Early arteriovenous fistula failure associated with mortality and major adverse cardiovascular events in patients undergoing incident hemodialysis.

BACKGROUND: Arteriovenous fistula (AVF) patency is important for patients undergoing hemodialysis. The association between early AVF failure and the prognosis, including all-cause mortality and major adverse cardiovascular events (MACE), has not been fully investigated. The present study was performed to investigate the association between early AVF failure and 3-year mortality, cardiovascular disease (CVD) mortality, and MACE. METHODS: We analyzed 358 patients who started hemodialysis in our institution from October 2008 to February 2020. We defined early AVF failure as cases requiring percutaneous transluminal angioplasty or reoperation within 1 year after AVF surgery. The patients were divided into two groups according to the presence or absence of early AVF failure, and the prognosis of each group was examined. The association between early AVF failure and outcomes (3-year all-cause mortality, CVD mortality, and MACE) was determined using Cox proportional hazards regression analysis. RESULTS: During the 3-year follow-up, 75 (20.9%) patients died (cardiovascular death: n = 39) and 145 patients developed MACE. According to the multivariable analysis, the early AVF failure group had a significantly higher risk of 3-year all-cause mortality (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.09-1.83; p = 0.009), CVD mortality (HR, 1.54; 95% CI, 1.29-2.08; p < 0.001), and MACE (HR, 1.68; 95% CI, 1.25-2.26; p < 0.001). When the patients were stratified by age, early AVF failure was associated with 3-year all-cause mortality in all groups except for the younger group (<65 years of age). CONCLUSIONS: Early AVF failure was associated with an increased risk of 3-year all-cause mortality, CVD mortality, and MACE.

Advantages of enhanced recovery after surgery program in robot-assisted radical cystectomy.

Radical cystectomy is a gold-standard treatment for muscle-invasive bladder cancer. We recently introduced robot-assisted radical cystectomy (RARC) with perioperative enhanced recovery after surgery (ERAS). The medical records of patients with bladder cancer who underwent open radical cystectomy (ORC) or RARC/ERAS at NTT Medical Center Tokyo were retrospectively reviewed to compare the surgical outcomes, hospital stay, and medical costs between groups. Multidisciplinary full ERAS items were provided for the RARC/ERAS group. The median estimated blood losses in the ORC and RARC/ERAS groups were 650 and 100 mL, and the median operative times were 312 and 445 min, respectively. In addition, the median times to liquid food intake in these groups were 6 and 0 days, the median times to first flatus and first defecation were 2 and 1 day, and 3 and 1.5 days, respectively. The rates of postoperative ileus in the ORC and RARC/ERAS groups were 27.5% and 4.5%, and the median postoperative hospital stays was 26.5 and 12 days, respectively. Medical costs excluding surgery were significantly lower in the RARC/ERAS group. In conclusion, RARC/ERAS represents a safe treatment option for muscle-invasive bladder cancer with decreased perioperative complications and lower medical costs.

Localization and Maintenance of Engrafted Mesenchymal Stem Cells Administered via Renal Artery in Kidneys with Ischemia-Reperfusion Injury.

Mesenchymal stem cells (MSCs) are a potential therapeutic tool for preventing the progression of acute kidney injury (AKI) to chronic kidney disease (CKD). Herein, we investigated the localization and maintenance of engrafted human bone marrow-derived MSCs in rats subjected to a renal ischemia-reperfusion injury (IRI) and compared the effectiveness of two intravascular injection routes via the renal artery or inferior vena cava. Renal artery injection of MSCs was more effective than intravenous injection at reducing IRI-induced renal fibrosis. Additionally, MSCs injected through the renal artery persisted in injured kidneys for over 21 days, whereas MSCs injected through the inferior vena cava survived for less than 7 days. This difference may be attributed to the antifibrotic effects of MSCs. Interestingly, MSCs injected through the renal artery were localized primarily in glomeruli until day 3 post-IRI, and they decreased in number thereafter. In contrast, the number of MSCs localized in tubular walls, and the interstitium increased gradually until day 21 post-IRI. This localization change may be related to areas of damage caused by IRI because ischemia-induced AKI leads to tubular cell damage. Taken together, these findings suggest renal artery injection of MSCs may be useful for preventing the progression of AKI to CKD.

[Selenoprotein-related myopathy in a patient with old-age-onset type 2 respiratory failure: a case report].

A 71-year-old woman was admitted to our hospital with type2 respiratory failure. Her daily life activities had been normal, although she had noticed mild truncal weakness in her sixties. Her parents were consanguineous, and her sister had suffered similar symptoms. Although Pompe disease was suspected on the basis of the clinical course and CT findings of selective muscular atrophy in the paraspinal, thigh flexor and sartorius muscle, acid alpha-glucosidase activity was normal. The serum creatine kinase level was not elevated, and muscle biopsy showed no specific change. Genetic analysis revealed a novel homozygous variant c.227T>C (p.Phe76Ser) in the SELENON gene, and she was suspected to have selenoprotein-related myopathy, which is reported to develop in childhood. Selenoprotein-related myopathy should be considered as a differential diagnosis in aged patients presenting with respiratory failure of unknown origin.

Interferon-γ enhances the therapeutic effect of mesenchymal stem cells on experimental renal fibrosis.

Mesenchymal stem cells (MSCs) administered for therapeutic purposes can be activated by interferon-γ (IFN-γ) secreted from natural killer cells in injured tissues and exert anti-inflammatory effects. These processes require a substantial period of time, leading to a delayed onset of MSCs' therapeutic effects. In this study, we investigated whether pretreatment with IFN-γ could potentiate the anti-fibrotic ability of MSCs in rats with ischemia-reperfusion injury (IRI) and unilateral ureter obstruction. Administration of MSCs treated with IFN-γ strongly reduced infiltration of inflammatory cells and ameliorated interstitial fibrosis compared with control MSCs without IFN-γ treatment. In addition, conditioned medium obtained from IFN-γ-treated MSCs decreased fibrotic changes in cultured cells induced by transforming growth factor-ß1 more efficiently than that from control MSCs. Most notably, secretion of prostaglandin E2 from MSCs was significantly increased by treatment with IFN-γ. Increased prostaglandin E2 in conditioned medium obtained from IFN-γ-treated MSCs induced polarization of immunosuppressive CD163 and CD206-positive macrophages. In addition, knockdown of prostaglandin E synthase weakened the anti-fibrotic effects of MSCs treated with IFN-γ in IRI rats, suggesting the involvement of prostaglandin E2 in the beneficial effects of IFN-γ. Administration of MSCs treated with IFN-γ might represent a promising therapy to prevent the progression of renal fibrosis.

Hypoxia-preconditioned mesenchymal stem cells prevent renal fibrosis and inflammation in ischemia-reperfusion rats.

BACKGROUND: Mesenchymal stem cells (MSCs) have been reported to promote the regeneration of injured tissue via their paracrine abilities, which are enhanced by hypoxic preconditioning. In this study, we examined the therapeutic efficacy of hypoxia-preconditioned MSCs on renal fibrosis and inflammation in rats with ischemia-reperfusion injury (IRI). METHODS: MSCs derived from rats and humans were incubated in 1% O2 conditions (1%O2 MSCs) for 24 h. After IRI, 1%O2 MSCs or MSCs cultured under normoxic conditions (21%O2 MSCs) were injected through the abdominal aorta. At 7 or 21 days post-injection, the rats were sacrificed and their kidneys were analyzed. In in vitro experiments, we examined whether 1%O2 MSCs enhanced the ability to produce anti-fibrotic humoral factors using transforming growth factor (TGF)-ß1-stimulated HK-2 cells incubated with conditioned medium from MSCs. RESULTS: Administration of rat 1%O2 MSCs (1%O2 rMSCs) attenuated renal fibrosis and inflammation more significantly than rat 21%O2 MSCs. Notably, human 1%O2 MSCs (1%O2 hMSCs) also attenuated renal fibrosis to the same extent as 1%O2 rMSCs. Flow cytometry showed that 1%O2 hMSCs did not change human leukocyte antigen expression. Further in vitro experiments revealed that conditioned medium from 1%O2 MSCs further suppressed TGF-ß1-induced fibrotic changes in HK-2 cells compared with 21%O2 MSCs. Hypoxic preconditioning enhanced vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) secretion. Interestingly, VEGF knockdown in 1%O2 MSCs attenuated HGF secretion and the inhibition of TGF-ß1-induced fibrotic changes in HK-2 cells. In addition, VEGF knockdown in 1%O2 hMSCs reduced the anti-fibrotic effect in IRI rats. CONCLUSIONS: Our results indicate that hypoxia-preconditioned MSCs are useful as an allogeneic transplantation cell therapy to prevent renal fibrosis and inflammation.

Incidence of metachronous gastric cancer in patients whose primary gastric neoplasms were discovered after Helicobacter pylori eradication.

BACKGROUND AND AIMS: The incidence of metachronous gastric cancer (MGC) in patients whose primary gastric neoplasm is discovered after Helicobacter pylori eradication remains unclear. Here, we evaluated the long-term effect of previous H pylori eradication on development of MGC after endoscopic submucosal dissection (ESD). METHODS: We analyzed prospectively collected data of consecutive patients with successful H pylori eradication more than 1 year before (eradicated group, 180 patients) or after (control group, 602 patients) initial curative ESD. These patients were also followed by endoscopy for over 2 years. Propensity score matching and inverse probability of treatment weighting (IPTW) were used to adjust for confounding variables during data analysis. The main outcome was the incidence of MGC after initial ESD. RESULTS: In a propensity-matched analysis of 174 pairs, the incidence of MGC was similar in the 2 cohorts (33.9 per 1000 person-years vs 40.8 per 1000 person-years in the control group, P = .454) at a median follow-up of 4.1 years (interquartile range, 3.0-5.6). Incidences were also similar in the 2 groups when data were analyzed using IPTW, even after exclusion of 123 patients with successful H pylori eradication <5 years before initial ESD. Multiple Cox regression analysis revealed age, differentiated-type histology, and initial multiplicity were predictors of MGC in patients after initial curative ESD. CONCLUSIONS: The frequency of follow-up surveillance after initial curative ESD should be kept constant, irrespective of whether H pylori eradication is performed before or after initial curative ESD.

[A case of multiple cerebral hemorrhage caused by sudden increase of eosinophil in a patient with eosinophilic granulomatosis with polyangiitis].

A 42-year-old woman with bronchial asthma was admitted to our hospital due to sensory dominant mononeuritis multiplex lasting for more than 6 months. At that time, her eosinophil count was 761/µl and her sural nerve biopsy showed no findings suggestive of vasculitis. Four months later, she experienced sudden convulsions and right hemiparesis due to left lobular parietal subcortical hemorrhage, when her eosinophil count was elevated to 3,257/µl. Numerous microbleeds and small infarctions were also detected in the intracerebral areas of different regions with MRI. Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotizing vasculitis of the small vessels, commonly affecting the peripheral nerves. Subarachnoid hemorrhage in patients with EGPA is extremely rare. Steep elevation of the eosinophil count may release certain cytokines, causing cerebral hemorrhage.

Tocilizumab histologically improved AA renal amyloidosis in a patient with multicentric Castleman disease: A case report
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Multicentric Castleman disease (MCD) is a rare systemic lymphoproliferative disorder and is infrequently associated with renal complications that include amyloid A (AA) amyloidosis. Although it has been reported that patients with MCD and amyloidosis usually have a poor prognosis, recently, tocilizumab, a humanized anti-interleukin-6 receptor antibody, has emerged as an effective and specific treatment for AA amyloidosis secondary to chronic inflammatory disorders. Here we report a case of an MCD patient with secondary AA renal amyloidosis who was successfully treated with tocilizumab. The patient was initially referred to nephrology specialists because of a decline in renal function and proteinuria. Percutaneous renal biopsy revealed the presence of Congo red-positive amorphous depositions and AA protein-positive areas in glomeruli, vessel walls, and interstitium, confirming a diagnosis of renal AA amyloidosis secondary to MCD. At 1 year after starting tocilizumab treatment, a second renal biopsy showed the clearance of amyloid deposits in the interstitium. These observations suggest that tocilizumab may be an effective therapy for AA amyloidosis secondary to MCD.
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Cone-Beam Computed Tomography Correlates with Conventional Helical Computed Tomography in Evaluation of Lipiodol Accumulation in HCC after Chemoembolization.

BACKGROUND & AIMS: The amount of drug-loaded lipiodol in an HCC tumor post-transarterial chemoembolization (TACE) correlates with the risk of local tumor recurrence. Lipiodol enhancement of a tumor on conventional CT, measured in Hounsfield units (HU), can predict tumor response. Here we investigate whether cone-beam CT (CBCT) can also be used to predict tumor response, providing the benefit of being able to optimize the patient's treatment plan intra-procedurally. METHODS: A total of 82 HCC nodules (82 patients), ≤5 cm in diameter, were treated with balloon-occluded TACE using miriplatin between December 2013 and November 2014. For each patient, both CBCT and conventional CT images were obtained post-TACE. The degree of correlation between CBCT and conventional CT was determined by comparing identical regions of interest for each imaging modality using pixel values. RESULTS: The pixel values from conventional CT and CBCT were highly correlated, with a Pearson correlation coefficient of 0.912 (p<0.001). The location of the nodules within the liver did not affect the results; the correlation coefficient was 0.891 (p<0.001) for the left lobe and 0.926 (p<0.001) for the right lobe. The mean pixel value for conventional CT was 439 ± 279 HU, and the mean pixel value for CBCT was 416 ± 311 HU. CONCLUSIONS: CBCT may be used as a substitute for conventional CT to quantitatively evaluate the amount of drug-loaded lipiodol within an HCC nodule and, hence, the efficacy of TACE treatment. The major benefit of using CBCT is the ability to predict the likelihood of local recurrence intra-procedurally, enabling subsequent treatment optimization.

The roles of interferon regulatory factors 1 and 2 in the progression of human pancreatic cancer.

OBJECTIVE: Pancreatic cancer is one of the most malignant diseases worldwide. Interferon regulatory factor (IRF) 1 and IRF2 function as a tumor suppressor and oncoprotein, respectively, in several types of cancers. We investigated whether IRF1 and IRF2 are involved in the progression of pancreatic cancer. METHODS: We examined the expressions of IRF1 and IRF2 in pancreatic cancer specimens and analyzed the association with clinicopathologic features. We evaluated the biological effects of IRF1 and IRF2 using a pancreatic cancer cell line. RESULTS: The expression levels of IRF1 and IRF2 were decreased and increased, respectively, in the pancreatic cancer cells compared with those observed in the paired normal areas. A higher expression of IRF1 was associated with better features of tumor differentiation, infiltration depth, tumor size, and survival, whereas that of IRF2 was associated with a worse feature of tumor infiltration depth. Interferon regulatory factor 2-overexpressing PANC-1 cells exhibited an increase in cell growth, less apoptotic features, and chemoresistance to gemcitabine treatment. In contrast, IRF1-overexpressing cells exhibited the opposite characteristics. CONCLUSIONS: Interferon regulatory factors 1 and 2 may regulate the progression of pancreatic cancer by functioning as an antioncoprotein and oncoprotein, respectively. These molecules may serve as potential targets of therapy.

Prophylactic effectiveness of suplatast tosilate in children with asthma symptoms in the autumn: a pilot study.

BACKGROUND: Exacerbations of bronchial asthma usually occur in the autumn. To our knowledge, however, the effectiveness of drugs for preventing exacerbations of asthma in the autumn has not been studied previously, except for leukotriene receptor antagonists and Omalizmab. METHODS: This study compared the prophylactic effectiveness of suplatast tosilate with that of mequitazine in children with asthma symptoms, which is usually exacerbated in the autumn. The study group comprised 27 children aged 2 to 15 years who required treatment for asthmatic attacks during the past year and tested positive at least for mite allergen in the preceding autumn. The subjects were randomly assigned to receive either suplatast or mequitazine. The primary endpoint of this study was the number of days without symptoms during the 8 weeks of treatment. In addition, the Japanese Pediatric Asthma Control Program (JPAC) scores were also recorded every 2 weeks in each group. RESULTS: Overall, 14 patients received suplatast, and 13 received mequitazine for 8 weeks from September through early October. During follow-up, the number of days without symptoms and the total JPAC scores did not differ significantly between the groups. However, as compared with weeks 1 to 2 of treatment, the mean number of days without symptoms during weeks 7 to 8 increased significantly in only the suplatast group (8.6 vs. 11.5 days; p = 0.004). CONCLUSIONS: Our results suggest that short-term additional treatment with suplatast is useful for preventing asthma symptoms in children with asthma, which is usually exacerbated in the autumn.

INSL5 may be a unique marker of colorectal endocrine cells and neuroendocrine tumors.

Insulin-like peptide 5 (INSL5) is a member of the insulin superfamily, and is a potent agonist for RXFP4. We have shown that INSL5 is expressed in enteroendocrine cells (EECs) along the colorectum with a gradient increase toward the rectum. RXFP4 is ubiquitously expressed along the digestive tract. INSL5-positive EECs have little immunoreactivity to chromogranin A (CgA) and might be a unique marker of colorectal EECs. CgA-positive EECs were distributed normally along the colorectum in INSL5 null mice, suggesting that INSL5 is not required for the development of CgA-positive EECs. Exogenous INSL5 did not affect the proliferation of human colon cancer cell lines, and chemically-induced colitis in INSL5 null mice did not show any significant changes in inflammation or mucosal healing compared to wild-type mice. In contrast, all of the rectal neuroendocrine tumors examined co-expressed INSL5 and RXFP4. INSL5 may be a unique marker of colorectal EECs, and INSL5-RXFP4 signaling might play a role in an autocrine/paracrine fashion in the colorectal epithelium and rectal neuroendocrine tumors.

Functional roles of TGF-ß1 in intestinal epithelial cells through Smad-dependent and non-Smad pathways.

BACKGROUND AND AIMS: Transforming growth factor-ß1 (TGF-ß1) is one of the growth factors expressed in the gut, and has been shown to play an important role in intestinal mucosal healing. We investigated the effects of TGF-ß1 on the cellular functions of intestinal epithelial cells, and also evaluated its signaling pathways in these cells. METHODS: We used the rat IEC-6 intestinal epithelial cell line for these studies. The expression of TGF-ß1/Smad signaling molecules was examined. We evaluated the effect of TGF-ß1 on the proliferation and differentiation by the BrdU incorporation assay and real-time PCR. We manipulated the expression levels of Smad2 and Smad3 using an adenovirus system and small interfering RNA to examine the signaling pathways. The expression of Smad2 and Smad3 along the crypt-villus axis was also examined in the murine intestine. RESULTS: IEC-6 cells produced TGF-ß1 and expressed functional TGF-ß/Smad signaling molecules. The addition of TGF-ß1 in the culture medium suppressed the proliferation and increased the expression of a differentiation marker of enterocytes, in a dose-dependent manner. The adenovirus-mediated and small interfering RNA-mediated studies clearly showed that the growth inhibitory effect and the promotion of differentiation were exerted through a Smad3-dependent and a Smad2-dependent pathway, respectively. IEC-6 cells exhibited upregulated expression of an inhibitory Smad (Smad7) as a form of negative feedback via a non-Smad pathway. Smad2 was predominantly expressed in villi, and Smad3 in crypts. CONCLUSIONS: TGF-ß1 regulates the cellular functions of intestinal epithelial cells through both Smad-dependent and non-Smad pathways.

Effect of Th1/Th2 cytokine pretreatment on RSV-induced gene expression in airway epithelial cells.

BACKGROUND: Respiratory syncytial virus (RSV) infection in infants with Th2 predisposition is thought to increase the risk of allergic sensitization, recurrent wheezing, and bronchial asthma during childhood. We attempted to clarify the molecular mechanisms by which Th1/Th2 predisposition in the host alters RSV infection and facilitates airway inflammation. METHODS: A549 human airway epithelial cells were inoculated with live or UV-treated RSV after pretreatment with either a combination of tumor necrosis factor (TNF)-α and interferon-γ (Th1-primed) or a combination of TNF-α and interleukin-4 (Th2-primed) for 48 h. The gene and protein expression profiles of RSV-infected A549 cells were examined. RESULTS: GeneChip analysis indicated that, at 96 h after inoculation with RSV, the expression of 62 genes was specifically enhanced (more than 2-fold by normalized data) in Th2-primed cells compared to that in unprimed or Th1-primed cells. An increase in mRNA and protein levels of monocyte chemoattractant protein (MCP)-1/CCL2 among those 62 genes was confirmed by real-time PCR and cytometric bead assay, respectively. RSV replication was markedly diminished in Th1-primed airway epithelial cells but not in Th2-primed cells, which was presumably caused at least in part by the early induction of antiviral genes. CONCLUSIONS: These results suggest that Th1/Th2 predisposition in the host prior to RSV infection critically regulates inflammatory reactions in the airways through alteration of gene expression, and that MCP-1/CCL2 plays an important role in the pathogenesis of severe RSV infection and the subsequent development of asthma in Th2-predisposed hosts.

Creola bodies in infancy with respiratory syncytial virus bronchiolitis predict the development of asthma.

BACKGROUND: Creola bodies (CrBs) in the sputum are an indicator of respiratory epithelial damage and appear specifically in bronchial asthma. We studied the presence and clinical significance of CrBs in infants with respiratory syncytial virus (RSV) bronchiolitis contributing to the development of asthma. METHODS: Aspirated sputum samples were collected from 33 infants admitted with acute RSV bronchiolitis. The samples were then examined for the presence (or absence) of CrBs and classified into the RSV-CrB group and RSV-non-CrB group. Eosinophil cationic protein (ECP) and neutrophil elastase (NE) concentrations in the sputum were compared between the two groups. History of wheeze and asthma was collected at 2 years and 5 years after their discharge from hospital. RESULTS: CrBs were detected in 23 of the 33 subjects (69.7%). No significant difference in the ECP and the NE concentration were observed between the RSV-CrB group and RSV-non-CrB group. A significant relationship was observed between CrBs detected with RSV bronchiolitis and the development of recurrent wheezing and asthma (after 2 years: relative risk [RR], 3.09; p = 0.002; after 5 years: RR 7.00; p = 0.019). CONCLUSIONS: These findings suggest that a high rate of CrBs in the sputum is present in infants with RSV bronchiolitis, and notably the CrBs are associated with the progression to recurrent wheezing and asthma.