Removal of α1-Microglobulin Using Post-Dilution Online Hemodiafiltration with Polymethylmethacrylate Membrane: An Open-Label, Single-Arm Study.

INTRODUCTION: The removal of low- and medium-molecular-weight proteins has been improved with online hemodiafiltration (OL-HDF) and hemodialysis using high-flux membranes; however, the outcomes of patients with end-stage kidney disease (ESKD) undergoing dialysis treatment are still worse than in the general population. α1-Microglobulin (α1-m), with a molecular weight of 33,000 Da, may contribute to dialysis-related disorders and mortality. However, the removal is insufficient even with current OL-HDF using the polysulfone (PS) membrane, which is common in Japan. Polymethylmethacrylate (PMMA) membranes can remove medium- to high-molecular-weight proteins by adsorption. This study aimed to assess the efficacy of removing medium- to high-molecular-weight proteins, such as α1-m and ß2-microglobulin (ß2-m), through post-dilution OL-HDF with PMMA (Post-PMMA). The assessment was conducted in comparison to pre-dilution OL-HDF with PS (Pre-PS), using an open-label, single-arm study. METHODS: Seven patients with ESKD on Pre-PS underwent Post-PMMA with replacement volume of 30 mL/min (low flow) and 50 mL/min (high flow). Clearance and removal rates of α1-m, ß2-m, small molecules, inflammatory cytokines, and albumin were measured at 60 and 240 min of treatment. RESULTS: Clearance rates of α1-m at 60 min were -2.8 ± 5.2 mL/min with Pre-PS, -0.4 ± 2.6 mL/min with Post-PMMA (low), and 0.6 ± 3.4 mL/min with Post-PMMA (high). The removal rate of α1-m was higher in Post-PMMA than that in Pre-HDF-PS (Post-PMMA [high] 17.7 ± 5.9%, Post-PMMA [low] 15.0 ± 5.6%, and Pre-PS 4.1 ± 5.5%). Adsorption clearance of ß2-m was increased with Post-PMMA. Albumin leakage in Post-PMMA was not higher than that in Pre-PS. CONCLUSION: The removal rate of α1-m with Post-PMMA was higher than that with Pre-PS. The PMMA membrane adsorbed ß2-m, suggesting the removal effect of medium- to high-molecular-weight proteins by the adsorption method. Since Post-PMMA effectively removes α1-m without excessive albumin leakage, it will be useful for patients with ESKD, especially those with a poor nutritional status.

Genome-wide association study of the risk of chronic kidney disease and kidney-related traits in the Japanese population: J-Kidney-Biobank.

Chronic kidney disease (CKD) is a syndrome characterized by a gradual loss of kidney function with decreased estimated glomerular filtration rate (eGFR), which may be accompanied by an increase in the urine albumin-to-creatinine ratio (UACR). Although trans-ethnic genome-wide association studies (GWASs) have been conducted for kidney-related traits, there have been few analyses in the Japanese population, especially for the UACR trait. In this study, we conducted a GWAS to identify loci related to multiple kidney-related traits in Japanese individuals. First, to detect loci associated with CKD, eGFR, and UACR, we performed separate GWASs with the following two datasets: 475 cases of CKD diagnosed at seven university hospitals and 3471 healthy subjects (dataset 1) and 3664 cases of CKD-suspected individuals with eGFR <60 ml/min/1.73 m2 or urinary protein ≥ 1+ and 5952 healthy subjects (dataset 2). Second, we performed a meta-analysis between these two datasets and detected the following associated loci: 10 loci for CKD, 9 loci for eGFR, and 22 loci for UACR. Among the loci detected, 22 have never been reported previously. Half of the significant loci for CKD were shared with those for eGFR, whereas most of the loci associated with UACR were different from those associated with CKD or eGFR. The GWAS of the Japanese population identified novel genetic components that were not previously detected. The results also suggest that the group primarily characterized by increased UACR possessed genetically different features from the group characterized by decreased eGFR.

Mood Disorder in Systemic Lupus Erythematosus Induced by Antiribosomal P Protein Antibodies Associated with Decreased Serum and Brain Tryptophan.

Antiribosomal P protein (anti-P) autoantibodies commonly develop in patients with systemic lupus erythematosus. We have previously established hybridoma clones producing anti-P mAbs. In this study, we explored the pathogenesis of behavioral disorders induced by anti-P Abs using these mAbs. New Zealand Black × New Zealand White F1, New Zealand White, C57BL/6, and BALB/c mice were treated with 1 mg of anti-P Abs once every 2 wk. The behavioral disorder was evaluated by the tail suspension test, forced swim test, and open field test. Following administration of anti-P Abs, New Zealand Black × New Zealand White F1 and C57BL/6 mice developed depressive behavior and showed increased anxiety with elevated serum TNF-α and IL-6 levels. Anti-P Abs were not deposited in the affected brain tissue; instead, this mood disorder was associated with lower serum and brain tryptophan concentrations. Tryptophan supplementation recovered serum tryptophan levels and prevented the behavioral disorder. TNF-α and IL-6 were essential for the decreased serum tryptophan and disease development, which were ameliorated by treatment with anti-TNF-α neutralizing Abs or dexamethasone. Peritoneal macrophages from C57BL/6 mice produced TNF-α, IL-6, and IDO-1 via interaction with anti-P Abs through activating FcγRs, which were required for disease development. IVIg, which has an immunosuppressive effect partly through the regulation of FcγR expression, also prevented the decrease in serum tryptophan and disease development. Furthermore, serum tryptophan concentrations were decreased in the sera of systemic lupus erythematosus patients with anti-P Abs, and lower tryptophan levels correlated with disease activity. Our study revealed some of the molecular mechanisms of mood disorder induced by anti-P Abs.

Assessing fluid volume and determining outcomes of acute heart failure using plasma human atrial natriuretic peptide.

BACKGROUND: The post-dialysis plasma level of human atrial natriuretic peptide (hANP) reflects the fluid volume in patients on hemodialysis. The threshold hANP level is reportedly 100 pg/mL; however, the clinical usefulness of the threshold hANP level for volume control has not been sufficiently studied. METHODS: We conducted a single-center, retrospective, observational study that included 156 hemodialysis patients without atrial fibrillation. First, we examined the usefulness of the threshold hANP level (100 pg/mL) for predicting hypoxemia due to congestion in a short-term observational study from December 30, 2015 to January 5, 2016. Subsequently, we conducted a 5-year follow-up study wherein the outcomes were hospitalization due to acute heart failure (AHF), development of cardiovascular diseases (CVD), and all-cause death. Finally, we collected echocardiography data to investigate the relationship between cardiac function and hANP. RESULTS: Our short-term observational study showed that patients with an hANP level ≥ 100 pg/mL developed hypoxemia due to congestion (odds ratio, 3.52; 95% confidence interval, 1.06-11.71; P = 0.040). At the 5-year follow-up, patients with an hANP level ≥ 100 pg/mL had significantly higher rates of hospitalization due to AHF, CVD, and all-cause death based on the log-rank test (P = 0.003, P = 0.019, P < 0.001, respectively). Cardiac disfunctions were significantly associated with the high hANP level. CONCLUSIONS: The hANP level is indicative of both fluid volume and cardiac dysfunction. A threshold hANP level of 100 pg/mL can serve as a predictive marker for AHF and a practical indicator for volume control.

Effect of Low-Density Lipoprotein Apheresis on Quality of Life in Patients with Diabetes, Proteinuria, and Hypercholesterolemia.

INTRODUCTION: Treating diabetic nephropathy with low-density lipoprotein (LDL) apheresis reduces proteinuria and improves prognosis. However, its impact on patients' quality of life (QoL) is unclear. This study evaluated the effect of LDL apheresis on QoL in patients with diabetes, proteinuria, and hypercholesterolemia. METHODS: In this nationwide multicenter prospective study, we enrolled 40 patients with diabetes. Inclusion criteria were proteinuria (defined as an albumin/creatinine ratio ≥3 g/g), serum creatinine levels <2 mg/dL, and serum LDL ≥120 mg/dL despite drug treatment. LDL apheresis was performed 6-12 times within 12 weeks. The 36-item Short Form Health Survey (SF-36) was used to analyze QoL. RESULTS: The study enrolled 35 patients (27 men and 8 women; mean age 58.9 ± 11.9 years). A comparison of baseline SF-36 values with those at the end of the course of apheresis found an improvement in the mean physical component summary (37.9 ± 11.4 vs. 40.6 ± 10.5, p = 0.051) and a significant increase in the mean mental component summary (MCS) (49.4 ± 8.4 vs. 52.5 ± 10.9, p = 0.026). A multivariable linear regression analysis revealed a history of coronary heart disease negatively correlated with the MCS increase at the end of the course of apheresis (ß coefficient -6.935, 95% confidence interval, 13.313 to-0.556, p = 0.034). CONCLUSION: Our results suggest that LDL apheresis may improve the mental and physical QoL in patients with diabetes, proteinuria, and hypercholesterolemia.

Juvenile hormone identification in the cabbage bug Eurydema rugosa.

Juvenile hormone (JH) plays a pivotal role in almost every aspect of insect development and reproduction. The chemical structure of the JH in heteropteran species has long remained elusive until methyl (2R,3S,10R)-2,3;10,11-bisepoxyfarnesoate, commonly named as juvenile hormone III skipped bisepoxide (JHSB3), was isolated from Plautia stali (Hemiptera: Heteroptera: Pentatomidae). Recently, several groups reported the presence of JHSB3 in other heteropteran species. However, most of the studies paid no attention to the determination of the relative and absolute structure of the JH. In this study, we investigated the JH of the cabbage bug Eurydema rugosa (Hemiptera: Heteroptera: Pentatomidae), known as a pest for wild and cultivated crucifers. JHSB3 was detected in the hexane extract from the corpus allatum (CA) product using a chiral ultraperformance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) which can inform the absolute stereochemistry of the JH. Its stereoisomers were not detected. Topical application of the synthetic JHSB3 to the last instar nymphs inhibited their metamorphosis and induced nymphal-type colouration of the dorsal abdomen in a dose-dependent manner. Additionally, the topical application of JHSB3 effectively terminated summer and winter diapauses in females. These results indicate that the JH of E. rugosa is JHSB3. Although individuals in summer and winter diapauses are physiologically distinct in E. rugosa, the results suggest that the physiological differences between these diapauses are based, not on the responsiveness to JH, but on the processes governing activation of the CA or on its upstream cascades.

Circadian clock outputs regulating insect photoperiodism: A potential role for glutamate transporter.

Many temperate ectotherms survive winter by entering diapause - a state of developmental (or reproductive) suppression or arrest - in response to short autumnal day lengths. Day lengths are assessed by the circadian clock, the biological time-keeping system that governs biological rhythms with a period of approximately 24 h. However, clock output molecules controlling this photoperiodic response are largely unknown for many insects. To identify these molecules in Hemiptera, we performed RNAi knockdowns of several candidate genes in the bean bug Riptortus pedestris to determine whether their silencing affects photoperiodic regulation of ovarian development (reproductive diapause). Knockdown of diuretic hormone 31, short neuropeptide F, neuropeptide F, ion transport peptide, neuropeptide-like precursor 1, and choline acetyltransferase had no effect on ovarian development and were therefore ruled out as regulators of the photoperiodic response. However, knockdown of vesicular glutamate transporter promoted ovarian development under diapause-inducing short days, and this is the first report of the functional involvement of glutamate signalling in insect photoperiodism. Improved knockdown of this transporter (or receptor) and RNAi of other genes involved in glutamate signal transduction is required to verify its role as an output of the circadian clock.

Inorganic polyphosphate potentiates lipopolysaccharide-induced macrophage inflammatory response.

Inorganic polyphosphate (polyP) is a linear polymer of orthophosphate units that are linked by phosphoanhydride bonds and is involved in various pathophysiological processes. However, the role of polyP in immune cell dysfunction is not well-understood. In this study, using several biochemical and cell biology approaches, including cytokine assays, immunofluorescence microscopy, receptor-binding assays with quartz crystal microbalance, and dynamic light scanning, we investigated the effect of polyP on in vitro lipopolysaccharide (LPS)-induced macrophage inflammatory response. PolyP up-regulated LPS-induced production of the inflammatory cytokines, such as tumor necrosis factor α, interleukin-1ß, and interleukin-6, in macrophages, and the effect was polyP dose- and chain length-dependent. However, orthophosphate did not exhibit this effect. PolyP enhanced the LPS-induced intracellular macrophage inflammatory signals. Affinity analysis revealed that polyP interacts with LPS, inducing formation of small micelles, and the polyP-LPS complex enhanced the binding affinity of LPS to Toll-like receptor 4 (TLR4) on macrophages. These results suggest that inorganic polyP plays a critical role in promoting inflammatory response by enhancing the interaction between LPS and TLR4 in macrophages.

Photoperiod controls egg laying and caudodorsal cell hormone expression but not gonadal development in the pond snail Lymnaea stagnalis.

Photoperiod is a reliable cue to regulate growth and reproduction for seasonal adaptation. Although photoperiodism has been well studied in Chordata and Arthropoda, less is known about Mollusca. We examined photoperiodic effects on egg laying, body size, gonad-somatic index, oocyte size and relative amounts of caudodorsal cell hormone mRNA in individual rearing conditions in the pond snail Lymnaea stagnalis. Twenty-five weeks after hatching, the percentages of egg-laying snails under a photoperiod of 12 h light and 12 h darkness (12L:12D) were significantly smaller than those under longer days. The total numbers of eggs and egg masses under 12L:12D were significantly smaller than those under longer days. Significant differences between 16L:8D and 12L:12D were not observed in the soft body and ovotestis weight, and the gonad-somatic index. Photoperiodic effects were also not observed in oocyte diameters twenty-two weeks after hatching. Twenty-seven weeks after hatching amounts of caudodorsal cell hormone mRNA were significantly lower in the cerebral ganglia with commissure under 12L:12D than 16L:8D. L. stagnalis exhibited a clear photoperiodic response in egg laying and the amount of caudodorsal cell hormone mRNA, but not in gonadal development. Under 12L:12D suppression of caudodorsal cell hormone expression might suppress egg laying.

Aberrant mucosal immunoreaction to tonsillar microbiota in immunoglobulin A nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by mesangial polymeric IgA1 deposition. IgAN is believed to develop owing to aberrant mucosal immunoreaction against commensals in the tonsils. However, the exact interrelation between pathogenic IgA and mucosal microbiota in IgAN patients is unclear. METHODS: Biopsy-proven IgAN or recurrent tonsillitis (RT) patients who had undergone tonsillectomy were enrolled. We used 16S ribosomal RNA gene amplicon sequencing with a flow cytometry-based bacterial cell sorting technique) and immunoglobulin repertoire sequencing of the IgA heavy chain to characterize IgA-coated bacteria of the tonsillar microbiota (IgA-SEQ) and their corresponding IgA repertoire. Furthermore, we fractionated patient serum using gel-filtration chromatography and performed flow cytometry-based analysis of IgA binding to bacteria cultured from incised tonsils. RESULTS: Tonsillar proliferation-inducing ligand and B-cell activating factor levels were significantly higher in IgAN than in RT patients. IgA-SEQ for tonsillar microbiota revealed the preferential binding ability of IgA to Bacteroidetes in IgAN tonsils compared with those from RT patients. Expression of immunoglobulin heavy (IGH) constant alpha 1 with IGH variable 3-30 was significantly higher in IgAN than that in RT, and positively correlated with the IgA-coated enrichment score of Bacteroidetes. Serum polymeric IgA, comprising high levels of GdIgA1, exhibited considerable binding to Bacteroidetes strains cultured from the tonsils of IgAN patients. CONCLUSIONS: These findings provide evidence that aberrant mucosal immune responses to tonsillar anaerobic microbiota, primarily consisting of members of the phylum Bacteroidetes, are involved in IgAN pathophysiology.

Effects of LDL apheresis on proteinuria in patients with diabetes mellitus, severe proteinuria, and dyslipidemia.

BACKGROUND: Patients with diabetes mellitus and severe proteinuria present with poor renal prognoses, despite improvements in diabetes and kidney disease therapies. In this study, we designed a low-density lipoprotein (LDL)-cholesterol apheresis treatment for patients with diabetic nephropathy (DN)/diabetic kidney disease and severe proteinuria. This was a multicenter prospective LICENSE study to confirm the impact of LDL apheresis on proteinuria that exhibited hyporesponsiveness to treatment. In addition, we sought to determine the efficacy and safety of LDL apheresis by comparing the outcomes to those of historical controls in patients with diabetes, refractory hypercholesterolemia, and severe proteinuria. METHODS: This was a prospective, multicenter study, including 40 patients with diabetes, severe proteinuria, and dyslipidemia. LDL apheresis was performed 6-12 times over a 12-week period. The primary endpoint was the proportion of patients with a decrease in proteinuria excretion of at least 30% in the 6 months after starting therapy. The secondary endpoints included serum creatinine levels and laboratory variables, which were evaluated 4, 6, 12, 18, and 24 months after therapy initiation. RESULTS: LDL apheresis was performed on 40 registered patients with diabetes. The proportion of cases in which proteinuria decreased by 30% or more after 6 months of LDL apheresis was 25%, which was similar to that of historical controls. The overall survival and end-stage kidney disease-free survival rates were significantly higher in the LICENSE group compared to those in historical controls. CONCLUSION: Our results suggest that LDL apheresis may be effective and safe for patients with diabetes, proteinuria, and dyslipidemia. TRIAL REGISTRATION: Trial registration number: jRCTs042180076.

Expression of aquaporins in response to distinct dehydration stresses that confer stress tolerance in the Antarctic midge Belgica antarctica.

Larvae of the Antarctic midge Belgica antarctica Jacobs (Diptera: Chironomidae) are highly tolerant of diverse environmental stresses, including freezing, severe desiccation, and osmotic extremes. Furthermore, dehydration confers subsequent desiccation and freeze tolerance. While a role for aquaporins-channels for water and other solutes-has been proposed in these dehydration processes, the types of aquaporins involved in dehydration-driven stress tolerance remain unknown. In the present study, we investigated expression of six aquaporins (Drip, Prip, Eglp1, Eglp2, Aqp12L, and Bib) in larvae of B. antarctica subjected to three different dehydration conditions: desiccation, cryoprotective dehydration, and osmotic dehydration. The expression of Drip and Prip was up-regulated under desiccation and cryoprotective dehydration, suggesting a role for these aquaporins in efficient water loss under these dehydration conditions. Conversely, expression of Drip and Prip was down-regulated under osmotic dehydration, suggesting that their expression is suppressed in larvae to combat dehydration. Larval water content was similarly decreased under all three dehydration conditions. Differences in responses of the aquaporins to the three forms of dehydration suggests distinct water management strategies associated with different forms of dehydration stress.

Expression of Acsm2, a kidney-specific gene, parallels the function and maturation of proximal tubular cells.

The acyl-CoA synthetase medium-chain family member 2 (Acsm2) gene was first identified and cloned by our group as a kidney-specific "KS" gene. However, its expression pattern and function remain to be clarified. In the present study, we found that the Acsm2 gene was expressed specifically and at a high level in normal adult kidneys. Expression of Acsm2 in kidneys followed a maturational pattern: it was low in newborn mice and increased with kidney development and maturation. In situ hybridization and immunohistochemistry revealed that Acsm2 was expressed specifically in proximal tubular cells of adult kidneys. Data from the Encyclopedia of DNA Elements database revealed that the Acsm2 gene locus in the mouse has specific histone modifications related to the active transcription of the gene exclusively in kidney cells. Following acute kidney injury, partial unilateral ureteral obstruction, and chronic kidney diseases, expression of Acsm2 in the proximal tubules was significantly decreased. In human samples, the expression pattern of ACSM2A, a homolog of mouse Acsm2, was similar to that in mice, and its expression decreased with several types of renal injuries. These results indicate that the expression of Acsm2 parallels the structural and functional maturation of proximal tubular cells. Downregulation of its expression in several models of kidney disease suggests that Acms2 may serve as a novel marker of proximal tubular injury and/or dysfunction.

Juvenile hormone III skipped bisepoxide, not its stereoisomers, as a juvenile hormone of the bean bug Riptortus pedestris.

Juvenile hormone (JH) plays a pivotal role in many aspects of insect physiology. Although its presence was first reported in a blood-sucking bug belonging to the suborder Heteroptera (true bugs), JH species in the group has long been controversial. Although some recent studies proposed a putative JH molecular species in several Heteropteran species, it is not conclusive because physicochemical analyses were insufficient in most cases. Here, we studied this issue with an ultraperformance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) equipped with C18 and chiral columns in the bean bug Riptortus pedestris (Heteroptera, Alydidae), in which the JH species has long been controversial. Although a recent study describes JHSB3 as the major JH of this species, that finding was not conclusive because its chirality has not been clarified. In the present study, we detected methyl (2R,3S,10R)-2,3;10,11-bisepoxyfarnesoate, commonly named juvenile hormone III skipped bisepoxide (JHSB3), in the culture media of the corpora cardiaca-corpus allatum (CC-CA) complex and in the hemolymph of this species by a chiral ultraperformance liquid chromatography- tandem mass spectrometer (UPLC-MS/MS). Other JHSB3 stereoisomers were not detected. Topical application of JHSB3 effectively averted diapause. These results indicate that JHSB3 is the major JH of R. pedestris. The present study further revealed that JHSB3 and its (2R,3S,10S) isomer are more potent than (2S,3R,10R) and (2S,3R,10S) isomers, which suggests that there is a significance to the configuration of the 2,3-epoxide moiety in JH action. We further found a supplemental significance to the configuration of the 10-position.

Adsorption of Protein-Bound Uremic Toxins Using Activated Carbon through Direct Hemoperfusion in vitro.

BACKGROUND/AIMS: Accumulation of protein-bound uremic toxins (PBUTs) is associated with mortality due to various systemic disorders in patients with chronic kidney disease (CKD), especially in those undergoing dialysis treatment. The clinical outcomes of such patients could be improved by removing sufficient amounts of PBUTs; however, conventional dialysis lacks this ability. We examined the efficacy of activated carbon in adsorbing circulating PBUTs through direct hemoperfusion (DHP) in vitro. METHODS: An in vitro blood circulating system was constructed with 8.5 mL blood circulating around a column containing activated carbon (50, 100, or 200 mg). Bovine blood containing a kind of PBUT (at the same concentration as that found in the blood of dialysis patients) and blood from hemodialysis patients (n = 8) were used. After circulation for the designated amount of time, sera were collected and the levels of PBUTs, including indoxyl sulfate (IS), p-cresyl sulfate, indole acetic acid (IAA), phenyl sulfate, and hippuric acid, were analyzed with mass spectrometry. RESULTS: Activated carbon decreased the PBUT level in bovine blood in a dose-dependent manner (e.g., reduction rate of IS: 67.9 ± 3.8, 83.3 ± 1.9, and 94.5 ± 1.1% after 60-min circulation in columns containing 50, 100, and 200 mg activated carbon respectively). IS, PCS, and IAA were dramatically adsorbed by activated carbon from the blood of patients undergoing hemodialysis (pre vs. post 240-min reaction: IS 2.835 ± 0.876 vs. 0.455 ± 0.108 mg/dL [p < 0.01], PCS 3.208 ± 2.876 vs. 0.768 ± 0.632 mg/dL [p < 0.01], IAA 0.082 ± 0.045 vs. 0.016 ± 0.005 mg/dL [p < 0.01]). CONCLUSION: Activated carbon effectively adsorbed blood PBUTs in vitro. DHP with activated carbon could be a promising strategy for removing circulating PBUTs from the blood of patients with CKD.

Northward expansion of the bivoltine life cycle of the cricket over the last four decades.

Recent climate warming has affected some life-history traits of insects, including voltinism and body size. The magnitude of changes in these traits may differ latitudinally within a species because of the differing lengths of season available for growth. The present study aims to estimate the change in voltinism of the lawn ground cricket, Polionemobius mikado (Shiraki) (Orthoptera: Trigonidiidae), over the last four decades by comparing the body size between adults collected from a wide range of latitudes in Japan in recent years (2015-2017) and those collected four decades ago (1969-1976). The body size of adults collected in recent years showed a latitudinal saw-tooth cline, in the same way as body size did four decades ago, and the cline shifted northward over the last four decades: In 2015-2017, the body size decreased slightly with increasing latitude from 31°N to 36°N, and then increased to 40°N, and again decreased from 40°N to 44°N. Comparison of the body size between recent years and four decades ago revealed that the body size has decreased significantly at the middle latitudes (36-40°N), suggesting that the proportion of smaller bivoltine individuals there has increased over the last four decades. The sum of effective temperatures for postdiapause embryonic development at around 36°N in recent years was comparable to that at 31-35°N four decades ago, at which P. mikado populations were bivoltine. Taken together, these findings suggested that the latitudinal range suitable for the bivoltine life cycle of P. mikado has expanded northward over the last four decades because of climate warming. This is the first report that shows that a decrease in body size can be caused by climate warming via an increase in voltinism.

Kidney morphological parameters measured using noncontrast-enhanced steady-state free precession MRI with spatially selective inversion recovery pulse correlate with eGFR in patients with advanced CKD.

BACKGROUND: It is well known that atrophic renal changes are associated with chronic kidney disease (CKD) progression, but conventional diagnostic imaging methods such as noncontrast-enhanced computed tomography and magnetic resonance imaging (MRI) have been insufficient for precisely assessing kidney function because they cannot clearly distinguish between the medulla and cortex. Hence, here we used noncontrast-enhanced steady-state free precession (SSFP) MRI with a spatially selective inversion recovery (IR) pulse to improve visibility for renal corticomedullary differentiation and evaluated the association between morphological parameters and kidney function in patients with CKD. METHODS: Kidney corticomedullary contrast ratio, cortical and medullary areas, and minimal cortical thickness of 107 patients with CKD G1-G5 were measured using SSFP MRI with a spatially selective IR pulse and the association between these morphological parameters and kidney function were evaluated. RESULTS: Corticomedullary contrast ratio was significantly improved on SSFP MRI compared with conventional in-phase T1-weighted gradient-echo MRI and positively correlated with estimated glomerular filtration ratio (eGFR), raw eGFR, and 24-h creatinine clearance. The medullary and cortical areas and minimal cortical thickness also positively correlated with those of kidney functional markers and the age. In patients with CKD and diabetes mellitus (DM), the correlation coefficients between raw eGFR and morphological parameters were higher than those in patients without DM, while minimal cortical thickness was larger in CKD patients with DM with a raw eGFR ≥ 45 mL/min. CONCLUSION: Kidney morphological parameters measured with SSFP MRI were clearly correlated with kidney function in patients with CKD, including those with advanced kidney dysfunction.

Adsorption of Protein-Bound Uremic Toxins Through Direct Hemoperfusion With Hexadecyl-Immobilized Cellulose Beads in Patients Undergoing Hemodialysis.

An accumulation of protein-bound uremic toxins (PBUTs) is one of major reasons for development of uremia-related complications. We examined the PBUT removal ability of a hexadecyl-immobilized cellulose bead (HICB)-containing column for patients undergoing hemodialysis. Adsorption of indoxyl sulfate (IS), a representative PBUT, to HICBs was examined in vitro. The HICB column was used in patients undergoing hemodialysis for direct hemoperfusion with a regular hemodialyzer. The serum IS, indole acetic acid (IAA), phenyl sulfate (PhS), and p-cresyl sulfate (PCS) levels were measured before and after passing the column. HICBs adsorbed protein-free (free) IS in a dose- and time-dependent manner in vitro (55.4 ± 1.4% adsorption of 1 millimolar, 251 µg/mL, IS for 1 h). In clinical studies, passing the HICB-containing column decreased the serum level of free IS, IAA, PhS, and PCS levels significantly (by 34.4 ± 30.0%, 34.8 ± 25.4%, 28.4 ± 18.0%, and 34.9 ± 22.1%, respectively), but not protein-bound toxins in maintenance hemodialysis patients. HICBs absorbed some amount of free PBUTs, but the clinical trial to use HICB column did not show effect to reduce serum PBUTs level in hemodialysis patients. Adsorption treatment by means of direct hemoperfusion with regular hemodialysis may become an attractive blood purification treatment to increase PBUT removal when more effective materials to adsorb PBUTs selectively will be developed.

Prolactin Upregulates Female-Predominant P450 Gene Expressions and Downregulates Male-Predominant Gene Expressions in Mouse Liver.

Prolactin is a polypeptide hormone with over 300 separate biologic activities. Its serum level is increased during pregnancy and lactation, and it has been reported that pregnancy and lactation affect drug and steroid metabolism in mice and humans. Several studies reported that pregnancy or lactation influences liver cytochrome P450 (P450) expression and its activity, affecting the biosynthesis of steroids and xenobiotics through growth hormone or sex hormones; however, the role of prolactin as the regulator of liver P450 expression has not been elucidated so far. In the present study, we focused on prolactin as the regulator of expression of liver sex-predominant genes, including P450s. To investigate the role of prolactin in the hepatic gene expressions, pCAGGS expression vector containing mouse prolactin cDNA was transfected by hydrodynamic injection into both male and female mice. Hyperprolactinemia phosphorylated signal transducer and activator of transcription 5 in the liver and augmented female mouse liver mRNA expression of Cyp3a16, Cyp3a41, Cyp3a44, Cyp2b9, and prolactin receptor genes, whose expressions were female-predominant in hepatocytes. Moreover, liver expression of male-predominant genes such as Cyp2d9, Cyp7b1, Mup1, and Alas2 were reduced in male mice with hyperprolactinemia. The serum levels of conventional regulators of hepatic gene expressions, growth hormone, and testosterone were not affected by hyperprolactinemia. We demonstrated that prolactin upregulated female-predominant genes in female mice and downregulated male-predominant genes in male mice. We conjecture that higher concentration of prolactin would alter steroid and xenobiotic metabolisms by modulating hepatic P450 gene expressions during pregnancy and lactation.