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The bacterial pathogen, lipopolysaccharide (LPS), elicits microglial response and induces cytokine secretion that subsequently activates astrocytes. Recent findings have indicated that LPS-induced activation of postnatal glial cells has led to alterations in synapse formation in hippocampal and cortical neurons, thereby resulting in a prolonged increased risk for seizure or depression. Nevertheless, its mechanisms remain to be fully elucidated. Cellular metabolism has recently gained recognition as a critical regulatory mechanism for the activation of peripheral immune cells, as it supplies the requisite energy and metabolite for their activation. In the present study, we report that LPS did not change the expression of reported astrocyte-derived synaptogenic genes in the postnatal hippocampus; however, it induced upregulation of astrocytic complement component regulator Serping1 within the postnatal hippocampus. As a regulatory mechanism, activation of glycogen degradation (glycogenolysis) governs the expression of a subset of inflammatory-responsive genes including Serping1 through reactive oxygen species (ROS)-NF-κB axis. Our study further demonstrated that glycogenolysis is implicated in neurotoxic phenotypes of astrocytes, such as impaired neuronal synaptogenesis or cellular toxicity. These findings suggested that activation of glycogenolysis in postnatal astrocytes is an essential metabolic pathway for inducing responses in inflammatory astrocytes.
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Background Since the larynx and pharynx are vital for respiration, swallowing, and speech, chemoradiotherapy (CRT) has been widely applied for T3 hypopharyngeal cancer (HPC) as an organ-preserving treatment. However, CRT can lead to severe late adverse events such as dysphagia and aspiration pneumonia, especially in patients who have difficulty swallowing and/or aspiration at the time of initial diagnosis. Patients and methods Between 2012 and 2020, 86 patients with T3 HPC treated with curative intent at Kobe University Hospital were included in this study. The average age was 69 years old, ranging from 43 to 89. Diseases were classified as Stage III in 29 patients, Stage IVA in 52 patients, and Stage IVB in five patients. Thirty-five (41%) patients were treated by CRT, and 51 (59%) patients were treated by surgery. Patients were followed up for at least two years, and the follow-up period ranged from four to 128 months (median: 45 months). Results Three-year progression-free survival (PFS) rates of patients treated by CRT and patients treated by surgery were 56.2% and 60.3%, respectively. Three-year disease-specific survival (DSS) rates of patients treated by CRT and surgically treated patients were 79.0% vs. 70.8%, respectively. Three-year overall survival (OS) rates of patients treated by CRT and surgically treated patients were 64.5% and 69.0%, respectively. Of note, a significant difference was observed between three-year DSS and three-year PFS (79.0% vs. 56.2%, p = 0.0014) in the patients treated by CRT but not in the patients treated by surgery. Conclusions No significant differences were observed between the PFS, DSS, and OS rates of patients treated by CRT and those of surgically treated patients. Locoregional recurrences after CRT were significantly successfully salvaged by surgical intervention. These results suggest that CRT can be applied as an alternative to surgery without reducing survival, especially for patients without severe clinical symptoms. Meticulous follow-up is mandatory for early detection of recurrence to salvage by surgery and for the management of late adverse events.
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Background: The natural history of venous malformation (VM) and Klippel-Trenaunay Syndrome (KTS) has not been quantitatively studied. To obtain benchmarks to guide designing clinical trials to assess safety and efficacy of novel drug candidates, the clinical course of the patients was followed for 6 months. Methods and Results: This is a multicenter prospective observational study evaluating the change rate in lesion volume from baseline with magnetic resonance images, as the primary endpoint. In addition, disease severities, performance status (PS), pain visual analog scale (VAS) score, quality of life (QoL), infections, and coagulation markers were also evaluated. Thirty-four patients (VM = 17, KTS = 17, 1-53 of age; median 15.9 years) with measurable lesion volume were analyzed. There was no statistically significant difference in the lesion volume between baseline and day 180, and the mean change rate (standard deviation) was 1.06 (0.28). There were no baseline characteristics that affected the change in lesion volume over 6 months. However, there were patients who showed more than 20% volume change and it was suggested that the lesion volume was largely impacted by local infection. There were no statistically significant changes in pain VAS score, severity, PS, QoL score, D-dimer, and platelet count over 6 months within all patients analyzed. Conclusion: The results showed the representative natural course of VM and KTS for a 6-month period with objective change of lesion volume and other factors, suggesting that it is scientifically reasonable to conduct a Phase 2 proof-of-concept study without a placebo arm, using the results of this study as the control. Clinical Trial Registration: NCT04285723, NCT04589650.
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Síndrome de Klippel-Trenaunay-Weber , Malformações Vasculares , Humanos , Síndrome de Klippel-Trenaunay-Weber/diagnóstico , Síndrome de Klippel-Trenaunay-Weber/diagnóstico por imagem , Dor , Estudos Prospectivos , Qualidade de Vida , Malformações Vasculares/diagnóstico , Malformações Vasculares/diagnóstico por imagem , Ensaios Clínicos como AssuntoRESUMO
Changes in genomic structures underlie phenotypic diversification in organisms. Amino acid-changing mutations affect pleiotropic functions of proteins, although little is known about how mutated proteins are adapted in existing developmental programs. Here we investigate the biological effects of a variant of the GLI3 transcription factor (GLI3R1537C) carried in Neanderthals and Denisovans, which are extinct hominins close to modern humans. R1537C does not compromise protein stability or GLI3 activator-dependent transcriptional activities. In contrast, R1537C affects the regulation of downstream target genes associated with developmental processes. Furthermore, genome-edited mice carrying the Neanderthal/Denisovan GLI3 mutation exhibited various alterations in skeletal morphology. Our data suggest that an extinct hominin-type GLI3 contributes to species-specific anatomical variations, which were tolerated by relaxed constraint in developmental programs during human evolution.
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Venous malformations (VMs) are histopathologically benign but can greatly impair patients' quality of life. Screlothprapy is known to be effective in improving symptoms without a scar, but surgical resection of residual lesions is sometimes necessary due to inadequate reduction. However, there is no consensus on what criteria should be used to consider switching to surgical treatment, and individualized decisions must be made for each case. To investigate the factors that contribute to the lack of efficacy of sclerotherapy in reducing lesions and how to predict this, the authors performed a retrospective clinical imaging and histopathological study of 6 cases of labial vein malformations treated with sclerotherapy and 3 cases without sclerotherapy. Clinical image investigations are based on magnetic resonance imaging before and after sclerotherapy. The authors found a significant decrease in the percentage of cystic components in the total lesion of VMs after sclerotherapy. Histopathological investigations are based on resected VMs with or without sclerotherapy. Elastica van Gieson stains suggested a significant increase in fibrotic tissue inside VMs treated with sclerotherapy compared with those without. In conclusion, magnetic resonance imaging signal changes inside the VMs after sclerotherapy was observed, and it may reflect fibrosis of the tissue. These changes in the VMs after sclerotherapy may reduce the effect of sclerotherapy on tissue reduction should be considered.
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Escleroterapia , Malformações Vasculares , Humanos , Escleroterapia/métodos , Estudos Retrospectivos , Lábio , Qualidade de Vida , Resultado do Tratamento , Imageamento por Ressonância Magnética , Malformações Vasculares/diagnóstico por imagem , Malformações Vasculares/terapia , Soluções Esclerosantes/uso terapêuticoRESUMO
This study aimed to elucidate the vasodilatory effects and cytotoxicity of various vasodilators used as antispasmodic agents during microsurgical anastomosis. Rat smooth muscle cells (RSMCs) and human coronary artery endothelial cells (HCAECs) were used to investigate the physiological concentrations and cytotoxicity of various vasodilators (lidocaine, papaverine, nitroglycerin, phentolamine, and orciprenaline). Using a wire myograph system, we determined the vasodilatory effects of each drug in rat abdominal aortic sections at the concentration resulting in maximal vasodilation as well as at the surrounding concentrations 10 min after administration. Maximal vasodilation effect 10 min after administration was achieved at the following concentrations: lidocaine, 35 mM; papaverine, 0.18 mM; nitroglycerin, 0.022 mM; phentolamine, 0.11 mM; olprinone, 0.004 mM. The IC50 for lidocaine, papaverine, and nitroglycerin was measured in rat abdominal aortic sections, as well as in RSMCs after 30 min and in HCAECs after 10 min. Phentolamine and olprinone showed no cytotoxicity towards RSMCs or HCAECs. The concentrations of the various drugs required to achieve vasodilation were lower than the reported clinical concentrations. Lidocaine, papaverine, and nitroglycerin showed cytotoxicity, even at lower concentrations than those reported clinically. Phentolamine and olprinone show antispasmodic effects without cytotoxicity, making them useful candidates for local administration as antispasmodics.
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Papaverina , Parassimpatolíticos , Humanos , Ratos , Animais , Parassimpatolíticos/farmacologia , Papaverina/farmacologia , Nitroglicerina/farmacologia , Fentolamina/farmacologia , Células Endoteliais , Microcirurgia , Músculo Liso Vascular , Vasodilatadores/farmacologia , Vasodilatação , Miócitos de Músculo Liso , Lidocaína/farmacologiaRESUMO
Abdominal incisional hernia is a complication of the rectus abdominis myocutaneous (RAMC) flap harvest. This study aimed to compare the incidence of abdominal incisional hernia and donor-site closure time between absorbable barbed continuous (ABC) and non-absorbable non-barbed interrupted (nAnBI) methods. Methods: This study included 145 patients who underwent free RAMC flap reconstruction after head and neck cancer surgery at Kobe University Hospital between January 2012 and March 2020. The nAnBI method was selected between January 2012 and August 2016, and the ABC method was selected between September 2016 and March 2020. The incidence of abdominal incisional hernia and the average time required for donor-site closure were compared between the two groups. Results: Of the 145 patients surveyed, 116 (57 and 59 in the nAnBI and ABC groups, respectively) were followed-up for at least 90 days after the surgery. The incidence rates of abdominal incisional hernia were 0% and 5.1% (n = 3) in the nAnBI and ABC groups, respectively, with no significant differences (p = 0.244). The average donor-site closure times were 127.6 and 111.3 minutes in the nAnBI and ABC groups, respectively, with no significant differences (p = 0.122). Conclusions: No significant differences in the incidence of abdominal incisional hernia and donor-site closure time were observed between the nAnBI and ABC groups. However, there was a tendency for increased hernia occurrence and shorter wound closure time in the ABC group. A randomized prospective multicenter study is warranted to validate our findings of the ABC method.
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In the present study, we examined neural circuit formation in the forebrain of the Olig2 knockout (Olig2-KO) mouse model and found disruption of the anterior commissure at the late foetal stage. Axon bundles of the anterior commissure encountered the wall of the third ventricle and ceased axonal extension. L1-CAM immunohistochemistry showed that Olig2-KO mice lose decussation formation in the basal forebrain. DiI tracing revealed that the thin bundles of the anterior commissure axons crossed the midline but ceased further extension into the deep part of the contralateral side. Furthermore, some fractions of DiI-labelled axons were oriented dorsolaterally, which was not observed in the control mouse forebrain. The rostral part of the third ventricle was much wider in the Olig2-KO mice than in wild-type mice, which likely resulted in the delay of midline fusion and subsequent delay and malformation of the anterior commissure. We analysed gene expression alterations in the Olig2-KO mice using a public database and found multiple genes, which are related to axon guidance and epithelial-mesenchymal transition, showing subtle expression changes. These results suggest that Olig2 is essential for anterior commissure formation, likely by regulating multiple biological processes.
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Axônios , Prosencéfalo , Animais , Camundongos , Prosencéfalo/metabolismo , Axônios/fisiologia , Camundongos Knockout , Fator de Transcrição 2 de Oligodendrócitos/genética , Fator de Transcrição 2 de Oligodendrócitos/metabolismoRESUMO
We report a case of a second free jejunal transfer to treat metastasis in the mesenteric lymph node of the first jejunal flap. A 73-year-old man underwent total pharyngolaryngectomy, bilateral neck dissection, and free jejunal transfer for recurrent hypopharyngeal cancer [left pyriform sinus, pT2N0, moderately differentiated squamous cell carcinoma (SCC)] after radiotherapy. Seven years post-surgery, he underwent transoral videolaryngoscopic surgery for oropharyngeal cancer (soft palate, pT1N0, well-differentiated SCC). Ten years after the first jejunal transfer, metastasis was found in the mesenteric lymph node surrounding the jejunal flap's vascular pedicle. Under general anesthesia, resection of the first jejunum including the affected lymph node, and second jejunal transfer were performed. Lymph node pathological examination revealed poorly differentiated SCC, compatible with pharyngeal cancer metastasis. After neck dissection and jejunal flap transfer, lymphatic collateral pathways toward the flap's mesenteric lymph node might form. Possibly, hypopharyngeal or oropharyngeal cancer metastasized via this pathway.
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Oligodendrocyte precursor cells (OPC) arise from restricted regions of the central nervous system (CNS) and differentiate into myelin-forming cells after migration, but their ultrastructural characteristics have not been fully elucidated. This study examined the three-dimensional ultrastructure of OPCs in comparison with other glial cells in the early postnatal optic nerve by serial block-face scanning electron microscopy. We examined 70 putative OPCs (pOPC) that were distinct from other glial cells according to established morphological criteria. The pOPCs were unipolar in shape with relatively few processes, and their Golgi apparatus were localized in the perinuclear region with a single cisterna. Astrocytes abundant in the optic nerve were distinct from pOPCs and had a greater number of processes and more complicated Golgi apparatus morphology. All pOPCs and astrocytes contained a pair of centrioles (basal bodies). Among them, 45% of pOPCs extended a short cilium, and 20% of pOPCs had centrioles accompanied by vesicles, whereas all astrocytes with basal bodies had cilia with invaginated ciliary pockets. These results suggest that the fine structures of pOPCs during the developing and immature stages may account for their distinct behavior. Additionally, the vesicular transport of the centrioles, along with a short cilium length, suggests active ciliogenesis in pOPCs.
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Células Precursoras de Oligodendrócitos , Camundongos , Animais , Microscopia Eletrônica de Varredura , Nervo Óptico , Olho , Centríolos , AntioxidantesRESUMO
Introduction: Post-sternotomy surgical site infection (SSI) is a serious complication of cardiovascular surgery. Here, we proposed a new clinical classification and reconstructive strategy for this condition. Methods: A retrospective study based on medical records was performed on 100 consecutive cases requiring wound management by plastic surgeons for post-sternotomy SSI at Kobe University Hospital between January 2009 and December 2021. We classified 100 cases into four categories according to the anatomical invasiveness of the infection (type 1, superficial SSI; type 2, sternal osteomyelitis; type 3, mediastinitis; and type 4, aortic graft infection). The standard treatment plan comprised initial debridement, negative pressure wound therapy with continuous irrigation, and reconstructive surgery. Reconstructive methods and their outcomes (in-hospital mortality rate, follow-up period, and infection recurrence rate) were investigated for each SSI category. Results: There were nine SSI cases in type 1, 28 in type 2, 25 in type 3, and 38 in type 4. The pectoralis major (PM) muscle advancement flap was mainly selected in types 1 and 2 (100 and 70.4%, respectively), while the omental flap or latissimus dorsi (LD) myocutaneous flaps were mainly selected in types 3 and 4 (77.3 and 81.8%, respectively) for reconstructive surgery. The in-hospital mortality rates for types 1, 2, 3, 4 were 44.4, 3.6, 12.0, and 15.8%, respectively. The mean follow-up periods for types 1, 2, 3, 4 were 542.8, 1514.5, 1154.5, and 831.1 days, respectively. Infection recurrence rates for types 1, 2, 3, 4 were 0, 11.5, 13.3, and 19.2%, respectively. All of these recurrent cases, except for 4 cases of type 4 that required surgical intervention, were treated with conservative wound management. Conclusion: A volume-rich flap (omental or LD flap) was required to fill the dead space after debridement in mediastinitis (type 3) or aortic graft infection (type 4), whereas superficial SSI (type 1) or sternal osteomyelitis (type 2) received a less-invasive flap (PM muscle advancement flap). Our new classification method was based on the anatomical invasiveness of the infection, providing both a simple and easy diagnosis and definitive treatment strategy.
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We report a case of palliative surgery in a 73-year-old patient with metastatic plantar sarcoma. The patient underwent resection and irradiation of an undifferentiated spindle cell sarcoma in the right plantar region. The wound was not closed and systemic metastases were observed. The chief complaint of the patient on his first visit to our department was difficulty walking due to pain in the right plantar region. Since we were unsuccessful in relieving the pain with conservative treatment, we decided to perform a palliative free tissue transfer to the right plantar. The surgery was successful, the skin ulcer healed, and the pain was relieved after the surgery. When performing palliative surgery, more detailed preoperative management and planning are necessary to achieve a successful outcome. The selection of the flaps according to the local lesion and metastatic lesions and changes in the local hemodynamics should be considered when planning.
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Motor neurons in the spinal cord are essential for movement. During the embryonic period, developing motor neurons store glycogen to protect against hypoglycemic and hypoxic stress. However, the mechanisms by which glycogen metabolism is regulated in motor neurons remain unclear. We herein investigated the transcriptional regulation of genes related to glycogen metabolism in the developing spinal cord. We focused on the regulatory mechanism of glycogen synthase (Gys1) and glycogen phosphorylase brain isoform (PygB), which play central roles in glycogen metabolism, and found that the transcription factor STAT3 regulated the expression of Gys1 and PygB via cis-regulatory promoter sequences in the developing spinal cord. These results suggest that STAT3 is important for the regulation of glycogen metabolism during motor neuron development.
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Glicogênio Sintase , Glicogenólise , Glicogênio Sintase/genética , Glicogênio Sintase/metabolismo , Glicogênio/metabolismo , Neurônios Motores/metabolismo , Regulação da Expressão GênicaRESUMO
Owing to recent advances in medical optical technology, a high-definition (4K) three-dimensional (3D) exoscope has been developed as an alternative tool to using conventional microscopes for microscopic surgery, and its efficacy for neurosurgery has been reported. We report a case who underwent simultaneous surgery aiming for en bloc resection of an anterior skull base malignancy with concurrent exoscopic transcranial and endoscopic endonasal approaches using a 4K 3D exoscope. The patient was a 76-year-old woman who underwent en bloc resection for an anterior skull base olfactory neuroblastoma 13 years ago. After confirming the recurrence of progressive olfactory neuroblastoma, tumor resection was again decided to be performed. As with the first procedure, surgery was performed in an en bloc manner, using both transcranial and endonasal approaches. Exoscope provided enough space above the surgical field to allow us to perform transcranial and endonasal surgeries simultaneously. Moreover, the surgeons could maintain a comfortable posture throughout the procedure, and total tumor removal was successfully achieved without any abnormal event. To our knowledge, this is the first report of the introduction of an exoscope aiming for en bloc resection of an anterior skull base malignancy while performing simultaneous surgery with both transcranial and endonasal approaches. We believe that the more cases are accumulated, the more efficacy of a 4K 3D exoscope will be elucidated.
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ABSTRACT: This study aimed to analyze the Hess area ratio (HAR%) in cases of blowout fracture treated in our department and clarify the outline of eye movement disorders in blowout fractures. Patients who underwent surgery for orbital blowout fractures in our department were included. Fracture locations were classified into 5 types (A, outside floor; B, C, anterior and posterior floor; and D, E, anterior and posterior medial wall). The HAR% was compared before and after surgery in eligible cases. The relationship between the fracture location and preoperative HAR% was investigated using multiple regression analysis. The study involved 85 patients. Hess area ratio was higher postoperatively than preoperatively (70.75â±â18.26 versus 90.06â±â13.99, Pâ <â0.01). The postoperative HAR% tended to be higher when the iliac bones were compared to other materials; however, this difference was not significant (90.73â±â12.91 versus 80.30â±â17.81, Pâ=â0.178). Fracture locations C and E significantly contributed to the prediction of HAR% as negative regression coefficients (Pâ=â0.024 and 0.013, respectively). The posterior fracture area on both the orbital floor and medial wall contributed to the decrease in preoperative HAR%. This observation indicates that the reconstruction of the posterior region is extremely crucial.
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Transtornos da Motilidade Ocular , Fraturas Orbitárias , Doenças da Língua , Humanos , Órbita/cirurgia , Fraturas Orbitárias/diagnóstico por imagem , Fraturas Orbitárias/cirurgia , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
Temporal control of neurogenesis is central for the development and evolution of species-specific brain architectures. The balance between progenitor expansion and neuronal differentiation is tightly coordinated by cell-intrinsic and cell-extrinsic cues. Wnt signaling plays pivotal roles in the proliferation and differentiation of neural progenitors in a temporal manner. However, regulatory mechanisms that adjust intracellular signaling amplitudes according to cell fate progression remain to be elucidated. Here, we report the transcriptional controls of Gsk3ß, a critical regulator of Wnt signaling, in the developing mouse neocortex. Gsk3ß expression was higher in ventricular neural progenitors, while it gradually declined in differentiated neurons. We identified active cis-regulatory module (CRM) of Gsk3ß that responded to cell type-specific transcription factors, such as Sox2, Sox9, and Neurogenin2. Furthermore, we found extensive conservation of the CRM among mammals but not in non-mammalian amniotes. Our data suggest that a mammalian-specific CRM drives the cell type-specific activity of Gsk3ß to fine tune Wnt signaling, which contributes to the tight control of neurogenesis during neocortical development.
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We introduce a treatment that combines the cross-leg free flap with the Masquelet technique and describe two cases using this method for bone and soft tissue reconstruction. Both patients were successfully treated and ambulatory. This novel method can be safely performed using the delay technique, indocyanine-green angiography and near-infrared spectroscopy.
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Ambient temperature significantly affects developmental timing in animals. The temperature sensitivity of embryogenesis is generally believed to be a consequence of the thermal dependency of cellular metabolism. However, the adaptive molecular mechanisms that respond to variations in temperature remain unclear. Here, we report species-specific thermal sensitivity of Notch signaling in the developing amniote brain. Transient hypothermic conditions increase canonical Notch activity and reduce neurogenesis in chick neural progenitors. Increased biosynthesis of phosphatidylethanolamine, a major glycerophospholipid components of the plasma membrane, mediates hypothermia-induced Notch activation. Furthermore, the species-specific thermal dependency of Notch signaling is associated with developmental robustness to altered Notch signaling. Our results reveal unique regulatory mechanisms for temperature-dependent neurogenic potentials that underlie developmental and evolutionary adaptations to a range of ambient temperatures in amniotes.
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Temperatura Corporal/genética , Desenvolvimento Embrionário/genética , Neocórtex/metabolismo , Neurônios/metabolismo , Receptor Notch1/genética , Transdução de Sinais/genética , Animais , Membrana Celular/metabolismo , Embrião de Galinha , Galinhas , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Neurônios/citologia , Fosfatidiletanolaminas/biossíntese , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptor Notch1/metabolismo , Especificidade da Espécie , Temperatura , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo , TartarugasRESUMO
We herein report three cases of mature teratomas with pineal gland differentiation, which is a less recognized phenomenon. Case 1 was a 6-year-old male with a neck mass, Case 2 was a 23-year-old female with a retroperitoneal mass, and Case 3 was a 45-year-old female with a retroperitoneal mass. Each case showed the typical macroscopic and histological findings of mature teratoma, such as solid and cystic lesions mainly lined with a mature squamous epithelium. All cases also showed glial differentiation. Small foci of lobulated cell nests were detected in the center of or adjacent to mature glial tissue. Cells had a clear to pale eosinophilic cytoplasm with small round nuclei. Immunohistochemically, cells were positive for synaptophysin, neurofilament protein with a perivascular "club-shaped swelling" pattern, and cone-rod homeobox protein. To the best of our knowledge, this is the first report of pineal gland differentiation arising in mature teratoma, which may be easily overlooked or misdiagnosed as somatic-type tumors, particularly neuroendocrine tumors. To avoid overtreatment, pathologists need to be aware that pineal gland differentiation may occur in mature teratomas.