Sodium-glucose cotransporter 2 inhibitors influence skeletal muscle pathology in patients with heart failure and reduced ejection fraction.

AIMS: Patients with heart failure and reduced ejection fraction (HFrEF) exhibit skeletal muscle pathology, which contributes to symptoms and decreased quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in HFrEF but their mechanism of action remains poorly understood. We aimed, therefore, to determine whether SGLT2i influence skeletal muscle pathology in patients with HFrEF. METHODS AND RESULTS: Muscle biopsies from 28 male patients with HFrEF (New York Heart association class I-III) treated with SGLT2i (>12 months) or without SGLT2i were compared. Comprehensive analyses of muscle structure (immunohistochemistry), transcriptome (RNA sequencing), and metabolome (liquid chromatography-mass spectrometry) were performed, and serum inflammatory profiling (ELISA). Experiments in mice (n = 16) treated with SGLT2i were also performed. Myofiber atrophy was ~20% less in patients taking SGLT2i (p = 0.07). Transcriptomics and follow-up measures identified a unique signature in patients taking SGLT2i related to beneficial effects on atrophy, metabolism, and inflammation. Metabolomics identified influenced tryptophan metabolism in patients taking SGLT2i: kynurenic acid was 24% higher and kynurenine was 32% lower (p < 0.001). Serum profiling identified that SGLT2i treatment was associated with lower (p < 0.05) pro-inflammatory cytokines by 26-64% alongside downstream muscle interleukin (IL)-6-JAK/STAT3 signalling (p = 008 and 0.09). Serum IL-6 and muscle kynurenine were correlated (R = 0.65; p < 0.05). Muscle pathology was lower in mice treated with SGLT2i indicative of a conserved mammalian response to treatment. CONCLUSIONS: Treatment with SGLT2i influenced skeletal muscle pathology in patients with HFrEF and was associated with anti-atrophic, anti-inflammatory, and pro-metabolic effects. These changes may be regulated via IL-6-kynurenine signalling. Together, clinical improvements following SGLT2i treatment in patients with HFrEF may be partly explained by their positive effects on skeletal muscle pathology.

The combination of isomalto-oligosaccharides (IMO)-based dietary fiber and hypocaloric high-protein diet could improve the anthropometric profile and fasting plasma glucose of healthy adults: A repeated single-arm clinical trial.

Background and aims: Meals with high protein and fiber could reduce weight and improve diabetes risk factors. Isomalto-oligosaccharide (IMO), a form of dietary fiber, could induce the afferent signal that causes appetite suppression. However, the direct effect of fiber supplementation in the form of IMO combined with a high-protein diet (HPF) on those parameters is still unknown. This study aims to investigate the effect of HPF on anthropometric parameters and blood glucose regulation of healthy subjects. . Methods: Thirteen healthy subjects were given a hypocaloric high protein diet (HPD) mixed with their prepared meals for two weeks. Followed by the HPF diet for another two weeks. Their anthropometric parameters, such as body composition (total body weight, body fat percentage, and fat-free mass), BMI and waist circumference, and fasting plasma glucose, were measured. Results: Compared to pre-intervention, HPF could significantly (p ≤ 0.004) reduce the anthropometric parameters and fasting plasma glucose. Compared to HPD, HPF could significantly (p ≤ 0.005) reduce more total body weight, body fat percentage, and BMI. In addition, HPF could induce more satiety than HPD (higher VAS score). Conclusion: HPF could improve the subject's anthropometric parameters which is obviously beneficial in preventing the risk of developing diabetes.

A Piezo1/KLF15/IL-6 axis mediates immobilization-induced muscle atrophy.

Although immobility is a common cause of muscle atrophy, the mechanism underlying this causality is unclear. We here show that Krüppel-like factor 15 (KLF15) and IL-6 are upregulated in skeletal muscle of limb-immobilized mice and that mice with KLF15 deficiency in skeletal muscle or with systemic IL-6 deficiency are protected from immobility-induced muscle atrophy. A newly developed Ca2+ bioimaging revealed that the cytosolic Ca2+ concentration ([Ca2+]i) of skeletal muscle is reduced to below the basal level by immobilization, which is associated with the downregulation of Piezo1. Acute disruption of Piezo1 in skeletal muscle induced Klf15 and Il6 expression as well as muscle atrophy, which was prevented by antibodies against IL-6. A role for the Piezo1/KLF15/IL-6 axis in immobility-induced muscle atrophy was validated in human samples. Our results thus uncover a paradigm for Ca2+ signaling in that a decrease in [Ca2+]i from the basal level triggers a defined biological event.

Hyperglycemia induces skeletal muscle atrophy via a WWP1/KLF15 axis.

Diabetes mellitus is associated with various disorders of the locomotor system including the decline in mass and function of skeletal muscle. The mechanism underlying this association has remained ambiguous, however. We now show that the abundance of the transcription factor KLF15 as well as the expression of genes related to muscle atrophy are increased in skeletal muscle of diabetic model mice, and that mice with muscle-specific KLF15 deficiency are protected from the diabetes-induced decline of skeletal muscle mass. Hyperglycemia was found to upregulate the KLF15 protein in skeletal muscle of diabetic animals, which is achieved via downregulation of the E3 ubiquitin ligase WWP1 and consequent suppression of the ubiquitin-dependent degradation of KLF15. Our results revealed that hyperglycemia, a central disorder in diabetes, promotes muscle atrophy via a WWP1/KLF15 pathway. This pathway may serve as a therapeutic target for decline in skeletal muscle mass accompanied by diabetes mellitus.

Prognostic significance of diabetes mellitus and dyslipidemia in men receiving androgen-deprivation therapy for metastatic prostate cancer.

OBJECTIVE: The outcome of the androgen-deprivation therapy (ADT) may be affected by metabolic diseases such as diabetes mellitus (DM) and dyslipidemia and/or by their treatments. We aimed to evaluate the prognostic impact of these disorders and corresponding medications in Japanese men treated with ADT for prostate cancer. METHODS: This study retrospectively included 121 patients with metastatic prostate cancer who were treated with primary ADT at our hospital between 2001 and 2013. All patients received primary ADT with castration and/or an antiandrogen agent (bicalutamide or flutamide). Associations between clinicopathological factors, metabolic disease profiles, medication use, and prognosis (progression-free survival [PFS] and overall survival [OS]) were evaluated by univariate and multivariate analysis. RESULTS: The median follow-up time was 54.9 months, and the median PFS and OS were 23.9 months and 73.0 months, respectively. High serum glucose levels at baseline (hazard ratio [HR], 95% confidence interval [CI]: 2.12, 1.16-3.76; P = 0.015), and concurrent DM (HR, 95% CI: 2.07, 1.06-3.94; P = 0.034) were significantly associated with poorer OS after adjustment for age, prostate-specific antigen levels at diagnosis, Gleason score, and clinical stage. Treatment with sulfonylurea drugs was significantly associated with a reduced risk of disease progression in men with DM (HR, 95% CI: 0.36, 0.12-0.90; P = 0.028). CONCLUSIONS: Impaired glucose tolerance and treatment with sulfonylureas have prognostic significance in prostate cancer. These findings demonstrate the importance of managing DM during ADT and point to a possible favorable effect of sulfonylureas on prostate cancer.

Portable negative-pressure wound therapy for pyoderma gangrenosum: Report of two cases.

Pyoderma gangrenosum is a chronic non-infectious neutrophilic dermatosis that causes undermining ulcers. Topical therapies for the deep ulcers of pyoderma gangrenosum have not been established. To investigate whether negative-pressure wound therapy is effective for a pyoderma gangrenosum ulcer, we used the PICO single use negative-pressure wound therapy system (Smith & Nephew, London, UK) for two pyoderma gangrenosum patients. In these cases, the ulcers decreased in size and necrolytic tissue was removed notably. Moreover, there were no secondary infections nor was there Koebner phenomena. Our cases suggest that portable negative-pressure wound therapy can be a treatment option for deep, intractable ulcers caused by pyoderma gangrenosum. Because portable negative-pressure wound therapy devices afford increased mobility to patients, they can give the patient a better quality of life than standard negative-pressure wound therapy systems do.

Median-lower normal levels of serum thyroxine are associated with low triiodothyronine levels and body temperature in patients with central hypothyroidism.

OBJECTIVE: Although it has been recommended that serum free thyroxine (FT4) levels should be targeted to middle-upper normal levels during levothyroxine (l-T4) replacement therapy in patients with central hypothyroidism (CeH), the rationale has not been clarified. METHODS: A retrospective single-center study enrolled 116 patients with hypothyroidism (CeH, n=32; total thyroidectomy (Tx), n=22; primary hypothyroidism (PH), n=33; and control benign thyroid nodule (C), n=29). The patients had received L-T4 therapy at the Kobe University Hospital between 2003 and 2013. They were stratified according to serum FT4 level (≥ 1.10 or <1.10 ng/dl), and body temperature (BT), serum free triiodothyronine (FT3) levels, FT3/FT4 ratio, and lipid profiles were compared. The effect of GH replacement therapy on thyroid function was also analyzed. RESULTS: FT3 levels and FT3/FT4 ratios were significantly lower in patients with CeH than in patients with PH (P<0.05) or C (P<0.05). In patients with FT4 <1.10 ng/dl, BT was significantly lower in patients with CeH (P=0.002) and Tx (P=0.005) than in patients with PH, whereas no differences were found in patients with FT4 ≥ 1.10 ng/dl. In patients with CeH, FT3 levels were higher in those with GH replacement therapy (P=0.018). CONCLUSION: In CeH, patients with median-lower normal levels of serum FT4 exhibited lower serum FT3 levels and lower BT. These results support the target levels of serum FT4 as middle-upper normal levels during l-T4 replacement therapy in patients with CeH.

Positive resection margins may not reflect the true margin in patients undergoing radical prostatectomy.

The aim of the present study was to evaluate the hypothesis that a positive resection margin (RM1) of an excised specimen may not reflect the true margin in patients that have undergone radical prostatectomy (RP). Between September 2003 and March 2011, 370 Japanese patients underwent an antegrade RP at the National Kyushu Cancer Center (Fukuoka, Japan), however, 95 of these patients were excluded from the study due to a history of receiving hormonal therapy or insufficient preoperative clinical data. The incidence of biochemical failure (BCF) was evaluated using multivariate analysis, which revealed that the preoperative prostate-specific antigen (PSA) level, pathological tumor stage, RP Gleason score and a PSA nadir <0.008 ng/ml were significant predictors (P=0.0065, 0.0006, 0.0002 and <0.0001, respectively). By contrast, an RM1 was not found to be a significant predictor of BCF, while the parameter with the highest hazard ratio (HR) was a PSA nadir <0.008 ng/ml (HR, 10.055; 95% confidence interval, 5.005-20.200). From the 56 cases that were RM1, 41 cases (73.2%) exhibited a PSA nadir <0.008 ng/ml. There were 42 cases (75.0%) in which only one site was identified to be RM1; among these cases, no significant difference was observed between a PSA level <0.008 ng/ml and a PSA level ≥0.008 ng/ml at the RM1 site (apex, P=0.1460; base, P=0.1384; anterior, P=0.3870; and posterolateral, P=0.5040). There were 14 cases (25.0%) in which multiple sites were RM1; these cases were classified by the number of sites that were RM1 (one vs. multiple) and no significant difference was observed between a PSA level <0.008 ng/ml and a PSA level ≥0.008 ng/ml (P=0.6090). Based on these results, an RM1 of an excised specimen may not reflect the true margin in patients that are treated with RP, specifically in cases where the PSA level is identified to decrease to below the postoperative measurement threshold value (PSA nadir <0.008 ng/ml).

Usefulness of ultra-sensitive prostate-specific antigen following radical prostatectomy.

This study aimed to evaluate the usefulness of ultra-sensitive prostate-specific antigen (PSA) following radical prostatectomy (RP). Between September, 2003 and March, 2009, a total of 311 prostate cancer patients underwent antegrade RP; following the exclusion of 111 patients due to prior hormonal therapy, 200 patients were finally included in this study. The results of the multivariate analysis identified RP Gleason score, extraprostatic extension, lymph node metastasis and PSA nadir as significant predictors of biochemical failure (P=0.0116, 0.0216, 0.0178 and <0.0001, respectively) and PSA nadir <0.008 ng/ml exhibited the highest hazard ratio (HR) [HR=26.34; 95% confidence interval (CI): 7.34-104.69]. After a median follow-up period of 52.2 months, the biochemical failure-free rate in the PSA nadir <0.008 and ≥0.008 ng/ml groups was 94.3 and 58.8%, respectively, with a statistically significant difference according to the log-rank test (P<0.001). In the multivariate analysis, statistically significant differences were observed only in pathological nodel stage within the PSA nadir <0.008 ng/ml group (P=0.0107). For this reason, postoperative follow-up using ultra-sensitive PSA is considered to be of value, since the use of high-sensitivity PSA to confirm a reduction to below postoperative measurement threshold value (PSA nadir <0.008 ng/ml) may avert administering unnecessary additional treatment, regardless of pathological reccurrence factors.

Acute acalculous cholecystitis in patients with clear cell renal cell carcinoma treated with sunitinib: report of two cases.

Although sunitinib is associated with a variety of adverse events, cases of sunitinib-related acute cholecystitis have rarely been reported. We herein report two cases of sunitinib-related acute acalculous cholecystitis in patients with clear cell renal cell carcinoma. In both cases, the gallbladder was surgically removed because it was difficult to improve the patient's condition with the cessation of sunitinib and non-surgical treatment only. Attention must be paid to the possibility of sunitinib-related acute cholecystitis, which, although uncommon, can be life-threatening.

Association of hyperglycemia on admission and during hospitalization with mortality in diabetic patients admitted for pneumonia.

OBJECTIVE: Information available on the clinical features and outcomes of pneumonia in diabetic patients is limited. There are no data on the association between glycemic control during hospitalization and mortality in this population. The objective of this study is to examine whether the presence of hyperglycemia on admission and during hospitalization is associated with mortality in diabetic patients admitted to the hospital for pneumonia. METHODS: This study is a retrospective observational cohort study of diabetic adults hospitalized for the first time for pneumonia between 2005 and 2011 in a 358-bed community hospital. Univariate and multivariate analyses were performed for 30-day all-cause hospital mortality adjusted for sex, age, type of pneumonia (community-acquired pneumonia or nursing and health care-associated pneumonia), severity of pneumonia according to the A-DROP score and various comorbidities in consideration of the serum glucose and hemoglobin A1c levels on admission and the mean plasma glucose level during hospitalization. RESULTS: Of the 1,499 pneumonia patients evaluated, 185 (12.3%) (mean age 75 years) had diabetes mellitus. Fourteen (7.6%) of the 185 diabetic patients died within 30 days after admission. According to the univariate analysis, 30-day mortality was significantly associated with the A-DROP score (p<0.0001), the admission glucose level (p=0.01) and the mean plasma glucose level during hospitalization (p<0.0001). Even after adjusting for factors related to the severity of pneumonia, the mean plasma glucose level during hospitalization remained significantly associated with 30-day mortality (p=0.004). CONCLUSION: Hyperglycemia determined according to the mean plasma glucose level during hospitalization is independently associated with 30-day all-cause hospital mortality in diabetic patients admitted for pneumonia.

Linear congenital molluscum contagiosum on the coccygeal region.

Congenital molluscum contagiosum is rare but has been reported previously. We present a unique case of linear congenital molluscum on the coccygeal region. To make a correct diagnosis, avoid unnecessary examination, and start appropriate treatment as soon as possible, it is beneficial for dermatologists to be aware that molluscum contagiosum can present at birth and can be linear.

A spectrophotometric biochemical oxygen demand determination method using 2,6-dichlorophenolindophenol as the redox color indicator and the eukaryote Saccharomyces cerevisiae.

A method to determine the spectrophotometric biochemical oxygen demand (BOD(sp)) was studied with high sensitivity and reproducibility by employing 2,6-dichlorophenolindophenol (DCIP) as a redox color indicator, the yeast Saccharomyces cerevisiae, and a temperature-controlling system providing a three-consecutive-stir unit. The absorbance of DCIP decreased due to the metabolism of organic substances in aqueous samples by S. cerevisiae. Under optimum conditions, a calibration curve for glucose glutamic acid concentration between 1.1 and 22mg O(2) L(-1) (r=0.988, six points, n=3) was obtained when the incubation mixture was incubated for 10min at 30 degrees C. The reproducibility of the optical responses in the calibration curve was 1.77% (average of relative standard deviations; RSD(av)). Subsequently, the characterization of this method was studied. The optical responses to pure organic substances and the influence of chloride ions, artificial seawater, and heavy metal ions on the sensor response were investigated before use with real samples. Measurements of real samples using river water were performed and compared with those obtained using the BOD(5) method. Finally, stable responses were obtained for 36 days when the yeast cell suspension was stored at 4 degrees C (response reduction, 89%; RSD(av) value for 9 testing days, 8.4%).