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The blood-brain barrier (BBB) impedes the influx of intravascular compounds from the blood to the brain. The elements composing the BBB are endothelial cells, pericytes and the end-feet of astrocytes. Among them, the endothelial cell barrier line is the most critical for preventing toxic substances from entering the brain. In this review, we focus on the ultrastructural distribution of important components in the intracellular junction and cytoplasm of brain endothelial cells. The ultrastructural distribution of tight junction-specific integral membrane proteins such as occludin, junctional adhesion molecules, claudin, peripheral zonula occludens protein-1 (ZO-1), adherens junction-specific transmembrane protein cadherin, and adherens junction-associated peripheral proteins α-catenin, β-catenin, and p120 catenin is reviewed. P-glycoprotein and some other transporters recently discovered in endothelial cells prevent several compounds from entering the brain parenchyma. It is likely that the transient inhibition of P-glycoprotein by antidepressants enables other medicines to enter the brain. Vesicular transport with clathrin-mediated or adsorptive endocytosis through endothelial cells is also critical for transportation of bloodborn substances from the bloodstream to the brain. How medicines pass the BBB to reach the brain parenchyma is discussed.

In this study, the authors show that layer V projection neurons require the presence of subcortical CX3CR1-positive microglia for survival. IGF1 secretion from these microglia appears to be necessary for this trophic effect. Inhibition of the microglial cell activation abrogates IGF1 secretion and compromises neuronal survival. Neurons require trophic support during neural circuit formation; however, how the cellular milieu contributes to neuronal survival remains unclear. We found that layer V cortical neurons require support from microglia for survival during postnatal development. Specifically, we found that microglia accumulated close to the subcerebral and callosal projection axons in the postnatal brain. Inactivation of microglia by minocycline treatment or transient ablation of microglia in CD11b-DTR transgenic mice led to increased apoptosis, specifically in layer V subcerebral and callosal projection neurons. CX3CR1 in microglia was required for the survival of layer V neurons. Microglia consistently promoted the survival of cortical neurons in vitro . In addition, we identified microglia-derived IGF1 as a trophic factor that maintained neuronal survival. Our results highlight a neuron-glia interaction that is indispensable for network formation during a specific period in the developing brain.

Brain injury causes serious motor, sensory, and cognitive disabilities. Accumulating evidence has demonstrated that histone deacetylase (HDAC) inhibitors exert neuroprotective effects against various insults to the central nervous system (CNS). In this study, we investigated the effects of the HDAC inhibition on the expression of brain-derived neurotrophic factor (BDNF) and functional recovery after traumatic brain injury (TBI) in mice. Administration of class I HDAC inhibitor increased the number of synaptic boutons in rewiring corticospinal fibers and improved the recovery of motor functions after TBI. Immunohistochemistry results showed that HDAC2 is mainly expressed in the neurons of the mouse spinal cord under normal conditions. After TBI, HDAC2 expression was increased in the spinal cord after 35 days, whereas BDNF expression was decreased after 42 days. Administration of CI-994 increased BDNF expression after TBI. Knockdown of HDAC2 elevated H4K5ac enrichment at the BDNF promoter, which was decreased following TBI. Together, our findings suggest that HDAC inhibition increases expression of neurotrophic factors, and promote neuronal rewiring and functional recovery following TBI.

Background Esophageal cancer is the eighth most common cause of cancer mortality in Japan. More than 11,000 people had died from esophageal cancer in 2018. The Japan Esophageal Society has collected the data on patients' characteristics, performed treatment, and outcomes annually. Methods We analyzed the data of patients who had first visited the participating hospitals in 2013. In 2019, the data collection method was changed from an electronic submission to a web-based data collection using the National Clinical Database (NCD). Japanese Classification of Esophageal Cancer 10th by the Japan Esophageal Society (JES) and UICC TNM Classification 7th were used for cancer staging Results A total of 8019 cases were registered from 334 institutions in Japan. Squamous cell carcinoma and adenocarcinoma accounted for 87.8% and 6.3%, respectively. The 5-year survival rates of patients treated using endoscopic resection, concurrent chemoradiotherapy, radiotherapy alone, or esophagectomy were 88.3%, 32.4%, 24.4%, and 59.3%, respectively. Esophagectomy was performed in 4910 cases. The operative and the hospital mortality rates were 0.77% and 1.98%, respectively. The survival curves showed a good discriminatory ability both in the clinical and pathologic stages by the JES system. The 5-year survival rate of patients with pStage IV in the UICC classification that included patients with supraclavicular node metastasis was better than that of patients with pStage IVb in JES classification. Conclusion We hope this report contributes to improving all aspects of the diagnosis and treatment of esophageal cancer in Japan.

Descending neural pathways to the spinal cord plays vital roles in motor control. They are often damaged by brain injuries such as stroke and trauma, which lead to severe motor impairments. Due to the limited capacity for regeneration of neural circuits in the adult central nervous system, currently no essential treatments are available for complete recovery. Notably, accumulating evidence shows that residual circuits of the descending pathways are dynamically reorganized after injury and contribute to motor recovery. Furthermore, recent technological advances in cell-type classification and manipulation have highlighted the structural and functional diversity of these pathways. Here, we focus on three major descending pathways, namely, the corticospinal tract from the cerebral cortex, the rubrospinal tract from the red nucleus, and the reticulospinal tract from the reticular formation, and summarize the current knowledge of their structures and functions, especially in rodent models (mice and rats). We then review and discuss the process and patterns of reorganization induced in these pathways following injury, which compensate for lost connections for recovery. Understanding the basic structural and functional properties of each descending pathway and the principles of the induction and outcome of the rewired circuits will provide therapeutic insights to enhance interactive rewiring of the multiple descending pathways for motor recovery.

The authors document a novel neurogenic mechanism to explain the clinical syndrome known as spinal cord injury–induced immune deficiency. Specifically, they show that new spinal–splenic sympathetic circuitry forms below the level of injury, creating an exaggerated sympathetic anti-inflammatory reflex. Inhibiting excitatory interneurons within this circuitry blocks immune suppression. Spinal cord injury (SCI) at high spinal levels (e.g., above thoracic level 5) causes systemic immune suppression; however, the underlying mechanisms are unknown. Here we show that profound plasticity develops within spinal autonomic circuitry below the injury, creating a sympathetic anti-inflammatory reflex, and that chemogenetic silencing of this reflex circuitry blocks post-SCI immune suppression. These data provide new insights and potential therapeutic options for limiting the devastating consequences of post-traumatic autonomic hyperreflexia and post-injury immune suppression.

BackgroundRecurrent esophageal cancer after radical therapy usually is thought to be incurable and treated with palliative-intent systemic therapy. However, it is empirically known that surgical resection may be effective for selected patients, although no consensus exists on the efficacy of surgery for recurrent esophageal cancer. This study sought to identify a group of patients for whom surgical resection is considered effective.MethodsThe study enrolled 206 patients at a single center who had recurrence after radical therapy for esophageal cancer. Prognostic factors after recurrence were identified, and efficacy of surgery was analyzed according to whether the recurrent lesions were oligometastases (i.e., ≤ 5 lesions in a single domain) or not.ResultsIn the multivariate analysis, oligometastatic presentation was the only factor associated with survival after recurrence (hazard ratio 6.29; 95% confidence interval, 4.10–9.71). The actuarial survival rates for the patients with oligometastases were 59.5% at 3 years and 51.7% at 5 years. The survival rates at 3 and 5 years were significantly higher for the patients who underwent resection (64.3% and 55.6%, respectively) than for those who did not (both 100%) and for the patients with multiple metastases (9.8% and 0%, respectively). The survival rates for the patients who had oligometastases without resection were comparably lower than for the patients with multiple metastases.ConclusionOligometastatic presentation at recurrence was associated with better survival outcomes for the patients who experienced recurrence after radical treatment for esophageal cancer, and surgical resection could be a choice of treatment for this group of patients.

Background The registration committee for esophageal cancer in the Japan Esophageal Society (JES) has collected the patients' characteristics, treatment, and outcomes annually. Methods We analyzed the data of patients who had visited the participating hospitals in 2014. We collected the data with a web-based data collection system using the National Clinical Database. We used the Japanese Classification of Esophageal Cancer 10th edition by JES and the TNM classification 7th edition by the Union of International Cancer Control (UICC) for cancer staging. Results A total of 9026 cases were registered from 344 institutions in Japan. Squamous cell carcinoma and adenocarcinoma accounted for 87.9% and 7.1%, respectively. The 5-year survival rates of patients treated using endoscopic resection, concurrent chemoradiotherapy, radiotherapy alone, and esophagectomy were 87.1%, 33.7%, 25.3%, and 59.3%, respectively. Esophagectomy was performed in 5204 cases. Concerning the approach used for esophagectomy, 48.1% of the cases were treated thoracoscopically. The operative mortality (within 30 days after surgery) was 0.75%, and the hospital mortality was 2.0%. The survival curves showed an excellent discriminatory ability both in the clinical and pathologic stages by the JES system. The survival of pStage IV was better than IIIC in the UICC system, because pStage IV included the patients with supraclavicular lymph-node metastasis (M1 LYM). Conclusion We hope that this report contributes to improving all aspects of diagnosing and treating esophageal cancer in Japan.

Background Adjuvant chemotherapy for resectable colorectal liver metastasis (CRLM) is widely used, but its efficacy lacks clear evidence. This retrospective cohort study investigated the effectiveness of neoadjuvant chemotherapy (NAC) compared to upfront surgery for CRLM. Methods Data from patients with resectable CRLM were analyzed. Short-term outcomes and long-term prognosis were analyzed using propensity score matching. CRLM was stratified according to the H-classification (H1 and H2), and the effectiveness of adjuvant chemotherapy was analyzed in each group. Results We analyzed 599 cases that were matched into an NAC group ( n  = 136) and an upfront surgery group ( n  = 136). The proportion of synchronous metastases, H2-classification, and postoperative chemotherapy rate did not differ between the groups. Overall survival (OS) after initial treatment was significantly worse in the NAC group than in the upfront surgery group ( P  = 0.029). The 5-, 7-, and 10-year OS rates for H1 patients were significantly better in the upfront surgery group than in the NAC group (64%, 51%, and 44% vs. 50%, 31%, and 18%, respectively) ( P  = 0.004). Conclusion Patients with resectable CRLM should undergo upfront surgery, because NAC did not improve OS after initial treatment in these patients.

BackgroundThoracic duct (TD) resection is performed when the tumor or a metastatic lymph node directly invades the TD, and is sometimes indicated for radical lymphadenectomy during esophagectomy in esophageal cancer patients. However, the effect of TD resection on nutritional status has not been established.Patients and MethodsIn total, 174 consecutive patients from October 2015 to March 2019 who underwent radical esophagectomy for esophageal cancer in Toranomon Hospital were classified into thoracic duct preserved group (n = 51) and TD-resected (TD-R) group (n = 123). We compared laboratory data, body composition data from bioelectrical impedance analysis measured preoperatively and at 1 and 12 months after surgery, and postoperative complications between the two groups.ResultsClinical stage was significantly more advanced in the TD-R group. Total body weight, body mass index, and fat mass continuously decreased in the two groups over 12 months after surgery, and the decreases were statistically greater in the TD-R group at 12 months after surgery. Skeletal muscle mass and fat-free mass decreased over 1 month after surgery and stayed in a reduced state until 12 months after surgery without statistically significant differences between the two groups. TD resection did not increase incidence of postoperative complications (Clavien–Dindo classification ≥ grade III), but TD resection increased incidence of chylothorax.ConclusionsOur results suggest that loss of body fat mass, which was a main contributor to body weight loss, was accelerated in the TD-R group, but TD resection does not deteriorate loss of muscle mass at 12 months after surgery.