Effect of orthostasis on the regulation of skin blood flow in upper and lower extremities in human.

OBJECTIVE: The research is aimed to investigate interactions between cardiovascular signals and to assess contributions of central and local mechanisms to skin blood flow regulation in upper and lower extremities at rest and under orthostasis. METHODS: Heart rate variability, respiration, forearm, and foot skin blood flow were assessed at rest and during postural test in 25 healthy volunteers. Spectral analysis was performed. Phase synchronization degree of analyzed signals was determined by group phase wavelet coherence function. RESULTS: Skin blood flow was lower on foot at rest and during postural test than on forearm. High-frequency component of heart rate variability was higher at ~0.3 Hz during postural test versus rest. Blood flow oscillation amplitudes on the foot were lower in frequency range including respiratory interval at rest than on forearm. Postural exposure increased amplitude of foot blood flow oscillations in respiratory interval and decreased amplitudes in cardiac interval versus rest. Orthostasis increased group wavelet phase coherence between foot blood flow and heart rate variability or respiration, as well as between forearm and foot blood flow at 0.3 Hz corresponding to respiration. CONCLUSIONS: The contribution of central mechanisms associated with respiration to blood flow regulation increased in lower extremities during orthostasis.

Nonlinear Behavior of the Autofluorescence Intensity on the Surface of Light-Scattering Biotissues and its Theoretical Proof.

In the up-to-date medical laser fluorescence spectroscopy (LFS) in vivo, there is a problem of quantification of fluorophores concentrations in optically-turbid biotissues by measurements of the laser induced autofluorescence flux on the surface of these tissues. One of the main problems is: whether the flux depends linearly or non-linearly on the concentration of fluorophores in tissues? The purpose of this work was both experimental and theoretical study of the character of dependencies between measured fluorescence intensities and fluorophores concentrations in optically-turbid media. In the experimental part of our study, measurements of the superficial fluorescence on phantoms at various known concentrations of fluorophores in them were carried out. As a result, experimental dependencies of registered intensities of the laser-induced autofluorescence emission were plotted against fluorophore concentrations. In the theoretical part of the study, the analytical solution for the fluorescence emission by Kokhanovsky's method based on the well-known two-flux Kubelka-Munk approach (KMA) was used. In addition, in our study the Kokhanovsky's method was modified by its association with our improved KMA, allowing us to receive exact analytical solutions for boundary intensities collected by optical probes. As a result, a set of theoretical curves describing the influence of fluorophore concentrations on the registered autofluorescence intensities was obtained, as well. Both experimental and theoretical results show a good qualitative agreement with each other. Also, these results demonstrate that the dependence of the fluorescence intensity on tissues' optical properties and on the concentration of fluorophores in light-scattering tissues can be both nonlinear and non-monotonic.

Modified kinetics of generation of reactive species in peripheral blood of patients with type 2 diabetes.

Level of reactive species in blood is an important pathogenic factor in diabetes mellitus leading to dysfunctions of vascular endothelial and smooth muscle cells and coagulation system abnormality. A massive release of reactive species (respiratory burst), catalyzed by NADPH oxidase in blood phagocytes, is not well understood in diabetes. The work aimed to study kinetics of response to microbial particles in blood to specify changes in regulatory mechanisms of generation of reactive species in patients with type 2 diabetes. Production of reactive species in blood and isolated granulocytes was measured by luminol-dependent chemiluminescence. Respiratory burst was initiated by serum opsonized zymosan in blood samples and phorbol ester in cell samples. Kinetic parameters were calculated from experimental kinetic curves of chemiluminescence intensity. ROC curve analysis and mathematical modeling were used to reveal the most significant predictors and clarify specific mechanisms of NADPH oxidase activation. It was shown that kinetic parameters of response to opsonized zymosan (lag-time, response rate, amplitude, production of reactive species) were higher in blood of patients than controls. Amplitude and response rate were the most statistically significant predictors for distinguishing patients and controls at high glucose. It indicated NADPH oxidase activation was the target of hyperglycemia. Mathematical modeling showed hyperglycemia increased stability of NADPH oxidase complex, decreased synchronization of its assembling and elevated neutrophil capacity to phagocytosis in patients. Weak or no dependence of response kinetics on ionomycin concentration was shown in patients indicating changed Ca2+-dependent mechanism of NADPH oxidase activation. Hyperglycemia in type 2 diabetes causes disturbances in mechanisms of NADPH oxidase activation associated with both phagocytosis and the state of intracellular signaling systems, including Ca2+-dependent. We suggest that NADPH oxidase in blood granulocytes can be a promising target for clinical intervention improving management of diabetic complications associated with inflammation.

Phase 2 Multicenter Single-Arm Study of Second-Line Axitinib in Favorable Risk Patients with Metastatic Renal Cell Carcinoma: FavorAx.

BACKGROUND: Targeted therapy with axitinib resulted in a greater objective response rate and prolonged progression-free survival (PFS) compared to sorafenib in patients with previously treated metastatic renal cell carcinoma (mRCC) in the phase 3 AXIS study, where 75% of patients had intermediate and poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk. OBJECTIVE: In this phase 2 study (FavorAx), we assessed the activity of axitinib in mRCC patients with a favorable risk and history of prior vascular endothelial growth factor receptor (VEGFR)-directed therapy. PATIENTS AND METHODS: Patients were required to have clear-cell mRCC, favorable risk according to IMDC criteria, and to have received first-line treatment with sunitinib or pazopanib. Prior treatment with other agents was not permitted. The primary endpoint of the study was 5 months PFS. Additional endpoints included response rate, safety, PFS, and overall survival (OS). RESULTS: A total of 21 patients were enrolled, 62% of whom were male. The mean age was 60 years. Eleven (52%) patients had two or more metastatic sites. 67% and 33% of patients received first-line sunitinib or pazopanib, respectively, with a median PFS of 17 months [95% confidence interval (CI), 14-20]. After a median follow-up of 25 months, the median PFS was 19 months (95% CI, 15-23). The current study did achieve its primary endpoint based on the 5-month PFS of 100%. The median OS was not yet reached. The 18 months OS rate was 85.7%. The objective response rate was 33% and one patient achieved a complete response. Seven patients had dose escalation of axitinib and four patients had dose reduction. Grade 3 adverse events were observed in 19% of cases. There was no discontinuation of therapy due to toxicity. CONCLUSIONS: The encouraging PFS and favorable safety profile observed in the FavorAx study support the administration of axitinib in mRCC patients with favorable IMDC risk and a history of prior sunitinib or pazopanib.