Human Exhaustion Research Articles

Complexity Analysis of Ocular Signal for Detection of Human Fatigue Using Small Datasets

The electrooculogram, often known as an EOG signal, can frequently be used to quantify the amount of drowsiness and exhaustion that a person is experiencing in their body. Electrooculogram signal analysis is primarily a process that does not include any invasive procedures and is used to evaluate the movement of the eye in both horizontal as well as in the vertical direction. The primary purpose of this research is to identify signs of exhaustion using the process of complexity analysis using non-invasive data collected from twenty people who are deemed to be in good physical and mental health. This investigation makes use of three distinct visual signals at three distinct frequencies, and it also considers three distinct time slots during the day. Based on real-time EOG signals that have been gathered in a non-invasive manner, oculo-parameters such as moving window fuzzy entropy and moving window dispersion entropy can be computed. According to the findings of the experiment, the level of complexity of both horizontal and vertical data steadily grows throughout the afternoon and evening as cue frequency steadily rises and we can ascertain the fatigue of the body. Drowsiness and exhaustion in humans may be caused by factors such as muscle stress, insufficient sleep, and a significant time gap between two different sleep cycles.

MobileNetV2-based Transfer Learning Model with Edge Computing for Automatic Fabric Defect Detection

In textile manufacturing, fabric defect detection is an essential quality control step and a challenging task. Earlier, manual efforts were applied to detect defects in fabric production. Human exhaustion, time consumption, and lack of concentration are the main problems in the manual defect detection process. Machine vision systems based on deep learning play a vital role in the Industrial Internet of things (IIoT) and fully automated production processes. Deep learning centered on Convolution Neural Network (CNN) models have been commonly used in fabric defect detection, but most of these models require high computing resources. This work presents a lightweight MobileNetV2-based Transfer Learning model to assist defect detection with low power consumption, low latency, easy upgrade, more efficiency, and an automatic visual inspection system with edge computing. Firstly, different image transformation techniques were performed as data augmentation on four fabric datasets for the model's adaptability in various fabrics. Secondly, fine-tuning hyperparameters of the MobileNetV2 with transfer learning gives a lightweight, adaptable and scalable model that suits the resource-constrained edge device. Finally, deploy the trained model to the NVIDIA Jetson Nano-kit edge device to make its detection faster. We assessed the model based on its accuracy, sensitivity rate, specificity rate, and F1 measure. The numerical simulation reveals that the model accuracy is 96.52%, precision is 96.52%, recall is 96.75%, and F1-Score is 96.52%.

Five Senses in Exhaustion: Toward the Development of Five-sense Augmentation Device that Considers Human Exhaustion

Five Senses in Exhaustion: Toward the Development of Five-sense Augmentation Device that Considers Human Exhaustion

Identification of human progenitors of exhausted CD8+ T cells associated with elevated IFN-γ response in early phase of viral infection

T cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. Limited knowledge exists of the initial viral and immune dynamics that characterise exhaustion in humans. We studied longitudinal blood samples from a unique cohort of individuals with primary infection using single-cell multi-omics to identify the functions and phenotypes of HCV-specific CD8+ T cells. Early elevated IFN-γ response against the transmitted virus is associated with the rate of immune escape, larger clonal expansion, and early onset of exhaustion. Irrespective of disease outcome, we find heterogeneous subsets of progenitors of exhaustion, based on the level of PD-1 expression and loss of AP-1 transcription factors. Intra-clonal analysis shows distinct trajectories with multiple fates and evolutionary plasticity of precursor cells. These findings challenge the current paradigm on the contribution of CD8+ T cells to HCV disease outcome and provide data for future studies on T cell differentiation in human infections.

Balanced engagement of activating and inhibitory receptors mitigates human NK cell exhaustion.

NK cell exhaustion is caused by chronic exposure to activating stimuli during viral infection, tumorigenesis, and prolonged cytokine treatment. Evidence suggests that exhaustion may play a role in disease progression. However, relative to T cell exhaustion, the mechanisms underlying NK cell exhaustion and methods of reversing it are poorly understood. Here, we describe a potentially novel in vitro model of exhaustion that uses plate-bound agonists of the NK cell activating receptors NKp46 and NKG2D to induce canonical exhaustion phenotypes. In this model, prolonged activation resulted in downregulation of activating receptors, upregulation of checkpoint markers, decreased cytokine production and cytotoxicity in vitro, weakened glycolytic capacity, and decreased persistence, function, and tumor control in vivo. Furthermore, we discovered a beneficial effect of NK cell inhibitory receptor signaling during exhaustion. By simultaneously engaging the inhibitory receptor NKG2A during activation in our model, cytokine production and cytotoxicity defects were mitigated, suggesting that balancing positive and negative signals integrated by effector NK cells can be beneficial for antitumor immunity. Together, these data uncover some of the mechanisms underlying NK cell exhaustion in humans and establish our in vitro model as a valuable tool for studying the processes regulating exhaustion.

The functional and molecular determinants of HCV-specific CD8 T cell responses during early infection

Abstract T-cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. However, limited knowledge exists of the initial dynamics that establish exhaustion in humans. We studied longitudinal blood samples from a unique cohort of primary HCV infection subjects using single cell multi-omics and viral dynamics to identify the functions and phenotypes of HCV-specific CD8+ T cells. The magnitude of IFN-γ production against the transmitted virus was associated with the rate of immune escape, larger clonal expansion, and a molecular profile consistent with a progenitor of early-exhaustion. Lineage tracing within clones revealed fate plasticity through the course of the infection and differentiation fates of progenitor exhausted subsets. This study provides new insights on the contribution of CD8+ T cells to HCV disease outcome and exhaustion, and supports future studies on early T-cell differentiation in human infections. Supported by grants from the NHMCR and scholarships from the Australian Government Research Training Program.

Vernacular Landscapes

This essay employs Anthropocene frameworks to examine United States independent director Kelly Reichardt’s quiet vignettes of American precarity through the interpretive cinematic apparatus. Reichardt’s slow style and lingering gaze are primarily read as affective interpretations of human exhaustion or as a critique of capital temporalities. However, the critical attention paid toward the human in Reichardt’s films overlooks the primacy of landscape as a site of knowledge in the visual aesthetic. It is the entanglement between the human and the landscape in Reichardt’s films that invites an Anthropocene reading based on core concepts of time, scale, and the disruption of the modernist nature/culture binary. In Old Joy (2006) and Wendy and Lucy (2008), local, global, and planetary scales are made explicit and conflict with human structures such as gender and neoliberal economies. Reichardt’s work explores the manufactured landscape of Oregon and the Florida Everglades (respectively) in Night Moves (2013) and River of Grass (1994), pointing toward larger structural issues at play in traditional conservationism and narratives of progress. Finally, in her Western-influenced films Meek’s Cutoff (2010) and Certain Women (2016), Reichardt’s use of environmental sound provides the critique of American expansionist ideology’s depiction of and attempt to consume Indigeneity. Taken together, Reichardt’s filmography presents a compelling case for cinema’s role as mediator of the Anthropocene crisis.

Rapamycin Prevents Surgery-Induced Immune Dysfunction in Patients with Bladder Cancer.

The mechanistic target of rapamycin (mTOR) integrates environmental inputs to regulate cellular growth and metabolism in tumors. However, mTOR also regulates T-cell differentiation and activation, rendering applications of mTOR inhibitors toward treating cancer complex. Preclinical data support distinct biphasic effects of rapamycin, with higher doses directly suppressing tumor cell growth and lower doses enhancing T-cell immunity. To address the translational relevance of these findings, the effects of the mTOR complex 1 (mTORC1) inhibitor, rapamycin, on tumor and T cells were monitored in patients undergoing cystectomy for bladder cancer. MB49 syngeneic murine bladder cancer models were tested to gain mechanistic insights. Surgery-induced T-cell exhaustion in humans and mice and was associated with increased pulmonary metastasis and decreased PD-L1 antibody efficacy in mouse bladder cancer. At 3 mg orally daily, rapamycin concentrations were 2-fold higher in bladder tissues than in blood. Rapamycin significantly inhibited tumor mTORC1, shown by decreased rpS6 phosphorylation in treated versus control patients (P = 0.008). Rapamycin reduced surgery-induced T-cell exhaustion in patients, evidenced by a significant decrease in the prevalence of dysfunctional programmed death-1 (PD-1)-expressing T cells. Grade 3 to 4 adverse event rates were similar between groups, but rapamycin-treated patients had a higher rate of wound complications versus controls. In conclusion, surgery promoted bladder cancer metastasis and decreased the efficacy of postoperative bladder cancer immunotherapy. Low-dose (3 mg daily) oral rapamycin has favorable pharmacodynamic and immune modulating activity in surgical patients and has the potential to decrease surgery-induced immune dysfunction.

Abstract A191: Novel approaches to the study of NK cell exhaustion in humans

Abstract The engagement of activating or inhibitory receptors and production of immunosuppressive factors in the tumor microenvironment can modulate NK cell activities, such as cytotoxicity and cytokine production. In certain instances, NK cells acquire a dysfunctional state, resembling the “exhaustion phenotype” described for T-cells characterized by (i) overexpression of inhibitory receptors such as PD-1, CTLA-4, LAG-3, TIGIT and TIM-3, (ii) down regulation of cytokine receptors, rendering them refractory to cytokine stimulation; (iii) loss of function (cytotoxicity, abnormally low cytokine production, and proliferation); and (iv) down regulation of transcription factors T-bet and Eomes. The mechanisms underlying NK cell exhaustion in cancer remain undefined. We hypothesized that the interaction between immunogenetics, education and environment may play an important role during induction of NK cell exhaustion. Checkpoint molecules and NK cell receptors such as Tim-3, TIGIT, inhibitory KIRs and NKG2A among others are key candidates for mediating the exhaustion profile. The aim of this project was to use a selected collection of healthy donors who are HLA and KIR genotyped, and whose CMV and EBV status are defined, to i) clarify the steady state distribution of checkpoint molecules on NK cells between individuals and ii) determine how these profiles change with exposure to immune suppressive environments. In order to do so we applied Mass Cytometry (CyTOF) technology for detailed analysis. In addition, we developed an in vitro NK cell exhaustion assay used to evaluate gradual changes in NK cell activity determined by their cytotoxicity and cytokine production capacities. Purified NK cells from healthy individuals were cultured for short- and long-term cultures with completed media supplemented with recombinant human (rh)-IL-2 or rhIL-15 in the presence of increasing TGF-β concentrations (from 0.05, 0.5, 5 to 50ng/ml); or co-culture with m44, Gmel and Skm147 melanoma cell lines at a ratio of 1:10. Analysis of NK cell dysfunction was determined by quantifying degranulation and IFN-γ production. Our preliminary results confirmed that both immunosuppressive factors and NK cell ligands from the tumor microenvironment are necessary to completely shut down NK cell function. Interactions between NK cell ligands and their specific NK cell receptors are crucial for the induction of NK cell exhaustion in vitro by reducing NK cell activity nearly 80% measured by degranulation and IFN-γ production, whereas addition of increasing concentrations of rhTGF-β1 into the culture gradually drives NK cells to a process of exhaustion by reducing their cytotoxicity and cytokine production capacities by 40-50%. TGF-β1 immunosuppressive effect on NK cells reaches a maximum at 6 days of in vitro culture by noncanonical TGF-β signaling. More than that, we are able to confirm differences in the expression of activating or inhibitory NK cell receptors presented by each individual based on host-genetics and NK cell education in response to immunosuppressive cytokine stimulation. In summary, these results should help us to predict NK-cell response to therapies based on the presence or absence of unique NK cell subsets. Citation Format: Elena Gonzalez-Gugel, Keerthi Caroline Sadanala, Adeeb Rahman, Richard Stephen Blumberg, Amir Horowitz, Nina Bhardwaj. Novel approaches to the study of NK cell exhaustion in humans [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A191.

What limits performance during whole-body incremental exercise to exhaustion in humans?

To determine the mechanisms causing task failure during incremental exercise to exhaustion (IE), sprint performance (10 s all-out isokinetic) and muscle metabolites were measured before (control) and immediately after IE in normoxia (P(IO2) 143 mmHg) and hypoxia (P(IO2): 73 mmHg) in 22 men (22 ± 3 years). After IE, subjects recovered for either 10 or 60 s, with open circulation or bilateral leg occlusion (300 mmHg) in random order. This was followed by a 10 s sprint with open circulation. Post-IE peak power output (W(peak)) was higher than the power output reached at exhaustion during IE (P < 0.05). After 10 and 60 s recovery in normoxia, W(peak) was reduced by 38 ± 9 and 22 ± 10% without occlusion, and 61 ± 8 and 47 ± 10% with occlusion (P < 0.05). Following 10 s occlusion, W(peak) was 20% higher in hypoxia than normoxia (P < 0.05), despite similar muscle lactate accumulation ([La]) and phosphocreatine and ATP reduction. Sprint performance and anaerobic ATP resynthesis were greater after 60 s compared with 10 s occlusions, despite the higher [La] and [H(+)] after 60 s compared with 10 s occlusion recovery (P < 0.05). The mean rate of ATP turnover during the 60 s occlusion was 0.180 ± 0.133 mmol (kg wet wt)(-1) s(-1), i.e. equivalent to 32% of leg peak O2 uptake (the energy expended by the ion pumps). A greater degree of recovery is achieved, however, without occlusion. In conclusion, during incremental exercise task failure is not due to metabolite accumulation or lack of energy resources. Anaerobic metabolism, despite the accumulation of lactate and H(+), facilitates early recovery even in anoxia. This points to central mechanisms as the principal determinants of task failure both in normoxia and hypoxia, with lower peripheral contribution in hypoxia.

Influência da administração de eritropoietina humana recombinante sobre o desempenho físico: estudo de revisão

ObjectiveDiscuss the influence of rHuEPO on physical performance, as well as the adverse effects of this practice, exposing results from experimental and clinical studies. MethodsWere selected articles published in the basis, PubMed and SciELO databases, in the period 1985‐2013, using the following keywords eritropoetina/erythropoietin, desempenho atlético/athletic performance, resistência física/physical endurance, efeitos adversos/adverse effects e doping nos esportes/doping in sports. ResultsAll articles (n=10) related to the influence of treatment with rHuEPO on sports performance, found improvement in the variables of maximal oxygen uptake (VO2max) and time to exhaustion in humans, using different protocols dosages between 50 to 60IU/kg during the first weeks with reduced throughout treatment. Among the most common adverse effects are the thrombovascular accidents, iron deficiency and hypertension. ConclusionTreatment with rHuEPO doses and at different periods, can enhance physical performance in humans, because of the different generated effects, including increased O2 transport, reduction of blood lactate concentrations, increased concentrations of free fatty acids in the blood and muscle glycogen.

Effects of garlic consumption on physiological variables and performance during exercise in hypoxia

Exposure to hypoxia results in vasoconstriction of the pulmonary vasculature (HPV) leading to pulmonary hypertension (HPH) and reductions in blood oxygen saturation and exercise performance. Alleviation of HPV and HPH via vasodilators has been shown to improve blood oxygen saturation and exercise performance in hypoxia. Garlic has been shown to reduce HPV and HPH in rats and has been suggested to have ergogenic effects in hypoxic exercise. We compared the effects of 7 days of supplementation with garlic and placebo on peripheral blood pressures, blood oxygen saturation, heart rate, oxygen consumption, and time to exhaustion during a progressive exercise test to exhaustion in humans under hypoxia (PIO2 ∼ 88 Torr). No significant differences were observed between treatments regarding oxygen consumption, exercise or resting peripheral blood pressures, blood oxygen saturation, heart rates, or exercise time to exhaustion. These results do not support garlic consumption as a method for improving peripheral blood pressure, maximal oxygen consumption, blood oxygen saturation, exercising heart rate, heart rate response, or exercise performance in hypoxia.

Human Failure and Humane Exhaustion: The Passion of Alain Platel

Human Failure and Humane Exhaustion: The Passion of Alain Platel

Integrative Genomic Analysis of HIV-Specific CD8+ T Cells Reveals That PD-1 Inhibits T Cell Function by Upregulating the AP-1 Transcription Factor BATF.

Abstract 916T cells responding to chronic infections such as HIV lose the ability to secrete cytokines or to proliferate, functions critical for control of viral replication, in a process termed exhaustion. However the molecular mechanisms of T cell exhaustion are not understood, and few therapeutic targets to reinvigorate exhausted T cells have been identified. We therefore conducted a comprehensive genomic analysis of HIV-specific CD8+ T cells to identify the mechanisms underlying defective function in T cell exhaustion. We used Affymetrix microarrays to study gene expression profiles from sorted Gag-specific tetramer+ CD8+ T cells in two cohorts of HIV-infected individuals that differed in their extent of T cell exhaustion: a) Progressors (n=24), who show chronic elevation of viral load and have defects in HIV-specific T cell cytokine secretion, proliferation and survival; and b) Controllers (n=18), who show spontaneous control of viral replication and have relatively good HIV-specific T cell function. Profiles of Gag-specific CD8+ T cells (median 21,500 cells/sample) from progressors showed marked alterations in gene expression compared with those from controllers (n=518 genes upregulated in progressors, moderated t-statistic >2.0). There was highly significant similarity at the whole-genome level between dysfunctional Gag-specific CD8+ T cells from progressors and exhausted CD8+ T cells in the mouse model of chronic LCMV infection (gene set enrichment analysis, P=4.8e−005), suggesting that T cell exhaustion is associated with an evolutionarily conserved program of gene expression. Next, we determined whether this exhausted signature was influenced by inhibitory signaling via the receptor PD-1, an inhibitory receptor known to be upregulated in expression on exhausted T cells. We developed an in vitro model of PD-1 signaling and identified a unique signature of genes upregulated by PD-1 ligation. The signature of PD-1 induced genes was highly significantly upregulated in profiles from Gag-specific CD8+ T cells in HIV progressors compared to controllers (P=5e−006), and in exhausted CD8+ T cells from the LCMV mouse model (P=2e−004). Thus the signature of T cell exhaustion in humans and mice is driven in part by the consequences of PD-1 signaling. Finally, we asked whether the genes upregulated by PD-1 in exhausted T cells directly inhibit T cell function. PD-1 ligation upregulated the transcription factor BATF in HIV-specific CD8+ T cells and in exhausted CD8+ T cells from the mouse model of LCMV infection. Enforced expression of BATF, an inhibitory member of the AP-1 family, in normal human T cells inhibited proliferation (P=0.02) and IL2 secretion (P=4.5e-05). Infection with LCMV in BATF transgenic mice resulted in marked acceleration of T cell exhaustion compared to wild-type animals, indicating that BATF represses T cell effector functions. Silencing of BATF using shRNA in primary human T cells showed that it was required for PD-1 mediated inhibition of T cell function. In summary, our results demonstrate that 1) PD-1 ligation induces a conserved transcriptional program in exhausted HIV-specific CD8+ T cells and in exhausted LCMV-specific CD8+ T cells in the mouse; 2) this transcriptional program includes the upregulation of genes such as BATF that directly inhibit T cell function. Our data suggest that BATF causes the functional defects seen in T cell exhaustion, and represents a new therapeutic target to rescue T cell function in HIV infection. Disclosures:No relevant conflicts of interest to declare.

Acute BDNF and cortisol response to low intensity exercise and following ramp incremental exercise to exhaustion in humans

The effect of short-term aerobic exercise and a following ramp incremental cycle ergometry to exhaustion on the acute response of the serum concentrations of brain derived neurotrophic factor (BDNF) and cortisol (COR) was examined in 8 healthy male athletes. Venous and capillary blood samples were drawn at rest, immediately after a 10 min warm-up period with aerobic exercise and after a ramp test to exhaustion, as well as 3, 6, 10 and 15 min post exercise. Capillary blood lactate (LA) concentration and blood gases as well as serum BDNF and COR concentrations did not change during the warm-up period. LA was increased ( p < 0.05) at the end of the ramp test and during recovery period while bicarbonate concentration, carbon dioxide pressure, pH and base excess were decreased ( p < 0.05) during this period. Serum BDNF was increased at the point of exhaustion ( p < 0.05) while no significant differences were found between values at rest and those during recovery period. At 10 and 15 min post incremental exercise, COR concentrations were increased ( p < 0.05) compared to rest. The present study is the first to demonstrate in humans that in contrast to short duration aerobic exercise immediately after a following short duration high-intensity exercise to exhaustion, there is a transient augmentation of serum BDNF concentration. Short-term response of serum BDNF and COR concentrations differs as BDNF returns to baseline level faster than COR.

Persistent HIV-1-Specific CTL Clonal Expansion Despite High Viral Burden Post In Utero HIV-1 Infection

To address the issue of clonal exhaustion in humans, we monitored HLA class I-restricted, epitope-specific CTL responses in an in utero HIV-1-infected infant from 3 mo through 5 years of age. Serial functional CTL precursor assays demonstrated persistent, vigorous, and broadly directed HIV-1 specific CTL activity with a dominant response against an epitope in HIV-1 Gag-p17 (SLYNTVATL, aa 77-85). A clonal CTL response directed against the immunodominant, HLA-A*0201-restricted epitope was found to persist over the entire observation period, as shown by TCR analysis of cDNA libraries generated from PBMC. The analysis of autologous viral sequences did not reveal any escape mutations within the targeted epitope, and viral load measurement indicated ongoing viral replication. Furthermore, inhibition of viral replication assays indicated that the epitope was properly processed from autologous viral protein. These data demonstrate that persistent exposure to high levels of viral Ag does not necessarily lead to clonal exhaustion and that epitope-specific clonal CTL responses induced within the first weeks of life can persist for years without inducing detectable viral escape variants.

Energy cost and running mechanics during a treadmill run to voluntary exhaustion in humans.

The aim of the present study was to examine the physiological and mechanical factors which may be concerned in the increase in energy cost during running in a fatigued state. A group of 15 trained triathletes ran on a treadmill at velocities corresponding to their personal records over 3000m [mean 4.53 (SD 0.28) m x s(-1)] until they felt exhausted. The energy cost of running (CR) was quantified from the net O2 uptake and the elevation of blood lactate concentration. Gas exchange was measured over 1 min firstly during the 3rd-4th min and secondly during the last minute of the run. Blood samples were collected before and after the completion of the run. Mechanical changes of the centre of mass were quantified using a kinematic arm. A significant mean increase [6.9 (SD 3.5)%, P < 0.001] in CR from a mean of 4.4 (SD 0.4) J x kg(-1) x m(-1) to a mean of 4.7 (SD 0.4) J x kg(-1) x m(-1) was observed. The increase in the O2 demand of the respiratory muscles estimated from the increase in ventilation accounted for a considerable proportion [mean 25.2 (SD 10.4)%] of the increase in CR. A mean increase [17.0 (SD 26.0)%, P < 0.05] in the mechanical cost (CM) from a mean of 2.36 (SD 0.23) J x kg m(-1) to a mean of 2.74 (SD 0.55) J x kg(-1) x m(-1) was also noted. A significant correlation was found between CR and CM in the non-fatigued state (r=0.68, P < 0.01), but not in the fatigued state (r=0.25, NS). Furthermore, no correlations were found between the changes (from non-fatigued to fatigued state) in CR and the changes in CM suggesting that the increase in CR is not solely dependent on the external work done per unit of distance. Since step frequency decreased slightly in the fatigued state, the internal work would have tended to decrease slightly which would not be compatible with an increase in CR. A stepwise regressions showed that the changes in CR were linked (r=0.77, P < 0.01) to the changes in the variability of step frequency and in the variability of potential cost suggesting that a large proportion of the increase in CR was due to an increase in the step variability. The underlying mechanisms of the relationship between CR and step variability remains unclear.

Release of prostacyclin into the bloodstream and its exhaustion in humans after local blood flow changes (ischemia and venous stasis)

The vessel wall produces PGI 2 which potently inhibits platelet aggregation and causes vasodilatation. In twenty young healthy volunteers (10 males and 10 females) we investigated whether blood flow changes in the forearm such as venous stasis (VS) and ischemia are able to induce PGI 2 release. PGI 2 has been detected in the venous blood by the Vane superfusion technique. VS of 15 minutes' duration induces PGI2 release (average output 184.6 ± 40. 2 ng/min) immediately after the beginning of V S that continues throughout the occlusion period. Production of PGI 2 takes place also after 3 minutes of ischemia (average output 580.25 ± 162.83 ng/min). The release of PGI 2 occurs almost exclusively during the first minute of post-ischemic hyperemia (PIH). The PGI 2 production becomes exhausted after several (4 to 6) subsequent and close periods of VS or ischemia. These results suggest that subsequent periods of VS or ischemia, as can occur in various clinical conditions, lead to an exhaustion of PGI 2 production and cause a loss of a potent mechanism against platelet aggregation.