for OA and joint-related diseases.

A bifunctional MoS2/SGCN nanocatalyst for the electrochemical detection and degradation of hazardous 4-nitrophenol.

Herein, we reported the dual functions of molybdenum disulfide/sulfur-doped graphitic carbon nitride (MoS2/SGCN) composite as a sensing material for electrochemical detection of 4-NP and a catalyst for 4-NP degradation. The MoS2 nanosheet, sulfur-doped graphitic carbon nitride (SGCN) and MoS2/SGCN were characterized using field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD) spectroscopy and X-ray photoelectron spectroscopy (XPS). Electrochemical characterization of these materials with electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) in 1 mM K4[Fe(CN)6]3-/4- show that the composite has the lowest charge transfer resistance and the best electrocatalytic activity. The limit of detection (LOD) and the linear range of 4-nitrophenol at MoS2/SGCN modified glassy carbon electrode (MoS2/SGCN/GCE) were computed as 12.8 nM and 0.1 - 2.6 µM, respectively. Also, the percentage recoveries of 4-NP in spiked tap water samples ranged from 97.8 - 99.1 %. The electroanalysis of 4-NP in the presence of notable interferons shows that the proposed electrochemical sensor features outstanding selectivity toward 4-NP. Additionally, the results of the catalytic degradation of 4-NP at MoS2/SGCN show that the nanocatalyst catalyzed the transformation of 4-NP to 4-aminophenol (4-AP) with a first-order rate constant (k) estimated to be 4.2 ×10-2 s-1. The results of this study confirm that the MoS2/SGCN nanocatalyst is a useful implement for electroanalytical monitoring and catalytic degradation of the hazardous 4-NP in water samples.

Monolithic DNApatite: An Elastic Apatite with Sub-Nanometer Scale Organo-Inorganic Structures.

Hydroxyapatite (HA) exhibits outstanding biocompatibility, bioactivity, osteoconductivity, and natural anti-inflammatory properties. Pure HA, ion-doped HA, and HA-polymer composites are investigated, but critical limitations such as brittleness remain; numerous efforts are being made to address them. Herein, the novel self-crystallization of a polymeric single-stranded deoxyribonucleic acid (ssDNA) without additional phosphate ions for synthesizing deoxyribonucleic apatite (DNApatite) is presented. The synthesized DNApatite, DNA1Ca2.2(PO4)1.3OH2.1, has a repetitive dual phase of inorganic HA crystals and amorphous organic ssDNA at the sub-nm scale, forming nanorods. Its mechanical properties, including toughness and elasticity, are significantly enhanced compared with those of HA nanorod, with a Young's modulus similar to that of natural bone.

Long-Term Care Insurance for Older Adults in Terms of Community Care in South Korea: Using the Framework Method.

This study aimed to analyze the long-term care insurance for older adults in South Korea in terms of community care. An analytical framework was designed for the study, focusing on comprehensiveness, adequacy, and integration. The findings suggest that Korean LTCI is significantly limited for the development of community care. First, in terms of comprehensiveness, the use of visiting nurses and the availability of short-stay services have been significantly reduced, and the supporting services for informal caregivers are at the beginning stage of their introduction. Second, in terms of adequacy, the quantity of benefits, such as three to four hours of care a day, are insufficient to meet older adults' substantial needs. Furthermore, the overall quality of home care services is low, particularly with regard to short-stay services and welfare equipment. Finally, in terms of integration, basic linkage of organizations has not been properly conducted in local areas, and there remains an absence of care managers in the LTCI system. To cope with these challenging issues, the following policy measures are suggested: the activation of rehabilitation services, the expansion of benefit quantities, the improvement of service quality, and the creation of organizational linkages through local authorities and long-term care centers.

Treatment of chronic mini-thoracotomy wound pain and lung herniation with intercostal cryoablation and surgical mesh repair: a case report.

BACKGROUND: The incidence of minimally invasive heart surgery via mini-thoracotomy (MT; right anterior thoracotomy) is on the rise, accompanied by an increase in post-MT intercostal nerve neuralgia and the risk of lung herniation through the incision site. While various methods have been proposed to address these issues, none have been commonly effective. In this case report, we attempted to simultaneously address these problems by performing intercostal cryoablation (IC) and mesh repair. CASE PRESENTATION: A 43-year-old male was referred to our hospital for chronic post-thoracotomy neuralgia following heart surgery via MT, involving patch closure of an atrial septal defect and tricuspid annuloplasty. He presented with intercostal nerve neuralgia and lung herniation accompanied by severe pain. Despite medication and lidocaine injections, there was no relief. Consequently, he underwent surgical treatment with IC for chronic MT wound pain and simultaneously underwent mesh repair for a lung hernia. He was discharged from hospital free of complications. Subsequently, he no longer required further pain medication and experienced a favorable recovery. CONCLUSION: Our findings suggest that concurrent IC and mesh repair can effectively relieve chronic post-MT intercostal nerve neuralgia and severe lung herniation pain in patients who underwent MT surgery, leading to a decrease in opioid medication usage.

Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target.

MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities.

The effect of preoperative botulinum toxin a injection on traction force during hernia repair: a prospective, single-blind study, intra-patient comparison using contralateral side as a control.

PURPOSE: Ventral hernias are a common complication of laparotomy, posing challenges particularly when primary fascial closure is unattainable. Although chemical component separation using preoperative botulinum toxin A (BTX) injections has emerged as a promising adjunct, objective evidence of its efficacy remains limited. This study aimed to objectively assess the effect of preoperative BTX on traction force during ventral hernia repair. METHODS: A prospective, single-blind study was conducted on patients with midline incisional hernias following liver transplantation. BTX was administered unilaterally, and the traction force required to medially advance the anterior rectus sheath was measured intraoperatively. Pre- and post-injection CT scans were analyzed for changes in hernia size and LAW muscle measurements. Statistical analyses were performed to evaluate traction force differences between BTX-injected and uninjected sides. RESULTS: Ten patients underwent hernia repair with primary fascial closure achieved in all cases. Comparison of pre- and post-injection CT scans showed no significant changes in hernia size. LAW muscle length increased by 1.8 cm, while thickness decreased by 0.2 cm. Intraoperative traction force measurements revealed a significant reduction on the BTX-injected side compared to the uninjected side (p < 0.0001). The traction force ratio on the BTX-injected to the uninjected side averaged 57%, indicating the efficacy of BTX in reducing tension. CONCLUSION: Preoperative BTX significantly reduces traction force during ventral hernia repair, highlighting its potential as an adjunctive therapy in complex cases. While challenges remain in patient selection and outcome assessment, BTX offers a promising avenue for enhancing abdominal wall reconstruction outcomes and reducing surgical complications.