Effects of hindlimb unloading on the mevalonate and mechanistic target of rapamycin complex 1 signaling pathways in a fast-twitch muscle in rats.

Fast-twitch muscles are less susceptible to disuse atrophy, activate the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, and increase protein synthesis under prolonged muscle disuse conditions. However, the mechanism underlying prolonged muscle disuse-induced mTORC1 signaling activation remains unclear. The mevalonate pathway activates the mTORC1 signaling pathway via the prenylation and activation of Ras homolog enriched in brain (Rheb). Therefore, we investigated the effects of hindlimb unloading (HU) for 14 days on the mevalonate and mTORC1 signaling pathways in the plantaris muscle, a fast-twitch muscle, in adult male rats. Rats were divided into HU and control groups. The plantaris muscles of both groups were harvested after the treatment period, and the expression and phosphorylation levels of metabolic and intracellular signaling proteins were analyzed using Western blotting. We found that HU increased the expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme of the mevalonate pathway, and activated the mTORC1 signaling pathway without activating AKT, an upstream activator of mTORC1. Furthermore, HU increased prenylated Rheb. Collectively, these findings suggest that the activated mevalonate pathway may be involved in the activation of the Rheb/mTORC1 signaling pathway without AKT activation in fast-twitch muscles under prolonged disuse conditions.

Noniatrogenic Meningitis Caused by Streptococcus salivarius Associated with Early Esophageal Cancer and Early Gastric Cancer.

Streptococcus salivarius is part of the normal oral cavity and gastrointestinal tract microflora and an unusual cause of acute bacterial meningitis. We herein report an 81-year-old man with S. salivarius meningitis, which led to a diagnosis of early esophageal cancer and early gastric cancer. S. salivarius infection may occur through the gastrointestinal mucosa when it is disrupted in association with early gastrointestinal cancer. To our knowledge, this is the first report describing S. salivarius meningitis associated with multiple early gastrointestinal cancers in the absence of other sources of infection.

Evolution of open aneurysmorrhaphy for management of sac expansion after endovascular repair of abdominal aortic aneurysms.

OBJECTIVE: We evaluated the perioperative and mid-term clinical outcomes of open aneurysmorrhaphy (OA) for the treatment of sac expansion after endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms. METHODS: OA involves sac exposure without dissection of the proximal or distal neck, sacotomy and ligation of back-bleeding vessels, preservation of the prior stent graft, and tight closure of the sac around the stent graft. We performed a retrospective review of all patients who had undergone OA for nonruptured sac expansion after standard EVAR at our institution between January 2015 and June 2021. The primary end points were 30-day mortality and aneurysm-related death. The secondary end points were postoperative complications, overall survival, freedom from reintervention, and sac regrowth rate. RESULTS: A total of 28 patients had undergone OA. Their mean age was 76.9 ± 6.7 years. The median sac diameter at OA was 79 mm (interquartile range [IQR], 76-92 mm). The median duration from the index EVAR to OA was 82 months (IQR, 72-104 months). Preoperative computed tomography angiography confirmed a type II endoleak (EL) in 20 patients, 1 of whom had had a coexisting type Ia EL; a type IIIb EL was identified in 1 patient. Concomitant endovascular procedures had been performed in six patients to treat a type I or III EL or reinforce the proximal and distal seals. The OA technique has been modified since 2017, with the addition of more aggressive dissection of the sac and complete removal of the mural thrombus to further decrease the sac diameter. Postoperative complications occurred in two patients and included abdominal lymphorrhea and failed hemostasis of the common femoral artery requiring surgical repair in one patient each. The 30-day mortality was 0%. During the median follow-up of 36 months (IQR, 14-51 months), the overall survival was 92.7% and 86.9% at 12 and 36 months, respectively, without any aneurysm-related death. In the late (2017-2021) treatment group, the median sac diameter immediately after OA was smaller than that in the early (2015-2016) treatment group (early group: median, 50 mm; IQR, 39-57 mm; vs later group: median, 41 mm; IQR, 32-47 mm; P = .083). Furthermore, in the late group, the sac regrowth rate was lower (early group: median, 0.36 mm/mo; IQR, 0.23-0.83 mm/mo; vs late group: median, 0 mm/mo; IQR, 0-0.11 mm/mo; P = .0075) and the freedom from reintervention rate was higher (late group: 94.7% at both 12 and 36 months, respectively; early group: 71.4% and 53.6% at 12 and 36 months, respectively; log-rank P = .070). CONCLUSIONS: Our results have shown that OA for the management of post-EVAR sac expansion is feasible with acceptable mid-term outcomes. Aggressive dissection and tight plication of the sac might be imperative for better mid-term outcomes after OA.

An autopsy case of retrograde in situ branched stent grafting for a complex aortic arch aneurysm.

Although retrograde in situ branched stent grafting (RIBS) is one possible treatment option for thoracic aortic aneurysms, concerns exist regarding the durability of the stent graft (SG) at the junction between the main SG and the branched SG. We report on the autopsy results of a patient treated with RIBS for a complex aortic arch aneurysm. The patient had died of a nonaortic cause 14 months after the RIBS procedure. On computed tomography analysis and a leak test, the harvested SG was intact without any stent fracture, stenosis, or junctional leak at 1 atm water pressure (760 mm Hg).

A case of methotrexate-associated Epstein-Barr virus-positive mucocutaneous ulcer.

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a B-cell proliferative disorder that has been designated as a provisional entity in the 2017 World Health Organization classification for lymphoid neoplasms. While EBVMCU may contain varying numbers of cells with Hodgkin and Reed-Sternberg cells-like morphology, the clinical course is benign and must be distinguished from lymphomas. Patients who develop EBVMCU are commonly immunocompromised, with methotrexate (MTX) as the leading cause. Most previously reported cases of EBVMCU describe mucosal ulcers with very little documentation on skin lesions and its course. Here, we report a case of MTX-associated EBVMCU of the lower leg that underwent spontaneous regression after MTX withdrawal, during which negative conversion of local Epstein-Barr virus activation was confirmed.

Fast evaluation technique for the shear viscosity and ionic conductivity of electrolyte solutions.

With the growing need to obtain ideal materials for various applications, there is an increasing interest in computational methods to rapidly and accurately search for materials. Molecular dynamics simulation is one of the successful methods used to investigate liquid electrolytes with high transport properties applied in lithium-ion batteries. However, further reduction in computational cost is required to find a novel material with the desired properties from a large number of combinations. In this study, we demonstrate an effective fast evaluation technique for shear viscosity and ionic conductivity by molecular dynamics simulation for an exhaustive search of electrolyte materials with high transport properties. The proposed model was combined with a short-time correlation function of the stress tensor and empirical relationships to address the issues of inefficient and uncertain evaluation by conventional molecular dynamics methods. Because we focus on liquid electrolytes consisting of organic solvents and lithium salts, our model requires dissociation ratio and effective diffusion size of lithium salts. Our method is applied to search for the compositional combinations of electrolytes with superior transport properties even at low temperatures. These results correlate well with experimental results.

Trans-stent graft thrombectomy for the treatment of long stent graft thrombosis in the femoropopliteal artery.

At present, no consensus has been reached regarding the optimal management of stent graft thrombosis in the femoropopliteal artery. We present a case of long thrombosis of a Viabahn stent graft implanted in the superficial femoral artery that was successfully treated by thrombectomy using a trans-Viabahn approach at the mid-thigh segment. The advantages of this approach include that it preserves the common femoral artery and popliteal artery untouched without scarring, allowing for a future site of surgical anastomosis. This technique could be a reasonable approach when performing surgical thrombectomy for stent graft thrombosis in the femoropopliteal artery.

Endovascular treatment with an iliac branch endoprosthesis for a right subclavian artery aneurysm.

Subclavian artery aneurysms are rare peripheral artery aneurysms, and open surgical repair is the reference standard treatment. We have reported the case a patient with a right subclavian artery aneurysm who was not indicated for open surgical repair because of comorbidities. Thus, endovascular treatment using the Gore Excluder Iliac Branch Endoprosthesis (WL Gore and Associates, Flagstaff, Ariz) was performed, leading to complete aneurysmal exclusion without perioperative complications. Although anatomic limitations exist, this technique could be alternative treatment option for right subclavian artery aneurysms.

Early clinical outcomes of retrograde in situ branched stent grafting for complex aortic arch aneurysms.

OBJECTIVE: To evaluate the early outcomes of retrograde in situ branched stent grafting (RIBS) using the gutter balloon technique for complex aortic arch aneurysms (CAAs). METHODS: The RIBS technique is an in situ needle fenestration procedure during thoracic endovascular aortic repair with the reconstruction of cervical branches. The double RIBS (D-RIBS) for the reconstruction of the left common carotid artery and the brachiocephalic artery using the gutter balloon technique was performed in 30 high-risk patients. We describe the early clinical results of the D-RIBS technique for CAAs. Primary end points were technical success and 30-day mortality. Secondary end points were postoperative complications, rates of endoleaks, overall survival, aneurysm-related death, and reinterventions. RESULTS: The mean age was 77.1 ± 6.6 years, and the mean maximum minor-axis aneurysmal diameter was 65.9 ± 8.9 mm. Twenty-six patients underwent D-RIBS for elective arch aortic aneurysm, and four patients were for reintervention after zone 2 thoracic endovascular aortic repair failure. Stent graft puncture was performed 60 times from the common carotid arteries, and technical success was achieved in all cases (100%). Postoperative complications included cerebral infarction in two patients (6.7%) and recurrent nerve palsy in one patient (3.3%). The 30-day mortality was 0%. During the median follow-up period of 14 months (6-56 months), overall survival at 12 months was 92.3% without any aneurysm-related death. Type 1 b and type 2 endoleaks were observed in one each, and no reintervention was encountered. CONCLUSIONS: Early clinical outcomes of the D-RIBS for high-risk patients with CAAs are acceptable. The gutter balloon method enables safe and reliable fenestration. Further studies and dedicated devices are warranted.

Evaluation of heparin-bonded ePTFE grafts for forearm loop vascular access: Comparison between Gore® PROPATEN vascular graft and ACUSEAL vascular graft.

BACKGROUND: This retrospective study evaluates the clinical outcomes of two heparin-bonded expanded polytetrafluoroethylene grafts, PROPATEN and ACUSEAL (W. L. Gore & Associates, Flagstaff, AZ, USA), for forearm loop vascular access. METHODS: We prospectively collected data on 60 patients who had undergone arteriovenous graft of the forearm loop type between January 2015 and December 2019. The primary endpoints were graft primary, assisted primary, and secondary patency rates. Secondary endpoints were time to first cannulation and postoperative complications. RESULTS: We enrolled 36 patients in the PROPATEN group (Group P) and 24 in the ACUSEAL group (Group A). All procedures were successful without any 30-day mortality. The median times to first cannulation were 16.5 days and 3 days in Groups P and A, respectively (p < 0.001). Mean follow-up periods were 13.4 ± 14.5 and 17.3 ± 9.3 months, respectively. Primary patency rates were 81% and 64%, respectively, at 6 months, and 60% and 40%, respectively, at 12 months (p = 0.008). Assisted primary patency rates were 96% and 83% at 6 months, 91% and 73% at 12 months, and 81% and 35% at 24 months (p = 0.044). Secondary patency rates were 96% and 81% at 12 months, and 87% and 62% at 24 months (p = 0.207). As a remote-period complication, disruption of the luminal layer of the graft was observed in two patients (4.2%) in Group A due to puncture and thrombectomy. CONCLUSIONS: Although the ACUSEAL graft offers the advantage of early cannulation, its primary and assisted primary patency outcomes were inferior to those of the PROPATEN graft. It is important for physicians to be aware of the different characteristics of each graft to select the best option for each patient.

The tertiary structure of the human Xkr8-Basigin complex that scrambles phospholipids at plasma membranes.

Xkr8-Basigin is a plasma membrane phospholipid scramblase activated by kinases or caspases. We combined cryo-EM and X-ray crystallography to investigate its structure at an overall resolution of 3.8 Å. Its membrane-spanning region carrying 22 charged amino acids adopts a cuboid-like structure stabilized by salt bridges between hydrophilic residues in transmembrane helices. Phosphatidylcholine binding was observed in a hydrophobic cleft on the surface exposed to the outer leaflet of the plasma membrane. Six charged residues placed from top to bottom inside the molecule were essential for scrambling phospholipids in inward and outward directions, apparently providing a pathway for their translocation. A tryptophan residue was present between the head group of phosphatidylcholine and the extracellular end of the path. Its mutation to alanine made the Xkr8-Basigin complex constitutively active, indicating that it plays a vital role in regulating its scramblase activity. The structure of Xkr8-Basigin provides insights into the molecular mechanisms underlying phospholipid scrambling.

Potential roles of neuronal nitric oxide synthase and the PTEN-induced kinase 1 (PINK1)/Parkin pathway for mitochondrial protein degradation in disuse-induced soleus muscle atrophy in adult rats.

Excessive nitric oxide (NO) production and mitochondrial dysfunction can activate protein degradation in disuse-induced skeletal muscle atrophy. However, the increase in NO production in atrophied muscles remains controversial. In addition, although several studies have investigated the PTEN-induced kinase 1 (PINK1)/Parkin pathway, a mitophagy pathway, in atrophied muscle, the involvement of this pathway in soleus muscle atrophy is unclear. In this study, we investigated the involvement of neuronal nitric oxide synthase (nNOS) and the PINK1/Parkin pathway in soleus muscle atrophy induced by 14 days of hindlimb unloading (HU) in adult rats. HU lowered the weight of the soleus muscles. nNOS expression showed an increase in atrophied soleus muscles. Although HU increased malondialdehyde as oxidative modification of the protein, it decreased 6-nitrotryptophan, a marker of protein nitration. Additionally, the nitrosocysteine content and S-nitrosylated Parkin were not altered, suggesting the absence of excessive nitrosative stress after HU. The expression of PINK1 and Parkin was also unchanged, whereas the expression of heat shock protein 70 (HSP70), which is required for Parkin activity, was reduced in atrophied soleus muscles. Moreover, we observed accumulation and reduced ubiquitination of high molecular weight mitofusin 2, which is a target of Parkin, in atrophied soleus muscles. These results indicate that excessive NO is not produced in atrophied soleus muscles despite nNOS accumulation, suggesting that excessive NO dose not mediate in soleus muscle atrophy at least after 14 days of HU. Furthermore, the PINK1/Parkin pathway may not play a role in mitophagy at this time point. In contrast, the activity of Parkin may be downregulated because of reduced HSP70 expression, which may contribute to attenuated degradation of target proteins in the atrophied soleus muscles after 14 days of HU. The present study provides new insights into the roles of nNOS and a protein degradation pathway in soleus muscle atrophy.

Exploitation of Elevated Extracellular ATP to Specifically Direct Antibody to Tumor Microenvironment.

The extracellular adenosine triphosphate (ATP) concentration is highly elevated in the tumor microenvironment (TME) and remains tightly regulated in normal tissues. Using phage display technology, we establish a method to identify an antibody that can bind to an antigen only in the presence of ATP. Crystallography analysis reveals that ATP bound in between the antibody-antigen interface serves as a switch for antigen binding. In a transgenic mouse model overexpressing the antigen systemically, the ATP switch antibody binds to the antigen in tumors with minimal binding in normal tissues and plasma and inhibits tumor growth. Thus, we demonstrate that elevated extracellular ATP concentration can be exploited to specifically target the TME, giving therapeutic antibodies the ability to overcome on-target off-tumor toxicity.

[Thrombectomy for right atrial thrombosis complicating a pyogenic liver abscess].

Vascular complications from a liver abscess are rare but life-threatening. Herein, we report the case of a man in his 40s with a pyogenic hepatic abscess complicated by an inferior vena caval thrombus extending to the right atrium. His presenting complaint was a high fever. Blood tests revealed elevated inflammatory markers and liver enzymes. An abdominal CT demonstrated a 10cm abscess in the right hepatic lobe. A blood culture grew Streptococcus intermedius, which was sensitive to ampicillin sulbactam. He was diagnosed with a pyogenic liver abscess and treated with metronidazole and ampicillin sulbactam. Three days following admission, an abdominal CT scan revealed the thrombus extending from the liver abscess into the right atrium. He underwent thrombectomy and received antibiotic therapy. Postoperatively, abdominal ultrasound revealed a significant decrease in the size of the hepatic abscess. The patient was discharged in good condition on the 46th day of hospitalization. When encountering a hepatic abscess, it is important to consider that it may be associated with a thrombus extending from the inferior vena cava into right atrium.

Discovery of attenuation effect of orexin 1 receptor to aversion of nalfurafine: Synthesis and evaluation of D-nor-nalfurafine derivatives and analyses of the three active conformations of nalfurafine.

The D-nor-nalfurafine derivatives, which were synthesized by contraction of the six-membered D-ring in nalfurafine (1), had no affinity for orexin 1 receptors (OX1Rs). The 17N-lone electron pair in 1 oriented toward the axial direction, while that of D-nor-derivatives was directed in the equatorial configuration. The axial lone electron pair can form a hydrogen bond with the 14-hydroxy group, which could push the 6-amide side chain toward the downward direction with respect to the C-ring. The resulting conformation would be an active conformation for binding with OX1R. The dual affinities of 1 for OX1R and κ opioid receptor (KOR) led us to elucidate the mechanism by which only 1 showed no aversion but U-50488H. Actually, 1 selectively induced severe aversion in OX1R knockout mice, but not in wild-type mice. These results well support that OX1R suppresses the aversion of 1. This is the elucidation of long period puzzle which 1 showed no aversion in KOR.

Li-ion transport at the interface between a graphite anode and Li2CO3 solid electrolyte interphase: ab initio molecular dynamics study.

Understanding and the control of Li-ion (Li+) transport across the interface between the anode and solid electrolyte interphase (SEI) film or electrolyte is a key issue in battery electrochemistry and interface science. In this study, we investigated the structural, electronic and free energy properties of Li+ migration between a Li-intercalated graphite anode LiCx and Li2CO3 SEI film, by using ab initio molecular dynamics and free energy calculations. We compared three types of graphite edges: H-, OH- and mixed (H, OH, COOH)-terminations, and three cases of transferred Li-ions: Li+ constructing the SEI, excess Li+ and excess Li0 (excess Li+ + e- in anode). After validation of our calculations with Li2CO3 and LiCx bulk systems, we sampled the interfacial structures under thermodynamic equilibrium and demonstrated that the OH- and mixed-terminations had larger binding energies. The calculated free energy profiles of Li+ intercalation from the Li2CO3 SEI to LiC24 showed barriers larger than 1.2 eV irrespective of the terminations and Li+ cases. We also clarified that the charges of Li ions did not change much upon the intercalation. Based on these results and the calculated Li chemical potential, we constructed the probable free energy profile of Li+ between the anode and cathode under charging and discharging. This profile model suggest a possible electric field approximation for the charging stage, and the resultant free energy profiles with such fields gave a ca. 0.5 eV barrier under charging, which was consistent with the experimental values. The present picture will give a crucial insight into Li-ion transport at the battery interfaces.

Effectiveness of an interprofessional education program using team-based learning for medical students: A randomized controlled trial.

BACKGROUND: To respond to increasingly complicated healthcare needs in primary care settings, all health and medical welfare professionals are required to collaborate with multiprofessionals, namely via "interprofessional work" (IPW). Interprofessional education (IPE) is essential for effective IPW, especially for medical students. This study aimed to determine whether participation in IPE can increase medical students' readiness for interprofessional learning. METHOD: We examined the difference in readiness of medical students for interprofessional learning before and after an IPE program that used team-based learning (TBL). Each student was assigned to either a uniprofessional or multiprofessional group. They were evaluated using the Japanese version of the Readiness for Interprofessional Learning Scale (RIPLS). Program participants were 126 second-year medical students and 18 students of healthcare professions other than medical doctor who participated in a combined IPE program conducted by two universities. Medical students were allocated to 12 uniprofessional and nine multiprofessional groups at random. RESULTS: One hundred and twelve medical students who replied to the questionnaire both before and after the program (valid response rate, 88.9%) were eligible for analysis. Of these, 42 were assigned to uniprofessional groups and 70 to multiprofessional groups. After the program, the RIPLS total score increased to a greater extent in the multiprofessional groups than in the uniprofessional groups (difference 3.17, 95% confidence interval 0.47-5.88, P = .022). Multiple regression analysis showed the same result. CONCLUSIONS: Learning in multiprofessional groups increased medical students' readiness for interprofessional learning in an IPE program using TBL.

Current status of endovascular treatment for thoracoabdominal aortic aneurysms.

Open surgical repair (OSR) for thoracoabdominal aortic aneurysms (TAAAs) is maximally invasive and associated with high rates of operative mortality and perioperative complications including spinal cord ischemia (SCI), despite improvements in surgical techniques and perioperative care. Elderly patients, patients with a history of aortic surgery, and patients with severe comorbidities are often considered ineligible for this surgery and endovascular treatment may be their only treatment option. Total endovascular aneurysm repair (t-EVAR) without debranching surgery does not require thoracotomy and laparotomy and could improve the outcomes of these patients. t-EVAR includes fenestrated EVAR (f-EVAR), multi-branched EVAR (b-EVAR), and physician-modified fenestration endograft (PMFG). Although these techniques have achieved lower mortality rates than OSR, there are concerns about perioperative complications including limb ischemia, SCI, and long-term outcomes such as endograft migration and endoleaks (ELs). This article provides an overview of available endovascular devices for TAAAs and reviews the short and mid-term results of t-EVAR, as well as alternative options.

A Novel Shaggy Aorta Scoring System to Predict Embolic Complications Following Thoracic Endovascular Aneurysm Repair.

OBJECTIVE: The aim of this study was to investigate the correlation between shaggy aorta and embolic complications during thoracic endovascular aneurysm repair (TEVAR), based on a shaggy aorta scoring system. METHODS: The entire aorta was assessed based on 5 mm slice computed tomography (CT) from the sinotubular junction to the aortic bifurcation using a three dimensional workstation. One shaggy point (shaggy score) was given when the following conditions were met: 1) ulcer like thrombus, 2) maximum thrombus thickness ≥ 5 mm, and 3) mural thrombus occupies more than two thirds of the circumference of the aortic diameter on reconstructed CT of the axial statue. Subsequently, each point was added to obtain the total shaggy score. RESULTS: The outcomes of 301 patients undergoing TEVAR were evaluated. Post-operative embolic complications including stroke, acute renal failure, and distal embolisation, were identified in 21 cases (7.0%). The average shaggy score for the entire cohort was 2.4 ± 5.6 points, whereas it was 7.9 ± 7.1 in those patients with embolic complications (E group) and 2.0 ± 5.3 in those without embolic complications (N group, p = .001). There were no statistical differences in 30 day mortality (p = .70), but overall survival at two years was significantly lower in the E group (E: 58.8%, N: 93.3%, p < .001). Multivariable analysis revealed that the predictors of post-operative embolic complication were past history of cerebrovascular disease (p = .001, OR 5.90, 95% CI 2.14-16.29) and shaggy score (p < .001, OR 1.13, 95% CI 1.06-1.19). The area under the ROC curve was 0.77, and the cut off value of the shaggy score using the Youden index was 3 points (sensitivity: 71.4%, specificity: 81.4%). CONCLUSION: This shaggy score is a useful method to predict post-operative embolic complications following TEVAR. Because the risk of embolic complications was relatively high in patients with a high shaggy score, the indication for TEVAR in such patients should be considered carefully.