Critical analysis of cerebrovascular autoregulation during repeated head-up tilt.

BACKGROUND AND PURPOSE: Cerebrovascular autoregulation has been described with a phase lead of cerebral blood flow preceding changes in cerebral perfusion pressure (CPP), but there has been less focus on the effect of CPP on cerebral vascular resistance. We investigated these relations during spontaneous fluctuations (control) and repeated head-up tilt. METHODS: Eight healthy adults were studied in supine rest and repeated tilt with 10-second supine, 10 seconds at 45 degrees head-up tilt for a total of 12 cycles. Cerebral blood flow was estimated from mean flow velocity (MFV) by transcranial Doppler ultrasound, CPP was estimated from corrected finger pressure (CPP(F)), and cerebrovascular resistance index (CVRi) was calculated in the supine position from CPP(F)/MFV. Gain and phase relations were assessed by cross-spectral analysis. RESULTS: In the supine position, MFV preceded CPP(F), but changes in CVRi followed CPP(F). Gain and phase relations for CPP(F) as input and MFV as output were similar in supine and repeated tilt experiments. Thus, changes in cerebrovascular resistance must have had a similar pattern in the supine and tilt experiments. CONCLUSIONS: Cerebrovascular autoregulation is achieved by changes in resistance in response to modulations in perfusion pressure whether spontaneous or induced by repeated tilt. The phase lead of MFV before CPP(F) is a mathematical and physiological consequence of the relation the input variable (CPP(F)) and the manipulated variable (cerebrovascular resistance) that should not be taken as an indication of independent control of cerebral blood flow

Faster femoral artery blood velocity kinetics at the onset of exercise following short-term training.

OBJECTIVE: The hypothesis that the adaptation to endurance exercise training included a faster increase in blood flow at the onset of exercise was tested in 12 healthy young men who endurance-trained (ET) 2 h/day, for 10 days at 65% VO2 peak on a cycle ergometer, and in 11 non-training control (C) subjects. METHODS: Blood flow was estimated from changes in femoral artery mean blood velocity (MBV) by pulsed Doppler. Beat-by-beat changes in cardiac output (CO) and mean arterial pressure (MAP) were obtained by impedance cardiography and a Finapres finger cuff, respectively. MBV, MAP and CO were measured at rest and during 5 min of dynamic knee extension exercise. Both legs worked alternately with 2 s raising and lowering a weight (15% maximal voluntary contraction) followed by 2 s rest while the other leg raised and lowered the weight. RESULTS: In the ET group the time to 63% (T63%) of the approximately exponential increase in MBV following 10 days of training (8.6 +/- 1.2 s, mean +/- s.e.) was significantly faster than the Day 0 response (14.2 +/- 2.1 s, P \u3c 0.05). The T63% of femoral artery vascular conductance (VCfa) was also faster following 10 days of ET (9.4 +/- 0.9 s) versus Day 0 (16.0 +/- 2.5 s) (0.05). There was no change in the T63% of both MBV and VCfa for the C group. The kinetics of CO were not significantly affected by ET, but the amplitude of CO in the adaptive phase, and at steady state, were significantly greater (P \u3c 0.05) at Day 10 compared to Day 0 for the ET group with no change in the C group. CONCLUSIONS: These data supported the hypothesis that endurance training resulted in faster adaptation of blood flow to exercising muscle, and further showed that this response occurred early in the training program

Implications of Therapy-Induced Selective Autophagy on Tumor Metabolism and Survival

Accumulating evidence indicates that therapies designed to trigger apoptosis in tumor cells cause mitochondrial depolarization, nuclear damage, and the accumulation of misfolded protein aggregates, resulting in the activation of selective forms of autophagy. These selective forms of autophagy, including mitophagy, nucleophagy, and ubiquitin-mediated autophagy, counteract apoptotic signals by removing damaged cellular structures and by reprogramming cellular energy metabolism to cope with therapeutic stress. As a result, the efficacies of numerous current cancer therapies may be improved by combining them with adjuvant treatments that exploit or disrupt key metabolic processes induced by selective forms of autophagy. Targeting these metabolic irregularities represents a promising approach to improve clinical responsiveness to cancer treatments given the inherently elevated metabolic demands of many tumor types. To what extent anticancer treatments promote selective forms of autophagy and the degree to which they influence metabolism are currently under intense scrutiny. Understanding how the activation of selective forms of autophagy influences cellular metabolism and survival provides an opportunity to target metabolic irregularities induced by these pathways as a means of augmenting current approaches for treating cancer

When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen

Hypoxia is a signature feature of growing tumors. This cellular state creates an inhospitable condition that impedes the growth and function of all cells within the immediate and surrounding tumor microenvironment. To adapt to hypoxia, cells activate autophagy and undergo a metabolic shift increasing the cellular dependency on anaerobic metabolism. Autophagy upregulation in cancer cells liberates nutrients, decreases the buildup of reactive oxygen species, and aids in the clearance of misfolded proteins. Together, these features impart a survival advantage for cancer cells in the tumor microenvironment. This observation has led to intense research efforts focused on developing autophagy-modulating drugs for cancer patient treatment. However, other cells that infiltrate the tumor environment such as immune cells also encounter hypoxia likely resulting in hypoxia-induced autophagy. In light of the fact that autophagy is crucial for immune cell proliferation as well as their effector functions such as antigen presentation and T cell-mediated killing of tumor cells, anticancer treatment strategies based on autophagy modulation will need to consider the impact of autophagy on the immune system

Effect of short-term lycopene supplementation and postprandial dyslipidemia on plasma antioxidants and biomarkers of endothelial health in young, healthy individuals

The objective of this study was to test the hypothesis that the effect of a high-fat meal (HFm) on plasma lipid-soluble antioxidants and biomarkers of vascular oxidative stress and inflammation would be attenuated by short-term lycopene supplementation in young healthy subjects. Following restriction of lycopene-containing foods for 1-wk (LYr), blood was collected in a fasting state and 3 h after a HFm and a low-fat meal (LFm) in N = 18 men aged 23 ± 2 years, and after a HFm only in N = 9 women aged 23 ± 1 years. Blood was also sampled pre- and post-meals following 1-wk of 80 mg/day lycopene supplementation (LYs) under continued dietary LYr. In the fasting state, LYs compared with LYr not only evoked a >2-fold increase in plasma lycopene but also increased plasma β-carotene and α-tocopherol (p < 0.01), though LYs did not affect plasma nitrate/nitrite (biomarker of nitric oxide), malondialdehyde (biomarker of lipid oxidative stress), vascular- and intercellular-adhesion molecules or C-reactive protein (biomarkers of inflammation). Contrary to the hypothesis, the HFm-induced dyslipidemic state did not affect plasma malondialdehyde, C-reactive protein, or adhesion molecules in either LYr or LYs. Both the HFm and LFm were associated with decreases in the nitric oxide metabolites nitrate/nitrite and lipid-soluble antioxidants (p < 0.05). The data revealed that 1-wk of LYs increased plasma lycopene, β-carotene, and α-tocopherol yet despite these marked changes to the plasma lipid-soluble antioxidant pool, biomarkers of vascular oxidative stress and inflammation were unaffected in the fasted state as well as during dyslipidemia induced by a HFm in young healthy subjects

Sporadic Creutzfeldt-Jakob disease infected human cerebral organoids retain the original human brain subtype features following transmission to humanized transgenic mice

Human cerebral organoids (COs) are three-dimensional self-organizing cultures of cerebral brain tissue differentiated from induced pluripotent stem cells. We have recently shown that COs are susceptible to infection with different subtypes of Creutzfeldt-Jakob disease (CJD) prions, which in humans cause different manifestations of the disease. The ability to study live human brain tissue infected with different CJD subtypes opens a wide array of possibilities from differentiating mechanisms of cell death and identifying neuronal selective vulnerabilities to testing therapeutics. However, the question remained as to whether the prions generated in the CO model truly represent those in the infecting inoculum. Mouse models expressing human prion protein are commonly used to characterize human prion disease as they reproduce many of the molecular and clinical phenotypes associated with CJD subtypes. We therefore inoculated these mice with COs that had been infected with two CJD subtypes (MV1 and MV2) to see if the original subtype characteristics (referred to as strains once transmitted into a model organism) of the infecting prions were maintained in the COs when compared with the original human brain inocula. We found that disease characteristics caused by the molecular subtype of the disease associated prion protein were similar in mice inoculated with either CO derived material or human brain material, demonstrating that the disease associated prions generated in COs shared strain characteristics with those in humans. As the first and only in vitro model of human neurodegenerative disease that can faithfully reproduce different subtypes of prion disease, these findings support the use of the CO model for investigating human prion diseases and their subtypes

Bank Vole Prion Protein As an Apparently Universal Substrate for RT-QuIC-Based Detection and Discrimination of Prion Strains

Prions propagate as multiple strains in a wide variety of mammalian species. The detection of all such strains by a single ultrasensitive assay such as Real Time Quaking-induced Conversion (RT-QuIC) would facilitate prion disease diagnosis, surveillance and research. Previous studies have shown that bank voles, and transgenic mice expressing bank vole prion protein, are susceptible to most, if not all, types of prions. Here we show that bacterially expressed recombinant bank vole prion protein (residues 23-230) is an effective substrate for the sensitive RT-QuIC detection of all of the different prion types that we have tested so far--a total of 28 from humans, cattle, sheep, cervids and rodents, including several that have previously been undetectable by RT-QuIC or Protein Misfolding Cyclic Amplification. Furthermore, comparison of the relative abilities of different prions to seed positive RT-QuIC reactions with bank vole and not other recombinant prion proteins allowed discrimination of prion strains such as classical and atypical L-type bovine spongiform encephalopathy, classical and atypical Nor98 scrapie in sheep, and sporadic and variant Creutzfeldt-Jakob disease in humans. Comparison of protease-resistant RT-QuIC conversion products also aided strain discrimination and suggested the existence of several distinct classes of prion templates among the many strains tested