Neurological Resilience in Patients With Anorexia Nervosa Following Prolonged Cardiopulmonary Resuscitation.

Anorexia nervosa (AN) is a psychiatric disorder with metabolic abnormalities. Prolonged cardiopulmonary resuscitation (CPR) is predicted to result in death and poor neurological outcomes. This report describes the case of a patient with AN who had an unexpectedly favorable outcome after prolonged CPR. A 12-year-old female with AN presented to the emergency department, requiring intubation due to worsening consciousness and respiratory distress. Refractory hypotension led to cardiac arrest. After 135 minutes of CPR, venoarterial extracorporeal membrane oxygenation (EMCO) was started, and the patient was treated for post-resuscitation management, refeeding syndrome, and sepsis. The cardiac function gradually improved, the patient was weaned from EMCO eight days after admission, and the patient was extubated 30 days after admission. The patient maintained a good central nervous system function. AN patients tend to be youngsters and have a lower metabolism, which may be associated with a favorable neurological prognosis after prolonged CPR.

Changes in severity of pediatric suicide attempts before and after coronavirus disease 2019.

BACKGROUND: The recent coronavirus disease 2019 (COVID-19) pandemic and school closures were reported to have negatively impacted the mental health of children and adolescents. This study aimed to examine the change in the number and severity of pediatric suicide attempts before and after the COVID-19 pandemic. METHODS: This study enrolled 54 patients (26 vs. 28 patients before and after the COVID-19 pandemic, respectively) under 19 years of age who were transported to the emergency department as a result of suicide attempts between April 2017 and December 2021. The primary outcome includes the rate of serious suicide attempts (SSAs). RESULTS: The SSA rates were 19% (5/26) and 43% (12/28) before and after the COVID-19 pandemic, respectively (p = 0.62). The average number of transported suicide attempts per month almost doubled (0.72 vs. 1.33, respectively) and suicide attempts as a percentage of all ambulance transportations of individuals under 19 years old increased significantly from 0.95% (26/2729)to 1.98% (28/1414) (p = 0.006). CONCLUSIONS: The COVID-19 pandemic increased the severity of pediatric suicide attempts but not to a statistically significant degree. Social preventive support and early psychological intervention are therefore needed currently and in the future.

Downregulation of osteoprotegerin in colorectal cancer cells promotes liver metastasis via activating tumor-associated macrophage.

Osteoprotegerin (OPG) is a secreted cytokine that functions as a decoy receptor for receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL). Anti-RANKL treatment for bone metastasis has been widely accepted for solid tumors. However, the mechanism of OPG-RANKL-RANK signaling in systemic colorectal cancer (CRC) metastasis remains unclear. In this study, we investigated the relevance and function of OPG expression in CRC liver metastasis. First, we performed in silico analysis using The Cancer Genome Atlas public database and found that lower OPG expression in CRC was associated with poor overall survival. Immunohistochemistry analyses using resected specimen from patients with CRC in our institute confirmed the result. Patient-matched primary CRC and liver metastases showed a significant downregulation of OPG expression in metastatic lesions. In CRC cell lines, OPG expression did not suppress cell proliferation and migration. However, OPG expression inhibited macrophage migration by suppressing the RANKL-RANK pathway. Moreover, in vivo mouse liver metastasis models showed that OPG expression in CRC cells suppressed liver metastases. In addition, treatment with an anti-RANKL neutralizing antibody also suppressed liver metastases. These results showed that downregulation of OPG expression in CRC cells promotes liver metastasis by activating tumor-associated macrophage, which can become a candidate for targeted therapy with anti-RANKL neutralizing antibody for CRC liver metastasis.

AAV-mediated editing of PMP22 rescues Charcot-Marie-Tooth disease type 1A features in patient-derived iPS Schwann cells.

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is one of the most common hereditary peripheral neuropathies caused by duplication of 1.5 Mb genome region including PMP22 gene. We aimed to correct the duplication in human CMT1A patient-derived iPS cells (CMT1A-iPSCs) by genome editing and intended to analyze the effect on Schwann cells differentiated from CMT1A-iPSCs. METHODS: We designed multiple gRNAs targeting a unique sequence present at two sites that sandwich only a single copy of duplicated peripheral myelin protein 22 (PMP22) genes, and selected one of them (gRNA3) from screening their efficiencies by T7E1 mismatch detection assay. AAV2-hSaCas9-gRNAedit was generated by subcloning gRNA3 into pX601-AAV-CMV plasmid, and the genome editing AAV vector was infected to CMT1A-iPSCs or CMT1A-iPSC-derived Schwann cell precursors. The effect of the genome editing AAV vector on myelination was evaluated by co-immunostaining of myelin basic protein (MBP), a marker of mature myelin, and microtubule-associated protein  2(MAP2), a marker of neurites or by electron microscopy. RESULTS: Here we show that infection of CMT1A-iPS cells (iPSCs) with AAV2-hSaCas9-gRNAedit expressing both hSaCas9 and gRNA targeting the tandem repeat sequence decreased PMP22 gene duplication by 20-40%. Infection of CMT1A-iPSC-derived Schwann cell precursors with AAV2-hSaCas9-gRNAedit normalized PMP22 mRNA and PMP22 protein expression levels, and also ameliorated increased apoptosis and impaired myelination in CMT1A-iPSC-derived Schwann cells. CONCLUSIONS: In vivo transfer of AAV2-hSaCas9-gRNAedit to peripheral nerves could be a potential therapeutic modality for CMT1A patient after careful examinations of toxicity including off-target mutations.

Charcot-Marie-Tooth disease type 1A (CMT1A) is a common heritable form of the condition that develops when nerves in the body's extremities, such as the hands, feet and arms, are damaged due to an extra copy of PMP22 gene being incorrectly produced. Currently, no known therapies exist. Here, we developed a method to delete the additional copy of PMP22 gene by 20­40% to prevent overproduction. Our results show that this method can reduce PMP22 protein production, leading to near normal production in patient's nerve cells. Further safety assessments should now be undertaken. If the treatment is safe for patients it could become a therapeutic option for CMT1A patients.

Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase.

Neutrophil extracellular traps (NETs) play important roles in host immunity, as there is increasing evidence of their contribution to the progression of several types of cancers even though their role in colorectal cancers (CRCs) remains unclear. To investigate the clinical relevance of NETs in CRCs, we examined the expression of citrullinated histone H3 using immunohistochemistry and preoperative serum myeloperoxidase-DNA complexes in CRC patients using an enzyme-linked immunosorbent assay. High expression of intratumoral or systemic NETs was found to correlate with poor relapse-free survival (RFS), for which it is an independent prognostic factor. In vitro investigations of CRC cells (HCT116, HT29) revealed that NETs did not affect their proliferation but did promote the migration of CRC cells mediated by neutrophil elastase (NE) released during NETosis to increase extracellular signal-regulated kinase (ERK) activity. In vivo experiments using nude mice (KSN/slc) revealed that NE inhibition suppressed liver metastases in CRC cells, although it did not affect the growth of subcutaneously implanted tumors. Taken together, these results suggest that NET formation correlates with poor prognoses of patients with CRC and that the inhibition of NE could be a potential therapy for CRC metastases.

The impact of preclinical clerkship in general surgery on medical students' attitude to a surgical career.

PURPOSE: With the advent of a new program for postgraduate medical students in 2004, the number of applicants choosing surgical careers in Japan has been declining. We conducted this study to evaluate the impact of preclinical clerkship and how it affects students' attitudes toward a surgical career. METHODS: The subjects of our study were fifth-year medical students who participated in a clinical clerkship in general surgery in our department between April 2021 and March 2022. We conducted pre- and post-preclinical clerkship surveys to assess the perceived image of surgeons and the impact of clerkship on surgical career interest. RESULTS: Among 132 medical students (77 men and 55 women) who rotated through preclinical clerkship in our department, 125 participated in the survey and 66% expressed interest in a surgical career. In the post-clerkship survey, an increased interest in a surgical career was expressed by 79% of the students; notably, including those who initially expressed interest. Approximately 77% of students were satisfied with the practical skill training they received. CONCLUSION: Engaging medical students early in surgical experience through a preclinical clerkship for general surgery appears to promote their interest in a surgical career.

Pancreatic serous cystadenocarcinoma diagnosed with liver metastasis at 7 years after the resection of the primary serous neoplastic lesion.

Pancreatic serous neoplasms are rare tumors that are usually benign. However, histopathological differentiation between benign (serous cystadenoma) and malignant (serous cystadenocarcinoma) lesions is difficult. We present the case of a patient with pancreatic serous cystadenocarcinoma that was diagnosed with liver metastasis 7 years after the resection of the primary serous neoplastic lesion. A woman in her 60 s was diagnosed with pancreatic serous cystadenoma based on imaging and histopathological examination findings. The tumor was resected, and the patient was followed up every 6 months to monitor tumor progression. At 7 years after the resection of the primary lesion, liver tumors showing marked flare-like contrast enhancements were detected on arterial phase computed tomography findings and on dynamic magnetic resonance imaging findings acquired 60 s after the administration of a contrast agent. Laparoscopic segmental hepatectomy of S4 and S6 was performed to resect these tumors. Histopathological examination revealed that these tumors were metastatic and developed from the primary lesion. Therefore, a diagnosis of serous cystadenocarcinoma was confirmed. The flare-like contrast enhancement around the metastatic liver lesions on computed tomography and dynamic magnetic resonance images may be an indicator of serous cystadenocarcinoma with liver metastasis that could assist in diagnosis.

Efficacy of side-to-end anastomosis to prevent anastomotic leakage after anterior resection for rectal cancer.

The present study aimed to investigate whether side-to-end anastomosis could provide an improved surgical outcome, such as lower anastomotic leakage rate, compared with end-to-end anastomosis, following anterior resection for rectal and rectosigmoid cancer. This retrospective study included 162 patients with rectal cancer who underwent elective anterior resection between January 2012 and October 2019 at a single institution. Patients with double cancers or colonic J-pouch were excluded. Anastomotic leakage was defined clinically and radiologically. Side-to-end anastomosis was introduced in the International University of Health and Welfare Mita Hospital in January 2017. Side-to-end anastomosis was performed in 63 patients, while end-to-end anastomosis was performed in 99 patients. Tumors tended to be located lower in the rectum in the side-to-end anastomosis group than in the end-to-end anastomosis group. No significant differences were observed in other patient characteristics. The incidence of anastomotic leakage was significantly lower in the side-to-end anastomosis group than in the end-to-end anastomosis group (3/63, 4.8% vs. 18/99, 18.2%, respectively, P=0.02). No significant differences were observed in the incidence rates of other complications. Univariate and multivariate analyses revealed that a smoking habit (P=0.04) and side-to-end anastomosis (P=0.02) were significantly associated with anastomotic leakage. In conclusion, side-to-end anastomosis using a double-stapling technique following anterior resection for rectal cancer may prevent anastomotic leakage.

Unexpected postmortem diagnoses in cases of clinically diagnosed amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that is clinically and pathologically characterized by impairment of the upper and lower motor neurons. The clinical diagnosis of ALS is not always straightforward because of the lack of specific biomarkers and clinical heterogeneity. This review presents the clinical and pathological findings of four autopsied cases that had been diagnosed with ALS before death. These cases had demonstrated definite and progressive motor neuron signs and symptoms, whereas postmortem assessment revealed miscellaneous disorders, including fungal infection, paraneoplastic syndrome, and amyloidosis. Importantly, nonmotor neuron signs and symptoms, including seizures, extra-pyramidal signs, ocular movement disorders, sensory disturbance, and dysautonomia, had also been documented during the disease course of the cases in the present study. The ALS-unlike symptoms were indicative of the "true" diagnosis in each case when those symptoms were isolated from motor neuron signs/symptoms.

Superiority of OxyMaskTM with less carbon dioxide rebreathing in children.

Despite the growing importance of oxygen-delivery devices worldwide, there are only a few reports of physiological data on various oxygen masks in children. The possibility of carbon dioxide (CO2) rebreathing has been a prevalent concern with the use of oxygen-delivery devices. OxyMask KidTM (Southmedic Inc. Canada; hereafter OxyMask) is expected to reduce CO2 rebreathing even at low oxygen flow rates because of its structural features. Biological data using OxyMask in children have not been well investigated. Measured respiratory parameters of OxyMask with those of a simple oxygen mask in healthy children were compared. Ten subjects were enrolled, with a median age of 5.4 years. All subjects used both OxyMask and a simple oxygen mask. The fraction of inspiratory oxygen (FIO2), partial pressure of inspiratory CO2 (PICO2), and partial pressure of end-tidal CO2 were measured using a sidestream gas-sampling monitor in all subjects. The oxygen flow rate was set at 1, 3, 5, and 10 L/min. FIO2 levels were higher with OxyMask than those with the simple oxygen mask at 3 L/min of oxygen. PICO2 levels were significantly lower with OxyMask than those with the simple oxygen mask (1.5 mmHg vs. 3.7 mmHg at 1 L/min, P = 0.005; 1.0 mmHg vs. 2.7 mmHg at 3 L/min, P = 0.005, respectively), whereas PICO2 levels were higher at low oxygen flow rates with both masks.Conclusion: Our results showed that higher FIO2 and less CO2 rebreathing were achieved with OxyMask than those with a simple oxygen mask at low flow rates of oxygen in healthy children. What is Known: • OxyMask is expected to reduce carbon dioxide rebreathing even at low oxygen flow rates because of its structural features. • Efficacy has been demonstrated in experimental models and adult data, but clinical data on the use of the OxyMask in children are limited. What is New: • Higher fraction of inspiratory oxygen and lesser carbon dioxide rebreathing were achieved with OxyMask than with a simple oxygen mask at low flow rates of oxygen in healthy children.

Successful recovery from severe hypertension in a patient with Leigh syndrome.

Hypertension is a rare complication of Leigh Syndrome (LS), but prognosis of patients with hypertension is poor and its presence is indicative of the terminal stage of the disease. Herein, we report a four-year-old girl case diagnosed with LS at 15 months of age who subsequently developed severe hypertension and respiratory failure. Physical examination and laboratory findings did not indicate a secondary cause of hypertension. Her respiratory failure was treated with non-invasive ventilation and hypertension controlled with enalapril, furosemide and spironolactone. To our knowledge, this is the first case of a patient with LS recovering from severe hypertension.

Laparoscopic gastrectomy with and without prophylactic drains in gastric cancer: a propensity score-matched analysis.

BACKGROUND: The number of patients who are undergoing laparoscopic gastrectomy for treating gastric cancer is increasing. Although prophylactic drains have been widely employed following the procedure, there are few studies reporting the efficacy of prophylactic drainage. Therefore, this study assessed the efficacy of prophylactic drains following laparoscopic gastrectomy for gastric cancer. METHODS: Data of patients who received laparoscopic gastrectomy for treating gastric cancer in our institution between April 2011 and March 2017 were reviewed, and the outcomes of patients with and without a prophylactic drainage were compared. Propensity score matching was used to minimize potential selection bias. RESULTS: A total of 779 patients who underwent surgery for gastric cancer were reviewed; of these, 628 patients who received elective laparoscopic gastrectomy were included in this study. After propensity score matching, data of 145 pairs of patients were extracted. No significant differences were noted in the incidence of postoperative complications between the drain and no-drain groups (19.3% vs 11.0%, P = 0.071). The days after the surgery until the initiation of soft diet (6.3 ± 7.4 vs 4.9 ± 2.9 days, P = 0.036) and the length of postoperative hospital stay (15.7 ± 12.9 vs 13.0 ± 6.3 days, P = 0.023) were greater in the drain group than those in the no-drain group. CONCLUSIONS: This study suggests that routinely using prophylactic drainage following laparoscopic gastrectomy for treating gastric cancer is not obligatory.

[A case of myasthenia gravis and myositis induced by pembrolizumab].

A 77-year-old woman with lung adenocarcinoma noticed bilateral ptosis 7 weeks after a first pembrolizumab infusion. Her symptoms rapidly progressed to generalized manifestations including limb and neck weakness, dyspnea, and dysphasia within the following two weeks. We diagnosed him with pembrolizumab-related myasthenia gravis and myositis based on clinical symptoms, elevation of muscle enzymes and anti-acetylcholine receptor antibodies, repetitive nerve stimulation and muscle biopsy. We commenced combination immunotherapy, including intravenous and oral steroid therapy, immune absorption therapy and plasma exchange therapy with noninvasive positive-pressure ventilation and tracheotomy positive pressure ventilation. She had gradual symptoms improvement and discharged after 209 days in a hospital. In this case, anti-titin antibodies, one of anti-striational antibodies, was positive and correlated with severity of myasthenia gravis. With the development of immune checkpoint inhibitors for various malignancies, clinicians should closely monitor patients for important immune-related adverse events and coordinate on early treatment.

Crystalline orientation control of the platelet Nd2Fe14B phase to produce magnetic anisotropy via electromagnetic vibration processing.

Controlled crystalline orientation of the discontinuous phase in a composite enables the production of improved anisotropic properties, e.g., well-aligned Nd2Fe14B platelets by hot pressing and then soaking in a low-melting Nd-Cu eutectic melt to infiltrate to grain boundary. Alternatively, an anisotropic magnet can be fabricated by sintering Nd2Fe14B powder pre-aligned with a static magnetic field. In this study, we used a two-step electromagnetic vibration (EMV) technique to solidify the Nd70Cu30-30wt% Nd2Fe14B alloy, by which the magnetic Nd2Fe14B compound could be segmented into short laths and the easy magnetisation axes of these discontinuous platelets could be highly aligned, as revealed by electron backscatter diffraction (EBSD) patterns. Magnetic properties showed that the alloy exhibited strong anisotropy in its magnetism. Our present results opened a new avenue for the simple production of anisotropic Nd2Fe14B magnets via solidification without the powder metallurgy routine. Moreover, the technique is highly expected to be applied to other systems, e.g., graphene-reinforced metallic and/or polymer composites in which the alignment of graphene can maximise the anisotropy in the thermal or electrical properties of the composites.

Evaluation of the extent of damage to the esophageal wall caused by press-through package ingestion.

Press-through package (PTP) is the most common accidentally ingested foreign body in Japan. Accidental ingestion of PTP can result in esophageal damage. An approach for evaluating the risk of esophageal injury has not been established. Therefore, we used porcine esophageal tissue and silicone sheets to establish a method for assessing the risk of esophageal damage on accidental PTP ingestion. We pathologically evaluated porcine lower esophageal tissue using a scratch tester. Using porcine esophageal tissue, scratch tests were performed with 4 test objects and pathological damage was compared. It was assumed that each object was accidentally ingested. The objects were polyvinylidene chloride (PVDC)-coated polyvinyl chloride (PVC) PTP, soft PThPa, round PTP, and a disposable scalpel. The porcine esophagus was replaced with a silicon sheet, and an automatic friction machine was used for quantitative evaluation. The silicon sheet was scratched using HHS 2000 with 750-g load at 50 mm/min. We investigated the frictional force exerted on the surface for each of the objects. The degree of damage (depth) was the highest for the disposable scalpel, followed by PVDC-coated PVC PTP, while the degree of damage (depth) was the lowest for soft PThPa and round PTP. The mean frictional forces on the silicon sheet were 524.0 gf with PVDC-coated PTP, 323.5 gf with soft PThPa, 288.7 gf with round PTP, and 922.7 gf with the disposable scalpel. We developed approaches to qualitatively and quantitatively evaluate the risk of esophageal damage after accidental PTP ingestion. Our findings indicate that the risk of gastrointestinal damage after accidental PTP ingestion is low with soft PTP and round PTP.

Suppression of the synaptic localization of a subset of proteins including APP partially ameliorates phenotypes of the Drosophila Alzheimer's disease model.

APP (amyloid precursor protein), the causative molecule of Alzheimer's disease, is synthesized in neuronal cell bodies and subsequently transported to synapses. We previously showed that the yata gene is required for the synaptic transport of the APP orthologue in Drosophila melanogaster. In this study, we examined the effect of a reduction in yata expression in the Drosophila Alzheimer's disease model, in which expression of human mutant APP was induced. The synaptic localization of APP and other synaptic proteins was differentially inhibited by yata knockdown and null mutation. Expression of APP resulted in abnormal synaptic morphology and the premature death of animals. These phenotypes were partially but significantly rescued by yata knockdown, whereas yata knockdown itself caused no abnormality. Moreover, we observed that synaptic transmission accuracy was impaired in our model, and this phenotype was improved by yata knockdown. Thus, our data suggested that the phenotypes caused by APP can be partially prevented by inhibition of the synaptic localization of a subset of synaptic proteins including APP.

Developmental YAPdeltaC determines adult pathology in a model of spinocerebellar ataxia type 1.

YAP and its neuronal isoform YAPdeltaC are implicated in various cellular functions. We found that expression of YAPdeltaC during development, but not adulthood, rescued neurodegeneration phenotypes of mutant ataxin-1 knock-in (Atxn1-KI) mice. YAP/YAPdeltaC interacted with RORα via the second WW domain and served as co-activators of its transcriptional activity. YAP/YAPdeltaC formed a transcriptional complex with RORα on cis-elements of target genes and regulated their expression. Both normal and mutant Atxn1 interacted with YAP/YAPdeltaC, but only mutant Atxn1 depleted YAP/YAPdeltaC from the RORα complex to suppress transcription on short timescales. Over longer periods, mutant Atxn1 also decreased RORα in vivo. Genetic supplementation of YAPdeltaC restored the RORα and YAP/YAPdeltaC levels, recovered YAP/YAPdeltaC in the RORα complex and normalized target gene transcription in Atxn1-KI mice in vivo. Collectively, our data suggest that functional impairment of YAP/YAPdeltaC by mutant Atxn1 during development determines the adult pathology of SCA1 by suppressing RORα-mediated transcription.