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Neonatal malnutrition is one of the most common causes of neurological disorders. However, the mechanism of action of the factors associated with neonatal nutrition in the brain remains unclear. In this study, we focused on fibroblast growth factor (FGF) 21 to elucidate the effects of malnutrition on the neonatal brain. FGF21 is an endocrine factor produced by the liver during lactation which is the main source of nutrition during the neonatal period. In this study, malnourishment during nursing mice induced decreased levels of Fgf21 mRNA in the liver and decreased levels of FGF21 in the serum. RNA-seq analysis of neonatal mouse brain tissue revealed that FGF21 controlled the expression of Kalrn-201 in the neonatal mouse brain. Kalrn-201 is a transcript of Kalirin, a Ras homologous guanine nucleotide exchange factor at the synapse. In mouse neurons, FGF21 induced the expression of Kalirin-7 (a Kalirin isoform) by down-regulating Kalrn-201. FGF21-induced Kalirin-7 stimulated neurite outgrowth in Neuro-2a cells. FGF21 also induced Growth hormone-releasing hormone (GHRH) expression in Neuro-2a cells. Kalirin-7 and GHRH expression induced by FGF21 was altered by inhibiting the activity of SH2-containing tyrosine phosphatase (SHP2) which is located downstream of the FGF receptor (FGFR). Additionally, malnourished nursing induced intron retention of the SHP2 gene (Ptpn11), resulting in the alteration of Kalirin-7 and GHRH expression by FGF21 signaling. Ptpn11 intron retention is suggested to be involved in regulating SHP2 activity. Taken together, these results suggest that FGF21 plays a critical role in the induction of neuronal neurite outgrowth and GHRH secretion in the neonatal brain, and this mechanism is regulated by SHP2. Thus, Ptpn11 intron retention induced by malnourished nursing may be involved in SHP2 activity.
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Factores de Crecimiento de Fibroblastos , Desnutrición , Ratones , Animales , Animales Recién Nacidos , Factores de Crecimiento de Fibroblastos/metabolismo , Neuronas/metabolismo , Desnutrición/metabolismo , Proyección Neuronal , Hormona Liberadora de Hormona del Crecimiento/metabolismo , Encéfalo/metabolismoRESUMEN
Background: A key challenge in the understanding and treatment of depression is identifying cell types and molecular mechanisms that mediate behavioral responses to antidepressant drugs. Because treatment responses in clinical depression are heterogeneous, it is crucial to examine treatment responders and nonresponders in preclinical studies. Methods: We used the large variance in behavioral responses to long-term treatment with multiple classes of antidepressant drugs in different inbred mouse strains and classified the mice into responders and nonresponders based on their response in the forced swim test. Medial prefrontal cortex tissues were subjected to RNA sequencing to identify molecules that are consistently associated across antidepressant responders. We developed and used virus-mediated gene transfer to induce the gene of interest in specific cell types and performed forced swim, sucrose preference, social interaction, and open field tests to investigate antidepressant-like and anxiety-like behaviors. Results: Cartpt expression was consistently upregulated in responders to four types of antidepressants but not in nonresponders in different mice strains. Responder mice given a single dose of ketamine, a fast-acting non-monoamine-based antidepressant, exhibited high CART peptide expression. CART peptide overexpression in the GABAergic (gamma-aminobutyric acidergic) neurons of the anterior cingulate cortex led to antidepressant-like behavior and drove chronic stress resiliency independently of mouse genetic background. Conclusions: These data demonstrate that activation of CART peptide signaling in GABAergic neurons of the anterior cingulate cortex is a common molecular mechanism across antidepressant responders and that this pathway also drives stress resilience.
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The ionic conductivity and lithium-ion transference number of electrolytes significantly influence the rate capability of Li-ion batteries. Highly concentrated Li-salt/sulfolane (SL) electrolytes exhibit elevated Li+ transference numbers due to lithium-ion hopping via a ligand exchange mechanism within their -Li+-SL-Li+- network. However, highly concentrated electrolytes (HCEs) are extremely viscous and have an ionic conductivity that is one order of magnitude less than that of conventional electrolytes. Dilution of HCEs with a non-coordinating hydrofluoroether (HFE) lowers the viscosity and produces localized high-concentration electrolytes (LHCE). However, the mechanism of Li+ transport in LHCEs is unclear. This study investigated the transport properties of LHCEs prepared by diluting a SL-based HCE with 1,1,2,2-tetrafluoroethyl-2,2,3,3-tetrafluoropropyl ether. Electrolyte viscosity decreases dramatically upon dilution, whereas ionic conductivity increases only slightly. Ion diffusivity increases with increasing HFE content due to the decrease in electrolyte viscosity. However, the Li+ transference number declines, because the HFE interferes with conduction via the Li+ hopping mechanism. The resulting decrease in the product of ionic conductivity and Li+ transference number indicates superior lithium-ion transport in the parent HCE compared with LHCEs.
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BACKGROUND: It can be difficult to differentiate psychiatric disorders from depressive states, with little knowledge on how to differentiate them. This study aimed to evaluate changes in brain activity during cognitive and emotional tasks in patients with depressive state to help with differential diagnoses. METHODS: Sixty-two patients with depressive states [17 with adjustment disorder (AD), 27 with major depressive disorder (MDD), and 18 with bipolar disorder (BD)] and 34 healthy controls (HC) were recruited. We used a verbal fluency task (VFT) and emotional word tasks with happy and threat words. Functional near-infrared spectroscopy measured the relative change in oxygenated hemoglobin in the frontotemporal areas. RESULTS: During the VFT, patients with AD or MDD showed significantly reduced activation in the bilateral frontotemporal region (all p < 0.01), whereas patients with BD demonstrated significantly reduced activation in the right frontotemporal areas compared to HC (p < 0.01). During the emotional words task with happy words, patients with MDD showed significantly increased activity in the frontopolar area compared to HC (p = 0.023). Binary logistic regression analysis showed that MDD or BD was significantly associated with brain activity during the happy word task. In distinguishing MDD or BD from HC, the happy words task performed equally well, with an area under the curve of 0.70. LIMITATIONS: All study patients were taking psychotropic drugs. CONCLUSIONS: Brain activation in response to a combination of cognitive or emotional stimuli could assist in distinguishing patients with depressive states from healthy controls.
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Trastorno Bipolar , Trastorno Depresivo Mayor , Trastorno Bipolar/psicología , Trastorno Depresivo Mayor/psicología , Emociones/fisiología , Humanos , Corteza Prefrontal/diagnóstico por imagen , Espectroscopía Infrarroja Corta/métodosRESUMEN
Colorectal cancer commonly metastasizes to the regional lymph nodes, liver, lungs and peritoneum. At present, mediastinal lymph node metastasis from colorectal cancer is uncommon and poorly understood. The present study reported a case of solitary anterior mediastinal lymph node metastasis with pericardial invasion from transverse colon cancer. An 82-year-old woman had a history of colectomy with regional lymph node dissection for transverse colon cancer (T1N1bM0 stage IIIA in the UICC classification). The patient had no symptoms, but follow-up contrast-enhanced computed tomography revealed an anterior mediastinal tumor compressing the heart 18 months after colectomy. The tumor showed fluorodeoxyglucose uptake on positron emission tomography. Resection of the anterior mediastinal tumor with pericardiectomy was performed. The tumor was 35x25 mm in size and was histopathologically characterized to be adenocarcinoma. These cells expressed cytokeratin (CK)20 and caudal-type homeobox protein 2 but not CK7 and thyroid transcription factor 1 on immunohistochemical analysis, confirming a diagnosis of metachronous mediastinal metastasis originating from colon cancer. The tumor cells invaded the adjacent pericardium and diaphragm pathologically. The patient has lived without recurrence 8 months after the surgery for mediastinal metastasis. In conclusion, clinicians should consider metastasis to the mediastinum during follow-up in patients with colorectal cancer. Surgery may be the most reliable treatment for solitary anterior mediastinal lymph node metastasis, preventing carcinomatous pericarditis through direct pericardial invasion.
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INTRODUCTION: Endometriosis is a common gynecological disease that affects approximately 10% of reproductive-age women. Inguinal endometriosis is uncommon, affecting only 0.6% of all patients with endometriosis. We present a case of inguinal endometriosis with a disappearing mass preoperatively. PRESENTATION OF CASE: A 44-year-old woman presented with a palpable mass and pain in her left inguinal region. Computed tomography showed a 20-mm mass near the pubic tubercle. After 2 months of observation, the mass became impalpable and could not be confirmed by computed tomography; however, the inguinal pain did not improve regardless of menstrual cycles. Resection of the inguinal mass and the entire extraperitoneal portion of the uterine round ligament was performed. Histopathological examination revealed endometrial glands and stroma with CD10-positive cells, which confirmed inguinal endometriosis diagnosis. Erythrophagocytic macrophages indicated endometriosis-related hematoma absorption. Her symptoms disappeared after surgery, and no postoperative complications occurred. DISCUSSION: For treating inguinal endometriosis, the complete removal of the mass and the entire extraperitoneal portion of the round ligament by an anterior approach is necessary to prevent postoperative residual symptoms and recurrence. However, the preoperative diagnosis of inguinal endometriosis remains a challenge and is frequently discovered incidentally by intraoperative findings and pathological examination. CONCLUSION: Clinicians should have a high suspicion of inguinal endometriosis and improved diagnostic precision to select the appropriate surgical approach. Regardless of menstrual variability, the feature of a decreased mass size caused by endometriosis-related hematoma absorption can serve as a preoperative diagnostic clue.
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BACKGROUND: The intestinal environment plays important roles in mucosal barrier homeostasis and intestinal inflammation, as clarified in studies using experimental animals but not in humans. AIMS: We investigated whether environmental changes in the fecal stream cause phenotypic changes in the human mucosal barrier. METHODS: We obtained human ileal samples after fecal stream diversions in patients with rectal cancer or Crohn's disease. We investigated the bacterial load and diversity in the human defunctioned ileum, defined as the anal side of the ileum relative to the ileostomy. We also examined the epithelium and lamina propria cell phenotypes in the defunctioned ileum. RESULTS: After fecal stream diversion, bacterial loads decreased significantly in the defunctioned ileum. Based on the Chao1, Shannon, and observed species indices, the diversity of mucosa-associated microbiota was lower in the defunctioned ileum than in the functional ileum. Moreover, the healthy defunctioned ileum showed reductions in villous height, goblet cell numbers, and Ki-67+ cell numbers. Additionally, interferon-γ+, interleukin-17+, and immunoglobulin A+ cell abundance in the lamina propria decreased. After the intestinal environment was restored with an ileostomy closure, the impaired ileal homeostasis recovered. The defunctioned ileum samples from patients with Crohn's disease also showed reductions in interferon-γ+ and interleukin-17+ cell numbers. CONCLUSIONS: Fecal stream diversion reduced the abundance and diversity of intestinal bacteria. It also altered the intestinal mucosal barrier, similar to the alterations observed in germ-free animals. In patients with Crohn's disease, Th1 and Th17 cell numbers were attenuated, which suggests that the host-microbiome interaction is important in disease pathogenesis.
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Enfermedad de Crohn , Enfermedad de Crohn/patología , Humanos , Íleon/patología , Interferón gamma , Interleucina-17 , Mucosa Intestinal/patologíaRESUMEN
Postpartum depression is an important mental health issue not only for the mother but also for the child's development, other family members, and the society. An appropriate animal model is desired to elucidate the pathogenesis of postpartum depression. However, methods for stress loading during pregnancy have not been established. Behavioral experiments to investigate postpartum depression-like behaviors should be conducted without stress because behavioral tests affect rearing behaviors such as lactation. Therefore, we developed a new mouse model of postpartum depression using a psychological stress method. Mating partners were made to witness their partners experiencing social defeat stress and then listen to their cries. Emotional stress loading during pregnancy significantly increased postpartum depression-like behaviors. Postpartum depression also affected nurturing behaviors and caused disturbances in pup care. Furthermore, nesting behavior was impaired in the stressed group, suggesting that the observation of nesting behavior may be useful for assessing social dysfunction in postpartum depression. These results demonstrate the utility of this new mouse model of postpartum depression.
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Conducta Animal , Depresión Posparto/fisiopatología , Depresión Posparto/psicología , Modelos Animales de Enfermedad , Comportamiento de Nidificación , Animales , Ansiedad , Prueba de Esfuerzo , Femenino , Humanos , Lactancia , Masculino , Ratones , Ratones Endogámicos BALB C , Distrés Psicológico , Estrés Psicológico , NataciónRESUMEN
INTRODUCTION: Jejunoileal diverticulitis is uncommon and poorly understood. We report a case of whole jejunoileal diverticulosis with recurrent inflammation and perforation. CASE PRESENTATION: A 72-year-old man with hemodialysis presented with fever and abdominal pain. The patient had a medical history of twice having jejunoileal diverticulitis. Serum testing indicated a white blood cell count of 15,670/µL and a C-reactive protein level of 10.31 mg/dL. Contrast-enhanced computed tomography showed jejunoileal diverticulosis with the concomitant mesenteric fat opacity and a 60-mm × 45-mm mass lesion containing extraluminal air bubbles. Jejunoileal partial resection was performed. Multiple diverticulosis was recognized over the entire jejunoileum, and the pouches existed along entry points of the bowel vascular supply through the mesentery. Intestinal resection was limited to the intestinal loop associated with complicated diverticulitis with abscess. Macroscopic examination revealed multiple jejunoileal diverticulosis. In the reddened mucosa, the diverticulitis and mesenteric perforation were recognized. Microscopic examination showed protrusion of mucosal and submucosal layers through a defect in the muscular layer with gangrenous inflammation. These findings supported a diagnosis of jejunoileal diverticulitis with perforation and abscess. The patient had no postoperative complications and no recurrence within 6 months. DISCUSSION: Treatment for jejunoileal diverticulitis should be individualized for each patient according to their degree of inflammation, recurrence, and the patient's background. CONCLUSION: Extensive diverticulosis over the entire jejunoileum is very rare. In this case, the section of the inflamed diverticulosis can be distinguished and resected to avoid a short-bowel syndrome, which should lead to an uneventful postoperative course.
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Although stressful events predispose individuals to psychiatric disorders, such as depression, not all people who undergo a stressful life experience become depressed, suggesting that gene-environment interactions (GxE) determine depression risk. The ventral hippocampus (vHPC) plays key roles in motivation, sociability, anhedonia, despair-like behaviors, anxiety, sleep, and feeding, pointing to the involvement of this brain region in depression. However, the molecular mechanisms underlying the cross talk between the vHPC and GxE in shaping behavioral susceptibility and resilience to chronic stress remain elusive. Here, we show that Ca2+/calmodulin-dependent protein kinase IIß (CaMKIIß) activity in the vHPC is differentially modulated in GxE mouse models of depression susceptibility and resilience, and that CaMKIIß-mediated TARPγ-8 phosphorylation enhances the expression of AMPA receptor subunit GluA1 in the postsynaptic sites to enable stress resilience. We present previously missing molecular mechanisms underlying chronic stress-elicited behavioral changes, providing strategies for preventing and treating stress-related psychiatric disorders.
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The heterogeneity of major depressive disorder (MDD) is attributed to the fact that diagnostic criteria (e.g., DSM-5) are only based on clinical symptoms. The discovery of blood biomarkers has the potential to change the diagnosis of MDD. The purpose of this study was to identify blood biomarkers of DNA methylation by strategically subtyping patients with MDD by onset age. We analyzed genome-wide DNA methylation of patients with adult-onset depression (AOD; age ≥ 50 years, age at depression onset < 50 years; N = 10) and late-onset depression (LOD; age ≥ 50 years, age at depression onset ≥ 50 years; N = 25) in comparison to that of 30 healthy subjects. The methylation profile of the AOD group was not only different from that of the LOD group but also more homogenous. Six identified methylation CpG sites were validated by pyrosequencing and amplicon bisulfite sequencing as potential markers for AOD in a second set of independent patients with AOD and healthy control subjects (N = 11). The combination of three specific methylation markers achieved the highest accuracy (sensitivity, 64%; specificity, 91%; accuracy, 77%). Taken together, our findings suggest that DNA methylation markers are more suitable for AOD than for LOD patients.
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Metilación de ADN/fisiología , Depresión/genética , Depresión/fisiopatología , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/fisiopatología , Anciano , Metilación de ADN/genética , Epigénesis Genética/genética , Epigenómica , Femenino , Marcadores Genéticos/genética , Marcadores Genéticos/fisiología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: In patients with Crohn's disease (CD) and intestinal failure, home parenteral nutrition (HPN) is a necessary lifesaving treatment. The aim of this study was to investigate the long-term outcomes of patients with CD after initiation of HPN. METHODS: This study included patients with CD receiving HPN for intestinal failure. The patients were treated at Osaka University Hospital between January 2000 and December 2019. Patients' demographic characteristics, HPN dependence and complications, and mortality were analyzed. HPN dependence was estimated using the Kaplan-Meier method. Cox regression analysis was used for between-group comparisons. RESULTS: Twenty-one patients with CD received HPN. HPN dependence rates were 85%, 75%, 75%, and 64%, respectively, at 2, 5, 10, and 15 y after HPN initiation. Patients who weaned off HPN exhibited lower rates of immunomodulator therapy and additional intensive CD treatment (P < 0.05). Multivariate analysis revealed that not requiring additional intensive CD treatment was a significant factor in weaning off HPN. Two patients (9%) died, at a median of 14.9 y after HPN initiation, due to HPN-related liver disease and CD-associated carcinoma. Among all patients, 61% experienced catheter-related bloodstream infections (CRBSIs), with an incidence of 0.32/1000 catheter-days. Methicillin-resistant bacteria and Candida spp. each accounted for 27% of all pathogens detected in CRBSI. CONCLUSIONS: Patients with CD receiving HPN had a good prognosis, despite frequent CRBSIs in which methicillin-resistant bacteria and fungi were common pathogens. Some patients with CD can wean off HPN, even after a long period of HPN treatment. A stable disease condition during HPN might be an important factor for weaning off HPN.
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Enfermedad de Crohn , Hepatopatías , Nutrición Parenteral en el Domicilio , Enfermedad de Crohn/terapia , Humanos , Incidencia , Estudios RetrospectivosRESUMEN
DNA methylation is an epigenetic modification that regulates gene transcription. DNA methyltransferase 1 (DNMT1) plays an important role in DNA methylation. However, the involvement of DNMT1 and DNA methylation in the pathogenesis of atopic dermatitis (AD) remains unclear. In this study, microarray analysis revealed that peripheral blood mononuclear cells of AD patients with low DNMT1 expression (DNMT1-low) highly expressed dendritic cell (DC) activation-related genes. Also, DNMT1-low AD patients exhibited a higher itch score compared to AD patients with high DNMT1 expression (DNMT1-high). By using an AD-like mouse model induced by the application of Dermatophagoides farinae body ointment, we found that Dnmt1 expression was decreased, while the expression of C-C chemokine receptor type 7 (Ccr7) was upregulated in mouse skin DCs. Furthermore, mice exposed to social defeat stress exhibited Dnmt1 downregulation and Ccr7 upregulation in skin DCs. Additionally, dermatitis and itch-related scratching behavior were exacerbated in AD mice exposed to stress. The relationship between low DNMT1 and itch induction was found in both human AD patients and AD mice. In mouse bone marrow-derived DCs, Ccr7 expression was inhibited by 5-aza-2-deoxycytidine, a methylation inhibitor. Furthermore, in mouse skin DCs, methylation of CpG sites in Ccr7 was modified by either AD induction or social defeat stress. Collectively, these findings suggest that social defeat stress exacerbates AD pathology through Dnmt1 downregulation and Ccr7 upregulation in mouse skin DCs. The data also suggest a role of DNMT1 downregulation in the exacerbation of AD pathology.
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ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Células Dendríticas/metabolismo , Dermatitis Atópica/enzimología , Regulación hacia Abajo , Receptores CCR7/genética , Derrota Social , Estrés Psicológico/enzimología , Regulación hacia Arriba , Adulto , Anciano , Anciano de 80 o más Años , Animales , Metilación de ADN , Dermatitis Atópica/sangre , Dermatitis Atópica/genética , Femenino , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Prurito/sangre , Prurito/patología , Receptores CCR7/metabolismo , Piel/patología , Estrés Psicológico/sangreRESUMEN
The prevalence of depression in later life is higher in women than in men. However, the sex difference in the pathophysiology of depression in elderly patients is not fully understood. Here, we performed gene expression profiling in leukocytes of middle-aged and elderly patients with major depressive disorder, termed later-life depression (LLD) in this context, and we characterized the sex-dependent pathophysiology of LLD. A microarray dataset obtained from leukocytes of patients (aged ≥50 years) with LLD (32 males and 39 females) and age-matched healthy individuals (20 males and 24 females) was used. Differentially expressed probes were determined by comparing the expression levels between patients and healthy individuals, and then functional annotation analyses (Ingenuity Pathway Analysis, Reactome pathway analysis, and cell-type enrichment analysis) were performed. A total of 1656 probes were differentially expressed in LLD females, but only 3 genes were differentially expressed in LLD males. The differentially expressed genes in LLD females were relevant to leukocyte extravasation signaling, Tec kinase signaling and the innate immune response. The upregulated genes were relevant to myeloid lineage cells such as CD14+ monocytes. In contrast, the downregulated genes were relevant to CD4+ and CD8+ T cells. Remarkable innate immune signatures are present in the leukocytes of LLD females but not males. Because inflammation is involved in the pathophysiology of depression, the altered inflammatory activity may be involved in the pathophysiology of LLD in women. In contrast, abnormal inflammation may be an uncommon feature in LLD males.
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Trastorno Depresivo Mayor , Anciano , Linfocitos T CD8-positivos , Trastorno Depresivo Mayor/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunidad Innata , Masculino , Análisis por Micromatrices , Persona de Mediana EdadRESUMEN
Although major depressive disorder (MDD) is a leading cause of disability worldwide, its pathophysiology is poorly understood. Increasing evidence suggests that aberrant regulation of transcription plays a key role in the pathophysiology of MDD. Recently, long noncoding RNAs (lncRNAs) have been recognized for their important functions in chromatin structure, gene expression, and the subsequent manifestation of various biological processes in the central nervous system. However, it is unclear whether the aberrant expression and function of lncRNAs are associated with the pathophysiology of MDD. In this study, we sought to evaluate the expression of lncRNAs in peripheral blood leukocytes as potential biomarkers for MDD. We measured the expression levels of 83 lncRNAs in the peripheral blood leukocytes of 29 MDD patients and 29 age- and gender-matched healthy controls using quantitative reverse transcription PCR (RT-qPCR) analysis. We found that MDD patients exhibited distinct expression signatures. Specifically, the expression level of one lncRNA (RMRP) was lower while the levels of four (Y5, MER11C, PCAT1, and PCAT29) were higher in MDD patients compared to healthy controls. The expression level of RMRP was correlated with depression severity as measured by the Hamilton Depression Rating Scale (HAM-D). Moreover, RMRP expression was lower in a mouse model of depression, corroborating the observation from MDD patients. Taken together, our data suggest that lower RMRP levels may serve as a potential biomarker for MDD.
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Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/fisiopatología , Epigénesis Genética/fisiología , Leucocitos/metabolismo , ARN Largo no Codificante/metabolismo , Adulto , Animales , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Intestinal failure is the most critical complication of Crohn's disease. Intestinal failure requires home parenteral nutrition, which worsens the quality of life of the patients and sometimes causes life-threatening complications. AIMS: The purpose of this study was to investigate the incidence and risk factors for intestinal failure in Crohn's disease. METHODS: We performed a retrospective analysis of Crohn's disease patients (162 cases) at Osaka University Hospital between January 2000 and December 2017. Kaplan-Meier analysis was used to investigate the cumulative incidence of intestinal failure. To identify the risk factors of intestinal failure, patient characteristics were analyzed by multivariate analysis, including disease classification, surgical history, medical treatment other than surgery, and cumulative inflammation was calculated using the average C-reactive protein value and disease duration. RESULTS: The cumulative incidence of intestinal failure 5, 10, and 15 years after Crohn's disease diagnosis was 2.6%, 3.4%, and 8.6%, respectively. Multivariate analysis identified the following as independent risk factors for intestinal failure in Crohn's disease: residual small intestinal length < 200 cm (odds ratio 7.51, 95% confidence interval 2.14-29.96), non-use of anti-tumor necrosis factor-alpha therapy (3.34, 1.22-10.74), and cumulative inflammation (1.01, 1.001-1.038). We created a new predictive nomogram consisting of these risk factors. CONCLUSIONS: Intestinal failure occasionally occurred during long-term treatment of Crohn's disease. Cumulative inflammation for the first time, in addition to short residual small intestinal length and non-use of anti-tumor necrosis factor-alpha therapy, was shown to be potential risk factors for intestinal failure in Crohn's disease.
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Enfermedad de Crohn/epidemiología , Absorción Intestinal , Intestino Delgado/fisiopatología , Síndromes de Malabsorción/epidemiología , Adolescente , Adulto , Anciano , Antiinflamatorios/uso terapéutico , Niño , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Duración de la Terapia , Femenino , Humanos , Incidencia , Japón/epidemiología , Síndromes de Malabsorción/diagnóstico , Síndromes de Malabsorción/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Adulto JovenRESUMEN
AIMS: Interferon-γ (IFN-γ) exhibits hepatotoxicity through signal transducer and activator of transcription 1 (STAT1) activation. On the contrary, interleukin-11 (IL-11) shows tissue-protective effects on various organs including the liver through STAT3 activation. Here, we found that IL-11 pretreatment protects hepatocytes from IFN-γ-induced death and investigated the molecular mechanisms, particularly focusing on signal crosstalk. METHODS AND RESULTS: Primary culture mouse hepatocytes were treated with IL-11 prior to IFN-γ, and cell death was evaluated by lactate dehydrogenase release into media. As a result, IL-11 pretreatment effectively suppressed IFN-γ-induced hepatocyte death. Since IFN-γ-induced hepatocyte death requires STAT1 signaling, the activity of STAT1 was analyzed. IFN-γ robustly activated STAT1 with its peak at 1 hr after stimulation, which was significantly attenuated by IL-11 pretreatment. Consistently, IL-11 pretreatment impeded mRNA increase of STAT1-downstream molecules promoting cell death, i.e., IRF-1, caspase 1, bak, and bax. IL-11-mediated suppression of STAT1 signaling was presumably due to upregulation of the suppressor of cytokine signaling (SOCS) genes, which are well-known negative feedback regulators of the JAK/STAT pathway. Interestingly, however, IFN-γ pretreatment failed to affect the following IL-11-induced STAT3 activation, although IFN-γ also upregulated SOCSs. Finally, we demonstrated that IL-11 pretreatment mitigated oxidative stress through increasing expression of ROS scavengers. CONCLUSION: IL-11 protects hepatocytes from IFN-γ-induced death via STAT1 signal suppression and ROS scavenging. Further investigation into the mechanisms underlying selective negative feedback regulation of IFN-γ/STAT1 signaling compared to IL-11/STAT3 signaling may shed new light on the molecular biology of hepatocytes.
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Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Interferón gamma/farmacología , Interleucina-11/farmacología , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Muerte Celular/fisiología , Células Cultivadas , Regulación hacia Abajo/efectos de los fármacos , Femenino , Hepatocitos/citología , Interferón gamma/metabolismo , Interleucina-11/metabolismo , Ratones , Ratones Endogámicos ICR , Estrés Oxidativo/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismoRESUMEN
No neuroanatomical substrates for distinguishing between depression of bipolar disorder (dBD) and major depressive disorder (dMDD) are currently known. The aim of the current multicenter study was to identify neuroanatomical patterns distinct to depressed patients with the two disorders. Further analysis was conducted on an independent sample to enable generalization of results. We directly compared MR images of these subjects using voxel-based morphometry (VBM) and a support vector machine (SVM) algorithm using 1531 participants. The VBM analysis showed significantly reduced gray matter volumes in the bilateral dorsolateral prefrontal (DLPFC) and anterior cingulate cortices (ACC) in patients with dBD compared with those with dMDD. Patients with the two disorders shared small gray matter volumes for the right ACC and left inferior frontal gyrus when compared with healthy subjects. Voxel signals in these regions during SVM analysis contributed to an accurate classification of the two diagnoses. The VBM and SVM results in the second cohort also supported these results. The current findings provide new evidence that gray matter volumes in the DLPFC and ACC are core regions in displaying shared and distinct neuroanatomical substrates and can shed light on elucidation of neural mechanism for depression within the bipolar/major depressive disorder continuum.
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Trastorno Bipolar/diagnóstico por imagen , Trastorno Depresivo Mayor/diagnóstico por imagen , Giro del Cíngulo/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Corteza Prefrontal/diagnóstico por imagen , Adulto , Trastorno Bipolar/psicología , Estudios de Cohortes , Trastorno Depresivo Mayor/psicología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: Hepatectomy including conversion therapy is recommended for colorectal liver metastasis (CRLM). CRLM complicated with bile duct tumor thrombus (BDTT) is rare, even though there are more opportunities to perform hepatectomy for CRLM in recent years. PRESENTATION OF CASE: A 76-year-old Japanese man with a history of right hemicolectomy for ascending colon carcinoma presented with a portal hepatic tumor and the dilatation of the right bile duct found by computed tomography (CT) eighteen months after the colectomy. Magnetic resonance imaging confirmed a tumor in liver segment VIII, and magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed a mass in the hilar bile duct. Bile cytology did not prove carcinoma. The patient underwent right and caudate lobectomy with extrahepatic biliary tract resection plus hepaticojejunostomy. Histopathological examination revealed that both the tumor in liver segment VIII and the BDTT comprised moderately differentiated tubular adenocarcinoma, originating from the previous colon carcinoma. Six months after hepatectomy, CT revealed tumor recurrence in the residual intrahepatic bile duct. Radiation therapy was administered for the recurrent lesion, which reduced the tumor size temporarily. Despite the multimodal therapy, the disease progressed and the patient died one year after the hepatectomy. DISCUSSION: Some studies reported no correlation between CRLM bile duct invasion and clinical outcomes, but there is no available evidence focused on BDTT which is of an advanced stage in the bile duct invasion. CONCLUSION: Hepatectomy is a common therapeutic procedure for CRLM, but CRLM with BDTT might be associated with a bad prognosis.