Allogenic Adipose-Derived Stem Cells in Diabetic Foot Ulcer Treatment: Clinical Effectiveness, Safety, Survival in the Wound Site, and Proteomic Impact.

Although encouraging results of adipose-derived stem cell (ADSC) use in wound healing are available, the mechanism of action has been studied mainly in vitro and in animals. This work aimed to examine the safety and efficacy of allogenic ADSCs in human diabetic foot ulcer treatment, in combination with the analyses of the wound. Equal groups of 23 participants each received fibrin gel with ADSCs or fibrin gel alone. The clinical effects were assessed at four time points: days 7, 14, 21 and 49. Material collected during debridement from a subset of each group was analyzed for the presence of ADSC donor DNA and proteomic changes. The reduction in wound size was greater at all subsequent visits, significantly on day 21 and 49, and the time to 50% reduction in the wound size was significantly shorter in patients who received ADSCs. Complete healing was achieved at the end of the study in seven patients treated with ADSCs vs. one treated without ADSCs. One week after ADSC application, 34 proteins significantly differentiated the material from both groups, seven of which, i.e., GAPDH, CAT, ACTN1, KRT1, KRT9, SCL4A1, and TPI, positively correlated with the healing rate. We detected ADSC donor DNA up to 21 days after administration. We confirmed ADSC-related improvement in wound healing that correlated with the molecular background, which provides insights into the role of ADSCs in wound healing-a step toward the development of cell-based therapies.

Salivary testosterone may not serve as a screening test in the diagnosis of biochemical hyperandrogenism.

AIM: The diagnosis of biochemical hyperandrogenism is still challenging because a set of appropriate, recommended diagnostic tests has not been established. In our study, we aimed to answer the question of whether salivary testosterone is a reliable test to establish the diagnosis of biochemical hyperandrogenism as compared to serum total testosterone (TT) measured either by liquid chromatography-tandem mass spectrometry (LC-MS/MS) or immunoassay and to assess which set of biochemical tests would be the most appropriate for the identification of biochemical hyperandrogenism. METHODS: A total of 39 women, aged 18-45 years, with clinical or biochemical hyperandrogenism and 41 healthy individuals, aged 19-45 years, were enrolled in the study. Salivary testosterone was measured using the Salimetrics test. Serum TT was measured either using the LC-MS/MS method or immunoassay, and dehydroepiandrosterone sulphate (DHEA-S) and androstenedione were measured using LC-MS/MS. RESULTS: In 15 of 17 (88%) patients with elevated serum TT measured by LC-MS/MS and in 14 of 16 (87%) measured with immunoassay, salivary testosterone showed normal levels. In 11 of 39 women (28%) with normal serum testosterone levels, DHEA-S was elevated. All patients with elevated androstenedione presented with an elevated concentration of either serum testosterone or DHEA-S. CONCLUSION: Salivary testosterone measurement may lead to the underdiagnosis of biochemical hyperandrogenism. Both serum testosterone and DHEA-S should be measured in the endocrine work-up toward biochemical hyperandrogenism.

Long-Term Effects of Pedicle Clamping during Major Hepatectomy for Colorectal Liver Metastases.

The use of the Pringle maneuver (PM) varies widely among surgical departments. Its use depends on the operator and type of liver resection. The aim of this study was to determine the impact of the PM on patient outcomes when undergoing major liver resections. This retrospective study comprised 179 colorectal liver metastasis patients from two liver centers from Leeds and Warsaw. Only right or right extended hepatectomies with negative oncological margins were included. The primary outcome measure was the 5-year overall survival (OS). The PM was applied during 60 (33.5%) major hepatectomies included in the study and was associated with a higher peak 3-day postoperative bilirubin concentration (p = 0.002), yet not with the peak 3-day alanine aminotransferase activity (p = 0.415). The 5-year OS after liver resections with the PM and without the PM were 55.0% and 33.4%, respectively (p = 0.019). Following stratification by the Tumor Burden Score, after resections with the use of the PM, superior survival was particularly found in the subgroup of patients at intermediate risk of recurrence (p = 0.004). However, the use of the PM had no significant effect on the 5-year overall survival following adjustment for the confounding effect of the carcinoembryonic antigen concentration (p = 0.265). The use of the PM had no negative effects on the long-term outcomes in patients undergoing major, oncologically radical liver resections for colorectal metastases.

The influence of oxygen deprivation and donor age on the effect of statins on human mesenchymal stromal cells.

To date, no study evaluated the effect of oxygen deprivation together with statins pretreatment on human mesenchymal stromal cells (MSCs). The aim of our study was to establish the influence of atorvastatin and rosuvastatin on MSC proliferation and cytotoxicity in different oxygenic conditions. Human MSCs isolated from the bone marrow (n = 12) were incubated with statins. The proliferation rate and cytotoxic effect were evaluated in normoxic (21 %O2) and hypoxic (2%O2) conditions, also in relation to donor age. The treatment with atorvastatin was associated with significantly higher proliferation rate compared to control, both in hypoxic (19 % median increase) and normoxic conditions (20 %), p = 0.02 and p = 0.04, respectively. Atorvastatin had no significant cytotoxic effect on MSCs. Treatment with rosuvastatin in hypoxia resulted in significantly higher proliferation rate (15 %, p = 0.02) comparing to control with no significant cytotoxicity. In atmospheric oxygen concentration, rosuvastatin was associated with no significant change in proliferation and higher cytotoxicity compared to untreated control (p = 0.042 and p = 0.015, for 0.04 µM and 1 µM solutions respectively). There were no differences in the effect of statins on MSC from young donors vs. aged donors. These results suggest that statins could support MSC-based therapy of acute myocardial infarction.

Plasma microRNA-126-3p and neutrophil-to-lymphocyte ratio in patients with chronic kidney disease: relationships to ambulatory 24-h blood pressure.

Pro-inflammatory milieu of chronic kidney disease (CKD) results in endothelial damage and contributes to increased cardiovascular risk. The aim of the study was to evaluate association between neutrophil-to-lymphocyte ratio (NLR) and plasma relative expression of endothelially abundant miR-126-3p with circadian blood pressure (BP) pattern in CKD patients. This single-center observational study involved CKD stage 1-5 patients and healthy age- and sex-matched control subjects. All study participants had 24-h automatic blood pressure measurement (ABPM) performed. Plasma miRNA was quantified by qRT-PCR, in relation to endogenous U6 snRNA. In total, 90 CKD patients (60 ± 14 years, 52% males, 33 renal transplant recipients) and 25 healthy control subjects (55 ± 13 years, 48% males, p > 0.05) were enrolled in the study. We observed a positive correlation between miR-126-3p and average nighttime SBP (rho = 0.27, P = 0.02), average nighttime DBP (rho = 0.32, P = 0.003), night-day SBP ratio (ND-SBP), rho = 0.23, P = 0.03 and night-day DBP ratio (ND-DBP), rho = 0.26, P = 0.02. A positive association was found between NLR and average nighttime SBP (rho = 0.25, P = 0.01), ND-SBP (rho = 0.26, P = 0.006), and ND-DBP (rho = 0.28, P = 0.03). In the multiple regression model, NLR remained an independent predictor of average nighttime SBP (Beta per log change of NLR [95% CI]: 11.2 [1.8-10.6], P = 0.02), whereas miR-126-3p of nighttime DBP (1.88 [0.48; 3.28], p = 0.009), The results of our study point towards a link between both NLR and miR-126-3p and nighttime hypertension in CKD patients.

CXCL12 in Patients with Chronic Kidney Disease and Healthy Controls: Relationships to Ambulatory 24-Hour Blood Pressure and Echocardiographic Measures.

BACKGROUND/AIMS: Chronic kidney disease is a pro-inflammatory condition where the interplay between different regulatory pathways and immune cells mediates an unfavorable remodeling of the vascular wall and myocardial hypertrophy. These mechanisms include the action of CXCL12. The aim of this study is to evaluate the association between serum CXCL12 with left ventricular hypertrophy (LVH) and blood pressure control in chronic kidney disease (CKD) patients. METHODS: This single-center observational study involved 90 stable CKD stage 1-5 patients (including 33 renal transplant recipients) and 25 healthy age- and sex-matched control subjects. CXCL12 was quantified by ELISA. 24-h ambulatory blood pressure monitoring was performed in 90 patients and 25 healthy controls. Left ventricular mass index (LVMI) was calculated based on the transthoracic echocardiography measurements in 27 patients out of the CKD population and in the whole control group. RESULTS: CXCL12 correlated significantly with LVMI by multivariate regression analysis (coefficient B = 0.33, p = 0.02) together with age (B = 0.30, p = 0.03) and gender (B = 0.41, p = 0.003). A positive correlation was observed between CXCL12 and average 24-h systolic blood pressure (SBP) (rho = 0.35, p = 0.001), daytime SBP (rho = 0.35, p = 0.001), and nocturnal SBP (rho = 0.30, p = 0.002). Nocturnal hypertension was frequent (46% of CKD patients). CONCLUSIONS: The results of our study point towards a link between CXCL12 and LVH as well as blood pressure control among patients with CKD, supporting the thesis that CXCL12 may be regarded as a new potential uremic toxin.