Obturator Hernia in a Patient Undergoing Hemodialysis.

Obturator hernia is a rare condition that commonly affects frail older women. A 54-year-old woman presented to our hospital with left hip joint pain. She had suffered a left pubic bone fracture and commenced maintenance hemodialysis. Pelvic computed tomography (CT) showed an incarcerated small intestine through the left obturator foramen, while abdominal CT showed marked intestinal dilatation. She underwent emergency laparotomy, and the incarcerated small intestine was found to be necrotic. Partial small intestinal resection and bilateral obturator hernioplasty were performed. Because obturator hernia is a potentially fatal condition, early detection and treatment are important.

Determining total energy expenditure in 3-6-year-old Japanese pre-school children using the doubly labeled water method.

The doubly labeled water (DLW, 2H218O) method for calculating the total production of CO2 over several days is currently considered to be the most accurate technique for the measurement of total energy expenditure (TEE), and the results obtained using this method have been used to review energy requirements. Presently, there is limited data available on TEE in Japanese children. The objective of this study was to assess the TEE in pre-school Japanese children using the DLW method. We used a cross-sectional population of 140 children (69 boys and 71 girls) aged 3-6 years. TEE was measured using the DLW method over 8 days under free-living conditions. The average weights (kg) of the boys and girls were 15.6 ± 2.5 and 15.0 ± 2.1 for the 3-4 years old and 19.8 ± 3.8 and 19.6 ± 2.7 for the 5-6 years old, respectively. The corresponding TEE (kcal/day) was 1260.9 ± 357.8 and 1265.2 ± 408.0, and 1682.3 ± 489.0 and 1693.1 ± 473.3, respectively, showing a significant difference with respect to age. Furthermore, TEE per body weight (kcal/kg/day) was 83.2 ± 29.2 and 84.9 ± 26.6, and 85.4 ± 23.2 and 86.7 ± 22.6, respectively. However, when TEE was adjusted for body weight or fat-free mass, there were no age or sex differences. We conclude that in Japanese children, TEE in those aged 3-4 years was similar to the current Ministry of Health recommendations. However, TEE in children aged 5-6 years was slightly higher than the recommendations. Based on these findings, the present results obtained from a large number of participants will provide valuable reference data for Japanese children.

Metformin ameliorates the severity of experimental Alport syndrome.

Metformin is widely used for the treatment of type 2 diabetes, and increasing numbers of studies have shown that metformin also ameliorates tumor progression, inflammatory disease, and fibrosis. However, the ability of metformin to improve non-diabetic glomerular disease and chronic kidney disease (CKD) has not been explored. To investigate the effect of metformin on non-diabetic glomerular disease, we used a mouse model of Alport syndrome (Col4a5 G5X) which were treated with metformin or losartan, used as a control treatment. We also investigated the effect of metformin on adriamycin-induced glomerulosclerosis model. Pathological and biochemical analysis showed that metformin or losartan suppressed proteinuria, renal inflammation, fibrosis, and glomerular injury and extended the lifespan in Alport syndrome mice. Transcriptome analysis showed that metformin and losartan influenced molecular pathways-related to metabolism and inflammation. Metformin altered multiple genes including metabolic genes not affected by losartan. Metformin also suppressed proteinuria and glomerular injury in the adriamycin-induced glomerulosclerosis mouse model. Our results showed that metformin ameliorates the glomerular sclerosis and CKD phenotype in non-diabetic chronic glomerular diseases. Metformin may have therapeutic potential for not only diabetic nephropathy but also non-diabetic glomerular disease including Alport syndrome.

Mild electrical stimulation with heat shock attenuates renal pathology in adriamycin-induced nephrotic syndrome mouse model.

Nephrotic syndrome (NS) is a renal disorder that is characterized by massive proteinuria, hypoalbuminemia and edema. One of the main causes of NS is focal segmental glomerulosclerosis (FSGS), which has extremely poor prognosis. Although steroids and immunosuppressants are the first line of treatment, some FSGS cases are refractory, prompting the need to find new therapeutic strategies. We have previously demonstrated that an optimized combination treatment of mild electrical stimulation (MES) and heat shock (HS) has several biological benefits including the amelioration of the pathologies of the genetic renal disorder Alport syndrome. Here, we investigated the effect of MES + HS on adriamycin (ADR)-induced NS mouse model. MES + HS suppressed proteinuria and glomerulosclerosis induced by ADR. The expressions of pro-inflammatory cytokines and pro-fibrotic genes were also significantly downregulated by MES + HS. MES + HS decreased the expression level of cleaved caspase-3 and the number of TUNEL-positive cells, indicating that MES + HS exerted anti-apoptotic effect. Moreover, MES + HS activated the Akt signaling and induced the phosphorylation and inhibition of the apoptotic molecule BAD. In in vitro experiment, the Akt inhibitor abolished the MES + HS-induced Akt-BAD signaling and anti-apoptotic effect in ADR-treated cells. Collectively, our study suggested that MES + HS modulates ADR-induced pathologies and has renoprotective effect against ADR-induced NS via regulation of Akt-BAD axis.

A novel condition of mild electrical stimulation exerts immunosuppression via hydrogen peroxide production that controls multiple signaling pathway.

Different modes of exogenous electrical stimulation at physiological strength has been applied to various diseases. Previously, we extensively demonstrated the usability of mild electrical stimulation (MES) with low frequency pulse current at 55 pulses per second (MES55) for several disease conditions. Here we found that MES with high frequency pulse-current (5500 pulse per second; MES5500) suppressed the overproduction of pro-inflammatory cytokines induced by phorbol myristate acetate/ionomycin in Jurkat T cells and primary splenocytes. MES5500 also suppressed the overproduction of inflammatory cytokines, improved liver damage and reduced mouse spleen enlargement in concanavalin-A-treated BALB/c mice. The molecular mechanism underlying these effects included the ability of MES5500 to induce modest amount of hydrogen peroxide and control multiple signaling pathways important for immune regulation, such as NF-κB, NFAT and NRF2. In the treatment of various inflammatory and immune-related diseases, suppression of excessive inflammatory cytokines is key, but because immunosuppressive drugs used in the clinical setting have serious side effects, development of safer methods of inhibiting cytokines is required. Our finding provides evidence that physical medicine in the form of MES5500 may be considered as a novel therapeutic tool or as adjunctive therapy for inflammatory and immune-related diseases.

Singular surfaces of revolution with prescribed unbounded mean curvature.

We give an explicit formula for singular surfaces of revolution with prescribed unbounded mean curvature. Using this mean curvature, we give conditions for certain types of singularities of those surfaces. Periodicity of that surface is also discussed.

A Split-Luciferase-Based Trimer Formation Assay as a High-throughput Screening Platform for Therapeutics in Alport Syndrome.

Alport syndrome is a hereditary glomerular disease caused by mutation in type IV collagen α3-α5 chains (α3-α5(IV)), which disrupts trimerization, leading to glomerular basement membrane degeneration. Correcting the trimerization of α3/α4/α5 chain is a feasible therapeutic approach, but is hindered by lack of information on the regulation of intracellular α(IV) chain and the absence of high-throughput screening (HTS) platforms to assess α345(IV) trimer formation. Here, we developed sets of split NanoLuc-fusion α345(IV) proteins to monitor α345(IV) trimerization of wild-type and clinically associated mutant α5(IV). The α345(IV) trimer assay, which satisfied the acceptance criteria for HTS, enabled the characterization of intracellular- and secretion-dependent defects of mutant α5(IV). Small interfering RNA-based and chemical screening targeting the ER identified several chemical chaperones that have potential to promote α345(IV) trimer formation. This split luciferase-based trimer formation assay is a functional HTS platform that realizes the feasibility of targeting α345(IV) trimers to treat Alport syndrome.

STAT3 inhibition attenuates the progressive phenotypes of Alport syndrome mouse model.

Background: Alport syndrome (AS) is a hereditary, progressive nephritis caused by mutation of type IV collagen. Previous studies have shown that activation of signal transducer and activator of transcription 3 (STAT3) exacerbates other renal diseases, but whether STAT3 activation exacerbates AS pathology is still unknown. Here we aim to investigate the involvement of STAT3 in the progression of AS. Method: Phosphorylated STAT3 expression was assessed by immunoblotting analysis of kidneys and glomeruli of an AS mouse model (Col4a5 G5X mutant). To determine the effect of blocking STAT3 signaling, we treated AS mice with the STAT3 inhibitor stattic (10 mg/kg i.p., three times per week for 10 weeks; n = 10). We assessed the renal function [proteinuria, blood urea nitrogen (BUN), serum creatinine] and analyzed the glomerular injury score, fibrosis and inflammatory cell invasion by histological staining. Moreover, we analyzed the gene expression of nephritis-associated molecules. Results: Phosphorylated STAT3 was upregulated in AS kidneys and glomeruli. Treatment with stattic ameliorated the progressive renal dysfunction, such as increased levels of proteinuria, BUN and serum creatinine. Stattic also significantly suppressed the gene expression levels of renal injury markers (Lcn2, Kim-1), pro-inflammatory cytokines (Il-6, KC), pro-fibrotic genes (Tgf-ß, Col1a1, α-Sma) and Mmp9. Stattic treatment decreased the renal fibrosis congruently with the decrease of transforming growth factor beta (TGF-ß) protein and increase of antifibrosis-associated markers p-Smad1, 5 and 8, which are negative regulators of TGF-ß signaling. Conclusion: STAT3 inhibition significantly ameliorated the renal dysfunction in AS mice. Our finding identifies STAT3 as an important regulator in AS progression and provides a promising therapeutic target for AS.

Bromide supplementation exacerbated the renal dysfunction, injury and fibrosis in a mouse model of Alport syndrome.

A seminal study recently demonstrated that bromide (Br-) has a critical function in the assembly of type IV collagen in basement membrane (BM), and suggested that Br- supplementation has therapeutic potential for BM diseases. Because salts of bromide (KBr and NaBr) have been used as antiepileptic drugs for several decades, repositioning of Br- for BM diseases is probable. However, the effects of Br- on glomerular basement membrane (GBM) disease such as Alport syndrome (AS) and its impact on the kidney are still unknown. In this study, we administered daily for 16 weeks 75 mg/kg or 250 mg/kg (within clinical dosage) NaBr or NaCl (control) via drinking water to 6-week-old AS mice (mouse model of X-linked AS). Treatment with 75 mg/kg NaBr had no effect on AS progression. Surprisingly, compared with 250 mg/kg NaCl, 250 mg/kg NaBr exacerbated the progressive proteinuria and increased the serum creatinine and blood urea nitrogen in AS mice. Histological analysis revealed that glomerular injury, renal inflammation and fibrosis were exacerbated in mice treated with 250 mg/kg NaBr compared with NaCl. The expressions of renal injury markers (Lcn2, Lysozyme), matrix metalloproteinase (Mmp-12), pro-inflammatory cytokines (Il-6, Il-8, Tnf-α, Il-1ß) and pro-fibrotic genes (Tgf-ß, Col1a1, α-Sma) were also exacerbated by 250 mg/kg NaBr treatment. Notably, the exacerbating effects of Br- were not observed in wild-type mice. These findings suggest that Br- supplementation needs to be carefully evaluated for real positive health benefits and for the absence of adverse side effects especially in GBM diseases such as AS.

Differential perceived exertion measured using a new visual analogue scale during pedaling and running.

The purpose of this study was to evaluate the differential perceived exertion measured using a new set of Visual Analogue Scales (VAS) during pedaling and running. The subjects were eleven healthy males. They performed an incremental maximal test and then three 4-min stages of exercise, for both pedaling and running. During the tests, VO2, V(CO2), V(E), f, and HR were monitored continuously. Bla and perceptual variables including VAS consisting of four scales (VAS 1-VAS 4) and Borg's RPE were measured at the end of each stage. Although the VO2 (%VO2max)) and HR for both pedaling and running were not significantly different, Bla in pedaling was significantly higher than that in running. A significant interaction (mode, stage) was also obtained. The VAS 1 of pedaling was significantly higher than that of running. A significant interaction in VAS 1 (mode, stage) was obtained. The VAS 2 of pedaling was significantly higher than that of running. The subjects indicated that local pain became stronger than central pain in pedaling, but they were almost equal in running. In both pedaling and running, leg pain became stronger than arm pain (VAS 3). VAS 4 showed that during running, breathing difficulty and heart pain were almost equal in perceived intensity. However, during pedaling, breathing difficulty became greater than heart pain. Thus, a new four-part visual analogue scale was found to be useful for monitoring exercise intensity. In addition, the new VAS gave us more information in relation to the differential perceived exertion reflected in the different physiological responses obtained by different exercise modes.

Measurement of ventilatory threshold by respiratory frequency.

This study was conducted to assess whether respiratory frequency can be used as a valid parameter for estimating ventilatory threshold and for examining differences in exercise modes such as a cycle ergometer and a treadmill. 24 men and 12 women performed an incremental exercise test to exhaustion on a cycle ergometer and on a treadmill. Oxygen uptake, carbon dioxide output, pulmonary ventilation, ventilatory frequency, and heart rate were measured continuously every 30 sec. during the test. Three different and independent reviewers detected the ventilatory threshold point and break point of respiratory rate, which were then compared. Analysis indicated that (1) ventilatory threshold was well correlated with break point of respiratory rate for both cycle (r=.88, p<.001) and treadmill exercise (r=.96, p<.001). However, on the average, ventilatory threshold was only 71% (cycle) or 88% (treadmill) of break point of respiratory rate. (2) The regression equation for treadmill exercise was more accurate than that for cycling, but the detected data samples were smaller. The break point of respiratory rate was more easily detected for the cycle ergometer test 33 of 36 subjects) than for the treadmill test (only 15 of 36). The cycle ergometer test identified the break point of respiratory rate more easily than did the treadmill test. (3) There was an association between physical fitness and whether the break point of respiratory rate was detectable, and the more fit the subject (above average), the more likely the break point was to be undetected. Our study demonstrates that the break point of respiratory rate is closely associated with ventilatory threshold and that the cycle ergometer test is more conducive than the treadmill test to the detectability of break point of respiratory rate.