Extracellular Vesicles and Cx43-Gap Junction Channels Are the Main Routes for Mitochondrial Transfer from Ultra-Purified Mesenchymal Stem Cells, RECs.

Mitochondria are essential organelles for maintaining intracellular homeostasis. Their dysfunction can directly or indirectly affect cell functioning and is linked to multiple diseases. Donation of exogenous mitochondria is potentially a viable therapeutic strategy. For this, selecting appropriate donors of exogenous mitochondria is critical. We previously demonstrated that ultra-purified bone marrow-derived mesenchymal stem cells (RECs) have better stem cell properties and homogeneity than conventionally cultured bone marrow-derived mesenchymal stem cells. Here, we explored the effect of contact and noncontact systems on three possible mitochondrial transfer mechanisms involving tunneling nanotubes, connexin 43 (Cx43)-mediated gap junction channels (GJCs), and extracellular vesicles (Evs). We show that Evs and Cx43-GJCs provide the main mechanism for mitochondrial transfer from RECs. Through these two critical mitochondrial transfer pathways, RECs could transfer a greater number of mitochondria into mitochondria-deficient (ρ0) cells and could significantly restore mitochondrial functional parameters. Furthermore, we analyzed the effect of exosomes (EXO) on the rate of mitochondrial transfer from RECs and recovery of mitochondrial function. REC-derived EXO appeared to promote mitochondrial transfer and slightly improve the recovery of mtDNA content and oxidative phosphorylation in ρ0 cells. Thus, ultrapure, homogenous, and safe stem cell RECs could provide a potential therapeutic tool for diseases associated with mitochondrial dysfunction.

MELAS-Derived Neurons Functionally Improve by Mitochondrial Transfer from Highly Purified Mesenchymal Stem Cells (REC).

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome, caused by a single base substitution in mitochondrial DNA (m.3243A>G), is one of the most common maternally inherited mitochondrial diseases accompanied by neuronal damage due to defects in the oxidative phosphorylation system. There is no established treatment. Our previous study reported a superior restoration of mitochondrial function and bioenergetics in mitochondria-deficient cells using highly purified mesenchymal stem cells (RECs). However, whether such exogenous mitochondrial donation occurs in mitochondrial disease models and whether it plays a role in the recovery of pathological neuronal functions is unknown. Here, utilizing induced pluripotent stem cells (iPSC), we differentiated neurons with impaired mitochondrial function from patients with MELAS. MELAS neurons and RECs/mesenchymal stem cells (MSCs) were cultured under contact or non-contact conditions. Both RECs and MSCs can donate mitochondria to MELAS neurons, but RECs are more excellent than MSCs for mitochondrial transfer in both systems. In addition, REC-mediated mitochondrial transfer significantly restored mitochondrial function, including mitochondrial membrane potential, ATP/ROS production, intracellular calcium storage, and oxygen consumption rate. Moreover, mitochondrial function was maintained for at least three weeks. Thus, REC-donated exogenous mitochondria might offer a potential therapeutic strategy for treating neurological dysfunction in MELAS.

Association of pediatric inguinal hernia contents with patient age and sex.

BACKGROUND: Although pediatric inguinal hernia (IH) is a very common disease, systematic reviews of herniated organs are scarce. The current study aims to clarify the contents of pediatric IH using preoperative ultrasonography (US) in association with patient age, sex, and risk for developing irreducible/strangulated hernia. METHODS: The medical records of pediatric IH patients who underwent inguinal US examination prior to surgery between 2014 and 2019 were reviewed. Hernia contents were categorized into four groups based on US findings: bowel, omentum, ovary with or without fallopian tube, and ascites. RESULTS: A total of 524 IH lesions found in 220 men and 304 women were analyzed. The most common hernia content in patients under 12 months of age was the bowel (91.0%) in males and ovaries (89.5%) in females. The omentum became the most common herniated organ in both men (78.6%) and women (88.0%) aged 2 years and older. Emergency operations were performed in 3 patients (0.57%) due to irreducible IH, where 2 patients with irreducible ovaries, 5 and 7 months old, developed ovarian torsion and needed to undergo emergent salpingo-oophorectomy. CONCLUSIONS: The contents of pediatric IH depended on patient age and sex. Herniated ovaries in infants can twist in the hernia sac and become strangulated. It is important for clinicians to expect the herniated organ and take appropriate measures in the pediatric primary care setting.

[Global Testicular Infarction during Treatment for Epididymitis].

We report a case of global testicular infarction associated with epididymitis. A 26-year-old man with a history of clean intermittent self-catheterization since he was 1 year old presented to our hospital with left scrotal pain and swelling. He was diagnosed with epididymitis and was prescribed levofloxacin. On the next day, he returned with worsened symptoms of left scrotal pain, swelling, and fever. He was admitted because of his severe symptoms and high C-reactive protein level in the blood test. Antimicrobial therapy with intravenous flomoxef and analgesic treatment with pentazocine and loxoprofen were started but the symptoms did not improve. The color-Doppler ultrasound repeated on the 1st, 4th, and 5th day of admission showed left epididymal hypervascularity but it did not indicate testicular hypovascularity in any examinations. On the 6th day of admission, a contrast-magnetic resonance imaging (MRI) scan revealed no contrast enhancement in the left testis and high orchiectomy was performed. On pathological examination, abscess of the entire epididymis and generalized necrosis of the testes were observed. Inflammatory cell infiltration and thrombus formation were observed in almost all veins of the testis and spermatic cord, and the diagnosis of global testicular infarction associated with epididymitis was made. Global testicular infarction has been reported as a rare complication of epididymitis and should be considered in the case of atypical course of epididymitis.

Prognostic value of hematological parameters in patients undergoing esophagectomy for esophageal squamous cell carcinoma.

BACKGROUND: It is now widely recognized that outcomes in cancer patients are not determined by their tumor characteristics alone. In this study, we retrospectively analyzed the clinical data of esophageal cancer patients to evaluate the impact of red blood cell distribution width (RDW), platelet distribution width (PDW), and mean platelet volume (MPV) on cancer-specific survival (CSS). STUDY DESIGN: We retrospectively reviewed a database of 144 consecutive patients who underwent curative esophagectomy for esophageal squamous cell carcinoma at our institute between 2006 and 2014. RESULT: In multivariate analysis, pathological stage (pStage) (p = 0.0002) and a high RDW (p = 0.0300) were found to be independently associated with poor survival. Patients with a high RDW had a significantly poorer prognosis in terms of CSS than those with a low RDW (p = 0.004). Among non-elderly patients, multivariate analysis demonstrated that pStage (p = 0.0120), and a high RDW (p = 0.0092) were independent risk factors for a worse prognosis. In addition, non-elderly patients with a high RDW had a significantly poorer prognosis in terms of CSS than those with a low RDW (p = 0.0003). On the other hand, univariate analysis demonstrated that pStage (p = 0.0008) was the only significant risk factor for a poor prognosis in elderly patients. CONCLUSIONS: We confirmed that a high RDW was significantly associated with the CSS of esophageal cancer patients after curative esophagectomy. Furthermore, in non-elderly patients, a high RDW was a significant and independent predictor of poor survival.

Prognostic value of preoperative inflammatory response biomarkers in patients with esophageal cancer who undergo a curative thoracoscopic esophagectomy.

BACKGROUND: Several inflammatory response biomarkers, including lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) have been reported to predict survival in various cancers. The aim of this study is to evaluate the clinical value of these biomarkers in patients undergoing curative resection for esophageal cancer. METHODS: The LMR, NLR and PLR were calculated in 147 consecutive patients who underwent esophagectomy between January 2006 and February 2015. We examined the prognostic significance of the LMR, NLR, and PLR in both elderly and non-elderly patients. We evaluated the cancer-specific survival (CSS), with the cause of death determined from the case notes or computerized records. RESULTS: Univariate analyses demonstrated that TNM pStage (p < 0.0001), tumor size (p = 0.0014), operation time (p = 0.0209), low LMR (p = 0.0008), and high PLR (p = 0.0232) were significant risk factors for poor prognosis. Meanwhile, TNM pStage (p < 0.0001) and low LMR (p = 0.0129) were found to be independently associated with poor prognosis via multivariate analysis. In non-elderly patients, univariate analyses demonstrated that TNM pStage (p < 0.0001), tumor size (p = 0.0001), operation time (p = 0.0374), LMR (p < 0.0001), and PLR (p = 0.0189) were significantly associated with a poorer prognosis. Multivariate analysis demonstrated that TNM pStage (p = 0.001) and LMR (p = 0.0007) were independent risk factors for a poorer prognosis. In elderly patients, univariate analysis demonstrated that that TNM pStage (p = 0.0023) was the only significant risk factor for a poor prognosis. CONCLUSIONS: LMR was associated with cancer-specific survival (CSS) of esophageal cancer patients after curative esophagectomy. In particular, a low LMR was a significant and independent predictor of poor survival in non-elderly patients. The LMR was convenient, cost effective, and readily available, and could thus act as markers of survival in esophageal cancer.

Open Gastrostomy by Mini-Laparotomy: Our Method.

When percutaneous endoscopic gastrostomy (PEG) is not feasible owing to anatomical obstacles, laparotomic or laparoscopic gastrostomy (LAG) is an alternative. At our institution, LAG has been the first choice for patients who are unable to undergo PEG; however, we have introduced a small open gastrostomy through a 2-cm-long transverse incision since 2020. By December 2022, 12 patients had undergone this procedure without complications. In one case where the stomach was located cephalad to the rib arch and the patient had a round dorsum, the incision wound was extended, and a lengthy operation was required. We believe that our small-incision gastrostomy is a useful option in addition to LAG for cases in which PEG is difficult to perform. Further studies are required to determine the indications for this procedure.