Evolutions of extracorporeal membrane oxygenator (ECMO): perspectives for advanced hollow fiber membrane.

Hollow fiber membrane is incorporated into an extracorporeal membrane oxygenator (ECMO), and the function of the membrane determines the ECMO's functions, such as gas transfer rate, biocompatibility, and durability. In Japan, the membrane oxygenator to assist circulation and ventilation is approved for ECMO support. However, in all cases, the maximum use period has been only 6 h, and so-called 'off-label use' is common for ECMO support of severely ill COVID-19 patients. Under these circumstances, the HLS SET Advanced (Getinge Group Japan K.K.) was approved in 2020 for the first time in Japan as a membrane oxygenator with a two-week period of use. Following this membrane oxygenator, it is necessary to establish a domestic ECMO system that is approved for long-term use and suitable for supporting patients. Looking back on the evolution of ECMO so far, Japanese researchers and manufacturers have also contributed to the developments of ECMO globally. Currently, excellent membrane oxygenators and systems have been marketed by Japanese manufacturers and some of them are globally acclaimed, but in fact, most of the ECMO membranes are not made in Japan. Fortunately, Japan has led the world in the fields of membrane separation technology and hollow fiber membrane production. In the wake of this pandemic, from the perspective of medical and economic security, the practical use of purely domestic hollow fiber membranes and membrane oxygenators for long-term ECMO is imperative in anticipation of the next pandemic.

3D porous structure imaging of membranes for medical devices using scanning probe microscopy and electron microscopy: from membrane science points of view.

The evolution of hemodialysis membranes (dialyzer, artificial kidney) was remarkable, since Dow Chemical began manufacturing hollow fiber hemodialyzers in 1968, especially because it involved industrial chemistry, including polymer synthesis and membrane manufacturing process. The development of hemodialysis membranes has brought about the field of medical devices as a major industry. In addition to conventional electron microscopy, scanning probe microscopy (SPM), represented by atomic force microscopy (AFM), has been used in membrane science research on porous membranes for hemodialysis, and membrane science contributes greatly to the hemodialyzer industry. Practical studies of membrane porous structure-function relationship have evolved, and methods for analyzing membrane cross-sectional morphology were developed, such as the ion milling method, which was capable of cutting membrane cross sections on the order of molecular size to obtain smooth surface structures. Recently, following the global pandemic of SARS-CoV-2 infection, many studies on new membranes for extracorporeal membrane oxygenator have been promptly reported, which also utilize membrane science researches. Membrane science is playing a prominent role in membrane-based technologies such as separation and fabrication, for hemodialysis, membrane oxygenator, lithium ion battery separators, lithium recycling, and seawater desalination. These practical studies contribute to the global medical devices industry.

Pseudohypercreatininemia after surgery for aortic dissection: a case report.

BACKGROUND: Elevated creatinine concentrations often indicate acute renal injury and renal biopsies are considered in this situation. However,pseudohypercreatininemia is potential cause of elevated creatinine concentrations, and invasive interventions should be avoided. CASE PRESENTATION: A 54-year-old woman underwent surgery for descending aortic dissection.Nine days postoperatively, her creatinine concentration increased from 1 mg/dl to 5.78 mg/dl (normal range, 0.47-0.7 mg/dl). Azotemia and hyperkalemia were absent and physical examination findings were unremarkable. Cystatin C concentration was 1.56 mg/l (normal range, 0.56-0.8 mg/l) and pseudohypercreatininemia was suspected. Testing with different reagents showed a creatinine concentration of 0.84 mg/dl. Immunoglobulin (Ig)G was markedly elevated, and creatinine and IgG fluctuated in parallel, suggesting the cause of the pseudohypercreatininemia. IgG4 was also elevated at 844 mg/dl. Immunosuppressive steroid therapy effectively decreased the IgG concentration and resolved the pseudohypercreatininemia. CONCLUSIONS: In cases of elevated creatinine concentration with the presence of abnormal proteins, pseudohypercreatininemia should be considered. We report a rare case of pseudohypercreatininemia caused by polyclonal IgG.

Barbadin Potentiates Long-Term Effects of Lorcaserin on POMC Neurons and Weight Loss.

Obesity is a serious global health problem because of its increasing prevalence and comorbidities, but its treatments are limited. The serotonin 2C receptor (5-HT2CR), a G-protein-coupled receptor, activates proopiomelanocortin (POMC) neurons in the arcuate nucleus of hypothalamus (ARH) to reduce appetite and weight gain. However, several 5-HT analogs targeting this receptor, e.g., lorcaserin (Lor), suffer from diminished efficacy to reduce weight after prolonged administration. Here, we show that barbadin (Bar), a novel ß-arrestin/ß2-adaptin inhibitor, can prevent 5-HT2CR internalization in cells and potentiate long-term effects of Lor to reduce appetite and body weight in male mice. Mechanistically, we demonstrate that Bar co-treatment can effectively maintain the sensitivity of the 5-HT2CR in POMCARH neurons, despite prolonged Lor exposure, thereby allowing these neurons to be activated through opening the transient receptor potential cation (TRPC) channels. Thus, our results prove the concept that inhibition of 5-HT2CR desensitization can be a valid strategy to improve the long-term weight loss effects of Lor or other 5-HT2CR agonists, and also provide an intellectual framework to develop effective long-term management of weight by targeting 5-HT2CR desensitization.SIGNIFICANCE STATEMENT By demonstrating that the combination of barbadin (Bar) with a G-protein-coupled receptor (GPCR) agonist can provide prolonged weight-lowering benefits in a preclinical setting, our work should call for additional efforts to validate Bar as a safe and effective medicine or to use Bar as a lead compound to develop more suitable compounds for obesity treatment. These results prove the concept that inhibition of serotonin 2C receptor (5-HT2CR) desensitization can be a valid strategy to improve the long-term weight loss effects of lorcaserin (Lor) or other 5-HT2CR agonists. Since GPCRs represent a major category as therapeutic targets for various human diseases and desensitization of GPCRs is a common issue, our work may provide a conceptual framework to enhance effects of a broad range of GPCR medicines.

A POMC-originated circuit regulates stress-induced hypophagia, depression, and anhedonia.

Chronic stress causes dysregulations of mood and energy homeostasis, but the neurocircuitry underlying these alterations remain to be fully elucidated. Here we demonstrate that chronic restraint stress in mice results in hyperactivity of pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (POMCARH neurons) associated with decreased neural activities of dopamine neurons in the ventral tegmental area (DAVTA neurons). We further revealed that POMCARH neurons project to the VTA and provide an inhibitory tone to DAVTA neurons via both direct and indirect neurotransmissions. Finally, we show that photoinhibition of the POMCARH→VTA circuit in mice increases body weight and food intake, and reduces depression-like behaviors and anhedonia in mice exposed to chronic restraint stress. Thus, our results identified a novel neurocircuitry regulating feeding and mood in response to stress.

Tocilizumab preserves renal function in rheumatoid arthritis with AA amyloidosis and end-stage kidney disease: Two case reports.

Case 1: A 59-year-old Japanese woman with rheumatoid arthritis (RA) for 36 years was admitted for evaluation of deteriorating renal function. Her serum creatine was 4.2 mg/dL, and proteinuria was 6.5 g daily. Renal and duodenal biopsy revealed AA amyloidosis. After treatment with tocilizumab (a humanized anti-interleukin-6 receptor antibody), proteinuria decreased to 1.1 g daily. The patient's renal function subsequently remained stable for 8 years. Case 2: A 71-year-old Japanese man with RA for 30 years was admitted due to deterioration of renal function. Serum creatine was 2.9 mg/dL, and urinary protein excretion was 0.06 g daily. Renal and duodenal biopsy identified AA amyloidosis. Tocilizumab was initiated, and his renal function remained stable for 6 years. The 2nd duodenal biopsy showed a marked decrease of AA amyloid deposits. Conclusion: These two cases suggest that tocilizumab may preserve renal function in the setting of end-stage kidney disease and shift the point of no return for RA patients with AA amyloidosis and renal dysfunction.

A case of thrombotic microangiopathy associated with polymyositis.

A 60-year-old Japanese woman with polymyositis (PM) developed hemolytic anemia (hemoglobin of 7.3 g/dL), thrombocytopenia (platelet of 9.1×104/µL), and acute kidney injury (Cre of 4.7 mg/dL) at 14 days after starting steroid therapy. Renal biopsy revealed glomerular endothelial swelling with fibrin thrombi and fragmented erythrocytes in the capillary lumens. Hemolytic uremic syndrome (HUS) with thrombotic microangiopathy (TMA) was diagnosed. Hemodialysis and plasma exchange/plasma transfusion were initiated, but HUS did not subside. After 45 days, the patient died of hemorrhagic respiratory failure. Autopsy showed fibrin thrombi filling the glomerular vascular pole and the small arteries in most glomeruli, resulting in glomerular collapse and glomerular basement membrane (GBM) duplication. Although renal involvement by PM is rare, HUS/TMA should be remembered as one of the serious renal complications of PM.

Impact of three-dimensional tortuous pore structure on polyethersulfone membrane morphology and mass transfer properties from a manufacturing perspective.

We examined typical commercial poly(ethersulfone) (PESf) hemodialysis and hemoconcentration membranes successfully used in manufacturing, and employed scanning probe microscope (SPM) to achieve a structural observation of the pores in the inner membrane surfaces, as well as measure the pore diameters and their distribution, verifying the relationship between the typical mass transfer properties. We focused on the differences between the PESf membranes which were expected to further improve the advanced pore structure control and functional design for various medical uses. The three-dimensional tortuous capillary pores on the inner surface of hollow fiber hemodialysis and hemoconcentrator membranes were investigated using dynamic force microscopy (DFM), and the pore diameter and distribution were measured through a line analysis. Compared with PUREMA-A, PES-Sα hemodialysis membranes have smaller three-dimensional tortuous capillary pore diameters and pore areas, as well as a smaller pore diameter distribution and pore area distribution, which make the accurate measurements of the pore diameter using FE-SEM impossible. These PESf membranes are almost the same in pure water permeability, but greatly differ in pore diameter and pore diameter distribution. By comparing and verifying as above, we may gain insight into the flexibility, versatility, and superior structural and functional controllability of PESf membrane pore structures, which could advance the development of pore structure control. Pending issues include the fact that, using a line analysis software of SPM devices, it is very difficult to measure hundred pores which clearly reflects the poor quality of pore size distributions obtained in this study, measurement accuracy must be improved further.

Shorter Relapse-Free Period after Leukocyte Removal Therapy in Younger than Older Patients with Ulcerative Colitis.

BACKGROUND: Leukocyte removal therapy (LRT) is an effective treatment for active ulcerative colitis (UC). The present study was performed to evaluate the relapse-free period after LRT and identify risk factors for relapse. METHODS: In total, 94 patients who underwent first-time LRT for remission of moderate to severe UC from April 2004 to March 2016 were enrolled in the present study. The patients were randomly assigned to one of 2 treatments: leukocytapheresis (LCAP; n = 43) or granulocyte and monocyte/macrophage adsorptive apheresis (GMA; n = 51). The 5-year cumulative relapse-free rate and risk factors for relapse were evaluated. RESULTS: The therapeutic response rate was 82% for GMA and 70% for LCAP without a statistically significant difference. The 5-year relapse-free rate was 34.7% in the LRT group. The 5-year relapse-free rate in patients aged > 40 years was 49.9%, which was significantly higher than that in patients aged ≤40 years (22.9%, p < 0.01). The relapse-free period was longer in the older than younger patients. CONCLUSIONS: The relapse-free period after LRT was examined in patients with UC, and 34.7% of patients achieved clinical remission within a 5-year period. The risk factor for early relapse after LRT was younger age.

Use of the Dorsal Vein of the Hand for Arteriovenous Fistula Creation.

A radiocephalic arteriovenous fistula (AVF) in the anatomical snuffbox is the most distal site of AVF in the upper limb. When the cephalic vein distal to the wrist is in poor condition or thrombosed, creating the typical radiocephalic AVF in the distal forearm just proximal to the wrist will likely be considered. However, we have adopted an operative technique for creating a transposed radial artery-dorsal metacarpal vein AVF (RDAVF) in the anatomical snuffbox when possible in such cases. RDAVF is AVF using the most peripheral autologous vein in the upper limb. To our knowledge, the creation of an RDAVF has not been previously reported. We herein describe the steps of the technique and report the successful treatment of a hemodialysis patient who developed occlusion of a radiocephalic AVF in the anatomical snuffbox.

Thyroid function in patients on continuous ambulatory peritoneal dialysis in comparison with chronic kidney disease
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BACKGROUND/METHODS: Thyroid function was evaluated in 14 Japanese patients on continuous ambulatory peritoneal dialysis (CAPD) with end-stage renal disease compared with 11 chronic kidney disease (CKD) stage 1+2 patients (glomerular filtration rate ≥ 60 mL/min/1.73m2). RESULTS: The serum free triiodothyronine (fT3) (2.2 ± 0.3 pg/mL, p < 0.05) levels were lower, and the rate of low triiodothyronine (T3) syndrome was higher (4 of 13 cases, 30.8%) in the CAPD patients than in the CKD stage 1+2 patients (1 of 10 cases, 10.0%, respectively) or the 57 age-matched healthy controls. The serum thyroglobulin (Tg) levels were significantly higher in the CAPD patients (39.7 (13.4 - 178.0) ng/mL) than in the CKD stage 1+2 patients (9.9 (5.5 - 28.8) ng/mL, p < 0.05). High serum Tg levels (> 30 ng/mL) were observed in 66.7% of the CAPD patients. CONCLUSION: The finding from our study suggested the deterioration of thyroid function with higher prevalence of low T3 syndrome in the CAPD patients. Although speculation as to the reasons for this would be unwise at this point, we did note that the serum Tg levels were very high in the CAPD patients.
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Restoration of Autologous Arteriovenous Fistula by Removal of the Occluded Short Venous Part and Venovenous End-To-End Anastomosis in a Hemodialysis Patient.

Standard salvage procedures for occuluded autologous arteriovenous fistula (AVF) in a hemodialysis patient are endovascular and/or surgical therapy. When endovascular therapy and thrombectomy prove unsuccessful, it is most likely that creating a new AVF or arteriovenous graft will be considered. However, if the occuluded venous part is short, we have adopted an operative technique for repair of AVF by removal of the occluded short venous part and venovenous end-to-end anastomosis. To our knowledge, the efficacy and clinical course of restoration of AVF by the technique have not been reported to date. Here, we describe the technique and report the successful treatment of a hemodialysis patient who developed AVF occlusion.

Long-term outcomes of tonsillectomy for IgA nephropathy patients: A retrospective cohort study, two-centre analysis with the inverse probability therapy weighting method.

AIM: The effect of tonsillectomy on IgA nephropathy remains controversial. The aim of this study was to compare the effect of tonsillectomy on the outcome, end stage kidney disease (ESKD) and all-cause death in IgA nephropathy patients who did and did not undergo tonsillectomy. METHODS: All basic data were retrospectively gathered from patients who had undergone renal biopsies at two Japanese clinical centres. Two hundred and twenty-seven patients were eligible for the study, with a median age of 34 (Interquartile range (IQR): 25-43) years and median follow-up of 92 (IQR: 40-178) months. The primary endpoint was the composite outcome of the onset of ESKD and all-cause death before ESKD. We performed a Cox proportional hazard regression analysis after adjusting for patient characteristics using the inverse probability therapy weighting (IPTW) method and a Cox analysis using the Matching method. Similarly, we analyzed these outcomes in a mild cohort. RESULTS: We were unable to find any significant advantages of tonsillectomy in either analysis (IPTW and matching, HR: 0.40 (0.12-1.36) P = 0.072 and 0.78 (0.13-4.64) P = 0.786). However, in the mild cohort analysis, our data showed that the Tonsillectomy group tended to be less likely to reach the composite outcomes than the Not Tonsillectomy group with statistical significance (hazard ratio (HR), <0.001 [CI <0.001 to <0.001, P = 0.039]). CONCLUSION: In this study, our findings led us to conclude that performing tonsillectomy in an early and timely manner may have predisposition of less poor prognosis.

The high prevalence of reversible subclinical hypothyroidism with elevated serum thyroglobulin levels in chronic kidney disease patients
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BACKGROUND: We examined the thyroid function of non-dialysis-dependent chronic kidney disease (CKD) patients in Japan. METHODS: Serum-free thyroxine, free triiodothyronine, thyroid-stimulating hormone (TSH), and thyroglobulin (Tg) levels were evaluated in 37 CKD patients. CKD was defined as sustained kidney damage for more than 3 months and was classified as CKD 1+2 (n = 11), 3+4 (n = 10), or 5 (n = 16), which were defined by glomerular filtration rates of ≥ 60, 15 - 59, or < 15 mL/min/1.73m2, respectively. RESULTS: The prevalence of primary hypothyroidism (TSH ≥ 4.83 mU/L) in CKD 1+2, CKD 3+4, and CKD 5 was 9%, 20%, and 56%, respectively (p < 0.05). Unexpectedly, elevated serum Tg levels (> 30 ng/mL), a marker of the reversible recovery of the thyroid function, were found in 67% of the CKD 5 patients (p < 0.05). The serum TSH and Tg levels became lower, without replacement therapy, after the initiation of hemodialysis and iodine restriction, and there was a significant correlation between the serum TSH and Tg levels in the CKD 5 patients (p < 0.05). CONCLUSION: The high prevalence of reversible hypothyroidism and the TSH-dependent elevation of the serum Tg levels was suggested in Japanese patients with advanced CKD. The excess ingestion and the impaired urinary excretion of iodine may be responsible for this reversible thyroid dysfunction.
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Successful treatment of a patient with refractory nephrotic syndrome with PCSK9 inhibitors: a case report.

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab is a low-density lipoprotein (LDL)-lowering drug with a new mechanism, which is currently available in Japan. Here, for the first time, we report the successful use of the PCSK9 inhibitor in a patient with refractory nephrotic syndrome. CASE PRESENTATION: A 61-year-old woman was diagnosed with minimal change-type nephrotic syndrome in October 2012. She received prednisolone (PSL) and cyclosporin A (CyA), but she experienced several cycles of relapse and remission and was hospitalized in May 2016 due to relapse. However, in spite of steroid pulse therapy and adrenocorticotropic hormone (ACTH) administration, her urinary protein level did not improve. We started her on evolocumab with the expectation of equivalent LDL-lowering effects as seen with LDL apheresis. After that, the LDL cholesterol level and UP/UC were concomitantly decreased, and the serum albumin was increased. This was maintained even when we reduced the PSL dose. This suggests that evolocumab clinically improves the nephrotic condition. CONCLUSION: No other report has described the use of evolocumab for nephrotic syndrome (NS) or its effect on similar nephrotic conditions. We believe that the findings presented here are unique and may be beneficial when treating similar cases.

Technical characterization of dialysis fluid flow and mass transfer rate in dialyzers with various filtration coefficients using dimensionless correlation equation.

The objective of the present study is to evaluate the effect of filtration coefficient and internal filtration on dialysis fluid flow and mass transfer coefficient in dialyzers using dimensionless mass transfer correlation equations. Aqueous solution of vitamin B12 clearances were obtained for REXEED-15L as a low flux dialyzer, and APS-15EA and APS-15UA as high flux dialyzers. All the other design specifications were identical for these dialyzers except for filtration coefficient. The overall mass transfer coefficient was calculated, moreover, the exponents of Reynolds number (Re) and film mass transfer coefficient of the dialysis-side fluid (k D) for each flow rate were derived from the Wilson plot and dimensionless correlation equation. The exponents of Re were 0.4 for the low flux dialyzer whereas 0.5 for the high flux dialyzers. Dialysis fluid of the low flux dialyzer was close to laminar flow because of its low filtration coefficient. On the other hand, dialysis fluid of the high flux dialyzers was assumed to be orthogonal flow. Higher filtration coefficient was associated with higher k D influenced by mass transfer rate through diffusion and internal filtration. Higher filtration coefficient of dialyzers and internal filtration affect orthogonal flow of dialysis fluid.

Role of the immunoreceptor tyrosine-based activation motif of latent membrane protein 2A (LMP2A) in Epstein-Barr virus LMP2A-induced cell transformation.

Latent membrane protein 2A (LMP2A) of Epstein-Barr virus (EBV) is widely expressed in EBV-associated malignancies. We demonstrate that LMP2A has a transformation ability. This study shows that LMP2A-induced transformation in several human nonhematopoietic cell lines was blocked in those cells expressing an immunoreceptor tyrosine-based activation motif (ITAM) LMP2A mutant. The Syk inhibitor or Syk-specific small interfering RNA (siRNA) inhibited LMP2A-induced transformation. These results indicate that the interaction of the LMP2A ITAM with Syk is a key step for LMP2A-mediated transformation.

Elevated resistin levels induce central leptin resistance and increased atherosclerotic progression in mice.

AIMS/HYPOTHESIS: Resistin was originally identified as an adipocyte-derived factor upregulated during obesity and as a contributor to obesity-associated insulin resistance. Clinically, resistin has also been implicated in cardiovascular disease in a number of different patient populations. Our aim was to simultaneously address these phenomena. METHODS: We generated mice with modest adipocyte-specific resistin overexpression. These mice were crossed with mice deficient in the LDL receptor (Ldlr (-/-)) to probe the physiological role of resistin. Both metabolic and atherosclerotic assessments were performed. RESULTS: Resistin overexpression led to increased atherosclerotic progression in Ldlr (-/-) mice. This was in part related to elevated serum triacylglycerol levels and a reduced ability to clear triacylglycerol upon a challenge. Additional phenotypic changes, such as increased body weight and reduced glucose clearance, independent of the Ldlr (-/-) background, confirmed increased adiposity associated with a more pronounced insulin resistance. A hallmark of elevated resistin was the disproportionate increase in circulating leptin levels. These mice thus recapitulated both the proposed negative cardiovascular correlation and the insulin resistance. A unifying mechanism for this complex phenotype was a resistin-mediated central leptin resistance, which we demonstrate directly both in vivo and in organotypic brain slices. In line with reduced sympathetic nervous system outflow, we found decreased brown adipose tissue (BAT) activity. The resulting elevated triacylglycerol levels provide a likely explanation for accelerated atherosclerosis. CONCLUSIONS/INTERPRETATION: Resistin overexpression leads to a complex metabolic phenotype driven by resistin-mediated central leptin resistance and reduced BAT activity. Hypothalamic leptin resistance thus provides a unifying mechanism for both resistin-mediated insulin resistance and enhanced atherosclerosis.