The mitochondrial protein frataxin is downregulated in hemodialysis patients

Background

The mitochondrial protein frataxin regulates iron metabolism for heme and iron sulfur cluster synthesis in the mitochondria and could be associated with the regulation of oxidative stress. To clarify the expression of frataxin and its association with uremia, we evaluated the mRNA and protein levels of frataxin in the polymorphonuclear leukocytes (PMNLs) of patients on hemodialysis (HD).

Methods

Uremic patients on HD (n = 18) and healthy control subjects (n = 18) were investigated. PMNLs were isolated by differential centrifugation. The mRNA levels of frataxin in isolated leukocytes were quantified by TaqMan real-time polymerase chain reaction. Frataxin protein expression in the cell lysate was evaluated using SDS-polyacrylamide gel electrophoresis and Western blotting.

Results

The frataxin/glyceraldehyde-3-phosphate dehydrogenase mRNA ratio in PMNLs from uremic patients was significantly lower than that in control subjects. Frataxin protein expression in uremic patients was also significantly lower than that in controls. Multiple regression analysis showed that frataxin mRNA levels were independently associated with the serum levels of both the oxidative stress marker malondialdehyde and the proinflammatory cytokine tumor necrosis factor-α.

Conclusion

The downregulation of frataxin seems to be linked with uremic status, which is usually associated with chronic inflammation and the acceleration of oxidative stress. Mitochondrial iron regulation may play a role in several comorbidities and in the poor prognosis in uremic patients. Further investigation is needed to elucidate whether reduced frataxin levels are linked to the pathological status of uremic patients and whether uremic substances affect frataxin expression.     

Gender as a significant predictor of intravesical recurrence in patients with urothelial carcinoma of the upper urinary tract following nephroureterectomy

ObjectivesTo retrospectively assess the significance of gender as a predictor of intravesical recurrence following nephroureterectomy for urothelial carcinoma of the upper urinary tract (UC-UUT).Materials and methodsThis study included 502 consecutive patients (360 male and 142 female) who were diagnosed as having clinically localized UC-UUT and underwent nephroureterectomy. Clinicopathologic outcomes of these patients were analyzed focusing on the impact of gender.ResultsThe incidence of intravesical recurrence in male patients (41.9%) was significantly greater than that in female patients (27.5%). Despite the lack of significant differences in cancer-specific and overall survivals with respect to gender, the intravesical recurrence-free survival in male patients was significantly worse than that in female patients. Of several parameters examined, univariate analysis identified gender, tumor site, and tumor focality as significant predictors of intravesical recurrence following nephroureterectomy. Of these, only gender and tumor site appeared to be independently associated with intravesical recurrence-free survival on multivariate analysis. Furthermore, there was a significant difference in intravesical recurrence-free survival according to positive numbers of these two independent factors; that is, intravesical recurrence occurred in 12 of 55 patients who were negative for both risk factors (21.8%), 96 of 280 positive for a single risk factor (34.3%), and 82 of 167 positive for both risk factors (49.1%).ConclusionsThe incidence of intravesical recurrence following nephroureterectomy for UC-UUT is comparatively high. Therefore, it would be potentially important to perform careful follow-up targeting intravesical recurrence for such patients, particularly for male patients and/or patients with tumor located at the ureter.     

Massive pulmonary hemorrhage before living donor liver transplantation in infants

A massive pulmonary hemorrhage in patients with liver cirrhosis is a life‐threatening complication that may result in a contraindication of a liver transplantation because of its high mortality rate. Herein, we present two infant biliary atresia cases that successfully underwent an LDLT that was followed by intensive respiratory care for the pretransplant massive pulmonary hemorrhage. Both cases exhibited severe respiratory failure (minimum PaO₂/FiO₂; 46 mmHg and 39 mmHg, respectively). To arrest the bleeding, we applied a very high positive pressure ventilation treatment (maximum PIP/PEEP; 38/14 cmH₂O and 55/15 cmH₂O, respectively), plasma exchange, several FFP transfusions, and recombinant factor VIIa via intrapulmonary administration. In addition, we used CHDF treatment, applied HFOV transiently, and treated the patient with inhalation of nitric oxide. Although we prepared ECMO for intra‐operative use, both cases were successfully managed with conventional mechanical ventilation without using ECMO, which may have worsened the pulmonary hemorrhage due to the use of an anticoagulant. Use of an excessive positive pressure management, although it poses a risk for barotrauma, could be acceptable to arrest the pulmonary bleeding in selected cases of liver failure patients who have no time remaining before LDLT.     

Antibody‐mediated rejection after ABO‐incompatible pediatric living donor liver transplantation for propionic acidemia: A case report

We herein present the case of a four‐yr‐old boy with PA who developed AMR after ABO‐incompatible LDLT despite undergoing B cell desensitization using rituximab. Although the CD19+ lymphocyte count decreased to 0.1% nine days after the administration of rituximab, he developed a high fever which was accompanied by arthralgia due to a streptococcal infection 13 days after rituximab prophylaxis. After the clearance of the infection, he underwent ABO‐incompatible LDLT 36 days after the administration of rituximab. The CD19+ lymphocyte count just prior to LDLT was 1.2%. He developed AMR five days after LDLT, and the antidonor‐type IgM and IgG antibody titers increased to 1:1024 and 1:1024, respectively. He was treated by plasma exchange, IVIG, steroid pulse therapy, and rituximab re‐administration; however, his liver dysfunction continued. Despite intensive treatment, he died due to complicated abdominal hernia, acute renal failure, and ARDS. This case suggests that a streptococcal infection may induce the activation of innate immune responses; thus, additional desensitization therapy should be considered prior to ABO‐incompatible LDLT if B cell reactivation is suspected.     

Gene delivery system of pDNA using the blood glycoprotein fetuin

Fetuin is a biocompatible plasma protein and strongly enhances phagocytosis of bacteria, DNA and apoptotic cells by peripheral blood cells such as monocytes, macrophages and dendritic cells. We developed a novel gene delivery system: ternary complexes constructed with pDNA, polyethylenimine (PEI) and fetuin. Without covalent binding, fetuin was able to coat pDNA–PEI complexes, and stable anionic nanoparticles formed at a weight ratio greater than 30. Optimised pDNA–PEI–fetuin complexes significantly decreased the cytotoxicity of pDNA–PEI complexes in the melanoma cell line B16F10. Furthermore, the pDNA–PEI–fetuin complexes had higher transgene efficiency compared to that of commercial lipofectin previously reported in B16F10 cells despite an anionic surface. The pDNA–PEI–fetuin complexes did not agglutinate with erythrocytes. The pDNA–PEI–fetuin complexes had high gene expression in the spleen after intravenous administration in mice. Thus, the pDNA–PEI–fetuin complexes were a useful in vivo gene delivery system with tropism for the spleen.     

Disruption of leptin receptor expression in the pancreas directly affects beta cell growth and function in mice

Obesity is characterized by hyperinsulinemia, hyperleptinemia, and an increase in islet volume. While the mechanisms that hasten the onset of diabetes in obese individuals are not known, it is possible that the adipose-derived hormone leptin plays a role. In addition to its central actions, leptin exerts biological effects by acting in peripheral tissues including the endocrine pancreas. To explore the impact of disrupting leptin signaling in the pancreas on beta cell growth and/or function, we created pancreas-specific leptin receptor (ObR) KOs using mice expressing Cre recombinase under the control of the pancreatic and duodenal homeobox 1 (Pdx1) promoter. The KOs exhibited improved glucose tolerance due to enhanced early-phase insulin secretion, and a greater beta cell mass secondary to increased beta cell size and enhanced expression and phosphorylation of p70S6K. Similar effects on p70S6K were observed in MIN6 beta cells with knockdown of the ObR gene, suggesting crosstalk between leptin and insulin signaling pathways. Surprisingly, challenging the KOs with a high-fat diet led to attenuated acute insulin secretory response to glucose, poor compensatory islet growth, and glucose intolerance. Together, these data provide direct genetic evidence, from a unique mouse model lacking ObRs only in the pancreas, for a critical role for leptin signaling in islet biology and suggest that altered leptin action in islets is one factor that contributes to obesity-associated diabetes.     

Pipeline flow diversion with adjunctive coil embolization for internal carotid artery aneurysms following an intradural component: results in 46 consecutive aneurysms from a Japanese single-center experience

In the treatment of an intracranial aneurysm with the flow diverter, the combined use of coil embolization can help promote subsequent progressive thrombosis within the aneurysm sac and reduce the risk of delayed aneurysm rupture. This study retrospectively reviewed outcomes of patients who had undergone the Pipeline Embolization Device (PED) with adjunctive coil embolization (PED/coil) at a single center to determine its safety and efficiency. Patients with internal carotid artery aneurysms following an intradural component were selected for PED/coil between 2015 and 2020. All patients were premedicated with dual antiplatelet therapy of aspirin plus clopidogrel or prasugrel. A minimal number of PEDs were deployed, with coils inserted using a stent-jail technique, avoiding dense packing. A total of 46 aneurysms (43 patients; median dome size, 11.6 mm; median neck width, 6.3 mm) were treated with PED/coil. The median volume embolization ratio was 14.8%. The degree of angiographic filling at the 6-month and latest angiography showed complete occlusion in 60.5% (26/43) and 70.5% (31/44), respectively. Small (<?10 mm) aneurysms achieved a higher complete occlusion rate in the early period; a lower cumulative incidence of aneurysm occlusion was observed in large and giant (≥?10 mm) aneurysms (P?=?.024). The median clinical follow-up was 22 months, and no aneurysm ruptures occurred. Favorable clinical outcomes were achieved, with permanent neurological morbidity of 4.7% and no mortality. PED/coil demonstrated a high angiographic occlusion rate at an early stage. Loosely packed coils are sufficient to obliterate aneurysms effectively.