Reduced Oxygen Supply Research Articles

The relationship between sudden severe hypoxia and ischemia-associated spreading depolarization in adult rat brainstem in vivo

Severe ischemia can induce spreading depolarization (SD) in the cerebral cortex, which is thought to contribute significantly to cerebral dysfunction. Whether the mature brainstem shows SD upon reduced oxygen supply has not been investigated although SDs may significantly influence brainstem functions. In anesthetized adult rats, we induced severe short-lasting hypoxia (SSH) by stopping artificial respiration for about 1 min or by ventilation with pure nitrogen for 1, 2 or 3 min, and milder hypoxia by ventilation with 6% O 2 in N 2 for 10 min. We measured DC potentials in the brainstem and cerebral cortex, systemic arterial blood pressure, heart rate and local blood flow at the brainstem or cerebral cortex surface. SSH lasting up to 1 min did not induce DC shifts in native brainstem but reduced heart rate, systemic blood pressure and blood flow in cortex and brainstem. Longer lasting SSH protocols both reduced systemic blood pressure and induced SD in the brainstem, but the magnitude of the cardiovascular response was not influenced by the simultaneous occurrence of SD. When neuronal excitability in the brainstem was artificially enhanced, SSH of 1 min evoked SD but again the magnitude of cardiovascular changes during SSH was not increased. SSH lasting 3 min evoked non-reversible sustained depolarization. SSH did not render the brainstem more excitable for classical SD evoked by local KCl application. Thus, sudden severe hypoxia/ischemia evokes SDs in the brainstem, but the occurrence of the so-elicited SD does not influence the immediate cardiovascular response to SSH.

Para-aminopropiophenone (PAPP) Research, Development, Registration, and Application for Humane Predator Control in New Zealand

Feral cat and stoat control is conducted in New Zealand to protect a number of threatened native species, including kiwi, from predation. Para-aminopropiophenone (PAPP) is being developed for predator control. Previously reported cage trials have shown PAPP presented in a meat bait was palatable and effective, while symptoms observed demonstrated PAPP to be humane. Subsequent field trials on stoats were undertaken in two blocks of native forest and achieved 83% and 87% reductions in the stoat abundance index, and a field trial on a population of radio-collared feral cats had an 84% kill. PAPP represents one compound from a new class of active ingredients, which we are calling red blood cell toxins. These vertebrate pesticides have humaneness, and low secondary and non-target poisoning risks, as their primary consideration. The dose is optimised to be effective in the field and reduces oxygen supply to the brain such that animals become lethargic, sleepy and unconscious prior to death within 1-2 hours. Results from these field trials on stoats and feral cats indicate that PAPP will be a useful additional tool for predator control.

Toxicodynamics of Methemoglobin (MtHb) Inducers

Author(s): Conole, Daniel; Brimble, Margaret; Rennison, David; Tingle, Malcolm; Eason, Charles | Abstract: There is a need in New Zealand for a new, more advanced generation of toxins to minimize the impact of invasive animals. A new pest control agent, para-aminopropiophenone (PAPP), represents a lead candidate presently undergoing registration for the humane control of stoats and feral cats. It exhibits low toxicity to most bird species, no secondary poisoning risk, and has a simple and highly effective antidote. PAPP induces methemoglobinemia (MtHb), which acts to prevent oxygen from binding to red blood cells. This reduces oxygen supply to the brain, causing animals to become lethargic, sleepy, and unconscious prior to eventual death in 1 to 2 hours. Despite such promise, to date no previous study has comprehensively examined the effect of modifying the structure of PAPP on MtHb induction. Using PAPP as a platform, this paper describes the design, synthesis, and bioevaluation of PAPP-like red blood cell toxins. The impacts of introducing groups of varying electronic nature at different positions on the PAPP molecule are presently being evaluated. Analogues are synthesized and their MtHb-inducing properties determined using an in vitro assay to establish a formal structure-activity profile. In vivo evaluation in rats is used to assess both their acute toxicity and humaneness of potential candidates. Structure-activity profiles are discussed with the objective of optimizing the bioavailability and potency of PAPP-like compounds to target, high priority pests, particularly rodents.

Mycoses in the elderly

Infections with dermatophytes are more prevalent in the elderly than in non-elderly adults; risk factors include local trophic disturbances, underlying diseases such as diabetes and a reduced oxygen supply due to diminished blood circulation. Vaginal mycoses are seldom found. In systemic yeast infections in patients of advanced age, Candida glabrata plays a relatively important role. The dimorphic fungus Coccidioides immitis is more prevalent in the elderly in endemic areas. Although there is no higher susceptibility to moulds in this age group, there are certain situations increasing the risk. The manifestations and symptoms of infection often differ from those of younger patients, which may hamper diagnosis. Deficits in organ function may influence the antifungal drug therapy. Preventive measures such as altering the social environment, avoiding malnutrition, as well as efforts to retard immunosenescence and to improve hygiene are important.

Inhibition of Mitochondrial Membrane Permeability as a Putative Pharmacological Target for Cardioprotection

Myocardial ischemia-reperfusion injury is a major cause of morbidity and mortality in developed countries. To date, the only treatment of complete ischemia is to restore blood flow; thus the search for new cardioprotective approaches is absolutely necessary to reduce the mortality associated with myocardial ischemia. Ischemia has long been considered to result in necrotic tissue damage but the reduction in oxygen supply can also lead to apoptosis. Therefore, in the last few years, mitochondria have become the subject of growing interest in myocardial ischemia-reperfusion since they are strongly involved in the regulation of the apoptotic process. Indeed, during ischemia-reperfusion, pathological signals converge in the mitochondria to induce permeabilization of the mitochondrial membrane. Two classes of mechanisms, which are not mutually exclusive, emerged to explain mitochondrial membrane permeabilization. The first occurs via a non-specific channel known as the mitochondrial permeability transition pore (mPTP) in the inner and the outer membranes causing disruption of the impermeability of the inner membrane, and ultimately complete inhibition of mitochondrial function. The second mechanism, involving only the outer membrane, induces the release of cell death effectors. Thus, drugs able to block or to limit mitochondrial membrane permeabilization may be cytoprotective during ischemia-reperfusion. The objective of this review is to examine the pharmacological strategies capable of inhibiting mitochondrial membrane permeabilization induced by myocardial ischemia-reperfusion.

Rat aversion to carbon monoxide

The most common method of killing laboratory rodents is exposure to carbon dioxide, but recent studies have shown that rodents find this gas aversive. Carbon monoxide (CO) is a colourless and odourless gas that reduces oxygen supply to the tissues and leads to hypoxia. The aim of this study was to use approach–avoidance testing to assess whether rats show aversion to CO-induced hypoxia when CO is delivered at 3%, 6% or 7% of the test cage volume per min. Although most animals chose to avoid CO, one rat remained in the test cage until recumbency when exposed to CO delivered at the highest flow rate, and another rat became recumbent immediately after leaving the test cage with the intermediate flow rate. A follow-up study revealed that all rats exposed to CO without the possibility of escape exhibited behaviours indicative of aversion. In conclusion, CO is the first agent that was tolerated until recumbency by a rat, but this agent was still aversive to most rats. The search for non-aversive euthanasia agents should continue.

Does Correcting the Numbers Improve Long-term Outcome?

Does Correcting the Numbers Improve Long-term Outcome?

Sex-dependent regulation of hypoxic ventilation in mice and humans is mediated by erythropoietin

Acclimatization to hypoxic exposure relies on an elevated ventilation and erythropoietic activity. We recently proposed that erythropoietin (Epo) links both responses: apart from red blood cell production, cerebral and plasma Epo interact with the central and peripheral respiratory centers. Knowing that women cope better than men with reduced oxygen supply (as observed at high altitude), we analyzed the hypoxic ventilatory response in Epo-overexpressing transgenic male and female mice with high Epo levels in brain and plasma (Tg6) or in wild-type animals injected with recombinant human Epo (rhEpo). Exposure to moderate and severe hypoxia as well as to hyperoxia and injection of domperidone, a potent peripheral ventilatory stimulant, revealed that the presence of transgenic or rhEpo extensively increased the hypoxic ventilatory response in female mice compared with their corresponding male siblings. Alterations of catecholamines in the brain stem's respiratory centers were also sex dependent. In a proof-of-concept study, human volunteers were intravenously injected with 5,000 units rhEpo and subsequently exposed to 10% oxygen. Compared with men, the hypoxic ventilatory response was significantly increased in women. We conclude that Epo exerts a sex-dependent impact on hypoxic ventilation improving the response in female mice and in women that most probably involves sexual hormones. Our data provides an explanation as to why women are less susceptible to hypoxia-associated syndromes than men.

Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis

The clinical complications of atherosclerosis are caused by thrombus formation, which in turn results from rupture of an unstable atherosclerotic plaque. The formation of microvessels (angiogenesis) in an atherosclerotic plaque contributes to the development of plaques, increasing the risk of rupture. Microvessel content increases with human plaque progression and is likely stimulated by plaque hypoxia, reactive oxygen species and hypoxia-inducible factor (HIF) signalling. The presence of plaque hypoxia is primarily determined by plaque inflammation (increasing oxygen demand), while the contribution of plaque thickness (reducing oxygen supply) seems to be minor. Inflammation and hypoxia are almost interchangeable and both stimuli may initiate HIF-driven angiogenesis in atherosclerosis. Despite the scarcity of microvessels in animal models, atherogenesis is not limited in these models. This suggests that abundant plaque angiogenesis is not a requirement for atherogenesis and may be a physiological response to the pathophysiological state of the arterial wall. However, the destruction of the integrity of microvessel endothelium likely leads to intraplaque haemorrhage and plaques at increased risk for rupture. Although a causal relation between the compromised microvessel structure and atherogenesis or between angiogenic stimuli and plaque angiogenesis remains tentative, both plaque angiogenesis and plaque hypoxia represent novel targets for non-invasive imaging of plaques at risk for rupture, potentially permitting early diagnosis and/or risk prediction of patients with atherosclerosis in the near future.

Placental HIFs as markers of cerebral hypoxic distress in fetal mice

Reduced oxygen supply during the pre- and perinatal period often leads to acquired neonatal brain damage. So far, there are no reliable markers available to assess the hypoxic cerebral damage and the resulting prognosis during the immediate postnatal period. Thus we aimed to determine whether the hypoxia-inducible transcription factors (HIF-1 and HIF-2) and/or their target genes in the placenta represent reliable indicators of hypoxic distress of the developing brain during systemic hypoxia at the end of gestation. To this end, pregnant mice were exposed to systemic hypoxia (inspired O2 fraction: 6%, 6 h) at gestational day 20. This hypoxic exposure significantly increased HIF-1alpha and HIF-2alpha protein levels in brain and placental tissue. Compared with normoxic controls, an increase of HIF-1alpha-immunoreactive neurons and HIF-2alpha-positive glial cells and vascular endothelial cells was observed in hypoxic cerebral cortex and hippocampus. In placenta, HIF-1alpha and HIF-2alpha were expressed in labyrinthine layer with increased staining intensity during hypoxia compared with normoxia. Significant upregulation of VEGF mRNA and protein in brain and placenta, as well as erythropoietin protein in placenta, indicated activity of the HIF system upon fetal hypoxia. Notably, hypoxia did not affect expression of the HIF target genes inducible nitric oxide synthase and GLUT-1. Taken together, at gestational day 20, systemic hypoxia led to upregulation of HIF-alpha in mouse brain that was temporally paralleled in placenta, implying that alpha-subunits of both HIF-1 and HIF-2 are indeed early markers of hypoxic distress in vivo. If our data reflect the situation in humans, analysis of the placenta will allow early identification of the hypoxic brain distress occurring near birth.

Gastrointestinal Blood Flow and Postprandial Metabolism in Swimming Sea BassDicentrarchus labrax

In trout and salmon, the metabolic costs of exercise and feeding are additive, which would suggest that gastrointestinal blood flow during exercise is maintained to preserve digestive and absorptive processes related to the specific dynamic action (SDA) of food. However, in most published studies, gastrointestinal blood flow drops during swimming, hypoxia, and general stress. To test whether gastrointestinal blood flow is spared during exercise after feeding, sea bass were instrumented with flow probes to measure cardiac output and celiacomesenteric blood flow while swimming in a respirometer before and after feeding. Swimming at 2 body lengths per second (bl s(-1)) increased metabolic rate considerably more than did feeding (208% vs. 32% increase, respectively, relative to resting), and a similar pattern was observed for cardiac output. In unfed fish, resting gastrointestinal blood flow was 13.8+/-0.5 mL min(-1) kg(-1). After feeding, resting gastrointestinal blood flow increased by 82% but then decreased progressively with increasing swimming speeds. At 2 bl s(-1), gastrointestinal blood flow in fed fish was not significantly different compared with that in unfed swimming fish, and, therefore, the data do not support the gastrointestinal sparing hypothesis. The magnitude of the SDA was maintained despite the decrease in gastrointestinal blood flow and the consequent reduction in oxygen supply to the gut. An estimate of maximal oxygen flow to the gastrointestinal tract after feeding yielded 2.6 mmol O(2) h(-1) kg(-1), but this amount is not able to cover the oxygen demand of 3.16 mmol O(2) h(-1) kg(-1). Therefore, the SDA must reflect metabolic processes in tissues other than those directly perfused by the celiacomesenteric artery.

Effects of Hegu Acupuncturing and Heating on Transcutaneous Oxygen Pressure and Subcutaneous Microcirculatory Perfusion along the Skin of Large Intestine Channel of Hand-Yangming

Abstract Objective This study attempts to clarify the causes behind a partially changed oxygen pressure by observing subcutaneous microcirculatory perfusion (abbr. SMP) and transcutaneous oxygen pressure (TcPO2) along the skin of Large Intestine Channel (LI) simultaneously. Methods Take SMP and TcPO2 as the two main indexes and one-cun-above-LI6 (Pianli), LI10 (Shousanli), and LI13 (Shouwuli) as the three destined points along the skin of LI to test the indexes on the destined points in 15 healthy volunteers using PeriFlux System 5000 and to observe their variation during acupuncturing Hegu (LI4). Besides, the experiment has also been performed in another 8 volunteers with all the other conditions equal but heating Hegu as the intervention instead. To investigate the difference in energy metabolism between Meridian and Non-Meridian further, SMP was observed on acupoints LI10, LI13, and their bilateral Non-Meridian control points. Results In Hegu acupuncturing group, the means of the two main indexes in the three vertical levels mentioned above before acupuncture and during acupuncture were analyzed by homebody paired sample T test, and SMP during acupuncture was a little higher than that before acupuncture, whereas TcPO2 significantly decreased (P Conclusion A reduced TcPO2 along the meridian course when acupoint being stimulated is not caused by reduced oxygen supply but rather by increased oxygen consumption resulted from enhanced energy metabolism in some relative tissues.

The Carnian (Late Triassic) flora from Lunz in Lower Austria: Paleoecological considerations

A recently completed systematic macromorphological and cuticular analysis of compressed gymnosperm foliage from the famous Carnian (Late Triassic) flora from Lunz in Lower Austria has provided detailed circumscriptions of the individual taxa and new information as to their ordinal and generic classification. Although the fossils represent several lineages of gymnosperms, including Cycadales, Bennettitales, Ginkgoales, it appeared that certain idiocuticular and epidermal features such as sunken stomata and papillate surfaces occur widespread among the taxa. The presence of coal seams indicates that the environmental conditions in the Lunz paleoecosystem were stable for longer periods and allowed for the accumulation of larger amounts of plant material. The formation of peat generally requires special conditions, including a stable, high groundwater table, reduced oxygen supply and low pH values, which are typically found in swamps or peat bogs. Many of the idiocuticular and epidermal features recorded for the Lunz plants can be interpreted as adaptations to ecological conditions characteristic of coal-producing peat swamps, e.g., physiological drought, and thus corroborate the interpretation of the Lunz paleoecosystem as a peat-forming environment.

Determination of efficiency of isolated hypertrophic and control rat papillary muscle from work and oxygen used

We hypothesize that the transition of ventricular hypertrophy to heart failure induced by chronic hypertension is caused by the development of cardiomyocyte hypoxia. Hypoxia may occur due to increased oxygen diffusion distances in hypertrophied myocardium, reduced oxygen supply and increased myocardial oxygen consumption (MVO2). Any reduction in myocardial efficiency will increase MVO2. Little is known of the effect of hypertrophy on myocardial efficiency.

Dysfunktion im Hepatosplanchnikusgebiet: Optimierung der O2–Versorgung

Microcirculatory dysfunction, reduced oxygen supply and thus impaired hepatosplanchnic organ function, play a pivotal role in the clinical manifestation of sepsis and septic shock. Early correction of the perfusion mismatch is essential to maintain end-organ and gut mu-cosa barrier function and thus to prevent bacterial translocation, bacteraemia and possible multiple organ failure. This review will outline the clinical tightrope-walk optimizing hepa-tosplanchnic oxygen supply while maintaining adequate end-organ perfusion pressure and highlight the diagnostic challenges and limitations faced in clinical practice.

Acute and chronic exposure to hypoxia alters ventilatory pattern but not minute ventilation of mice overexpressing erythropoietin

Apart from enhancing red blood cell production, erythropoietin (Epo) has been shown to modulate the ventilatory response to reduced oxygen supply. Both functions are crucial for the organism to cope with increased oxygen demand. In the present work, we analyzed the impact of Epo and the resulting excessive erythrocytosis in the neural control of normoxic and hypoxic ventilation. To this end, we used our transgenic mouse line (Tg6) that shows high levels of human Epo in brain and plasma, the latter leading to a hematocrit of approximately 80%. Interestingly, while normoxic and hypoxic ventilation in Tg6 mice was similar to WT mice, Tg6 mice showed an increased respiratory frequency but a decreased tidal volume. Knowing that Epo modulates catecholaminergic activity, the altered catecholaminergic metabolism measured in brain stem suggested that the increased respiratory frequency in Tg6 mice was related to the overexpression of Epo in brain. In the periphery, higher response to hyperoxia (Dejours test), as well as reduced tyrosine hydroxylase activity in carotid bodies, revealed a higher chemosensitivity to oxygen in transgenic mice. Moreover, in line with the decreased activity of the rate-limiting enzyme for dopamine synthesis, the intraperitoneal injection of a highly specific peripheral ventilatory stimulant, domperidone, did not stimulate hypoxic ventilatory response in Tg6 mice. These results suggest that high Epo plasma levels modulate the carotid body's chemotransduction. All together, these findings are relevant for understanding the cross-talk between the ventilatory and erythropoietic systems exposed to hypoxia.

Growth stress triggers riboflavin overproduction in Ashbya gossypii

The filamentous fungus Ashbya gossypii is used for riboflavin biosynthesis on an industrial scale, but even the wild type displays overproduction. Because riboflavin overproduction was known to start at the transition between growth and stationary phase, it was suspected that overproduction was induced at low growth rates. However, chemostatic cultivations performed at different growth rates did not result in any detectable riboflavin formation. In this study, we report that it was not the final growth rate that triggered riboflavin overproduction but a decline in growth rate. Therefore, continuous fermenter cultivations with dilution rate shifts were performed. Peaks of riboflavin overproduction were observed in the wild type and in a RIB3placZ reporter strain after downshifts in dilution rate. Accumulation of riboflavin correlated with an increased expression of lacZ reporter activity. The step size of the downshifts corresponded to the peak size of riboflavin formation and reporter activity. Expression of further RIB genes encoding riboflavin biosynthetic enzymes was analyzed by RT-PCR. RIB mRNA levels of the ribulose-5-phosphate branch of the divided riboflavin biosynthesis pathway (RIB3, RIB4, and RIB5) were found to increase in the riboflavin production phase, whereas the RIB2 and RIB7 mRNA levels belonging to the GTP branch remained constant. We propose that a decline in growth rate triggers the increased expression of RIB3, RIB4, and RIB5 resulting in riboflavin overproduction. Because although a reduction in oxygen supply, temperature increase or decrease, or salt stress did affect growth, but neither did lead to riboflavin overproduction nor did induce RIB3 reporter expression, we conclude that declining nutrition must be the stress stimulus. Because about half of the cells in the hyphae of Ashbya gossypii did not accumulate riboflavin, the regulatory response on the cellular level can be estimated to be at least twice as great in comparison to what we detected as overall signals.

How sweet it is: sensing low glucose in the carotid body

How sweet it is: sensing low glucose in the carotid body

Guidelines for the treatment of arterial insufficiency ulcers

1. Co-chaired panel 2. University of Utah, Salt Lake City, UT 3. University of Texas, San Antonio, TX 4. Sinai Hospital/Johns Hopkins Medical Institutions, Baltimore, MD 5. GKT School of Medicine, King’s College, London, UK 6. University of Texas Health Science Center at Houston, TX 7. Sequoia Hospital, Redwood City, CA 8. Maricopa Medical Center, Phoenix, AZ 9. Tufts-New England Medical Center, Boston, MA 10. Southampton University Hospitals Trust NHS, Southampton, UK 11. Penrose–St. Francis Health Services, Colorado Springs, CO 12. Beverly Surgical Associates, Beverly, MA 13. Saint Francis Memorial Hospital, San Francisco, CA 14. Northbay Center for Wound Care, Vacaville, CA, and 15. University of California, San Francisco, CA

Effects of hypoxia on muscle response to tendon vibration in humans

Previous animal studies have shown that hypoxia markedly reduces the activation of muscle spindles. The present study was undertaken to determine whether a reduced oxygen supply to muscle affects the tonic vibration reflex (TVR) in humans. In resting healthy volunteers, the effects of inhalation of hypoxic gas, apnea, and total forearm ischemia produced by cuff inflation were studied on separate days. The TVR was recorded in flexor digitorum superficialis and the neuromuscular conduction time (CT) was measured from the compound muscle action potential; the latency and amplitude of the H reflex were also determined. TVR depression began during inhalation of the hypoxic gas, at the end of apnea, and during cuff inflation, and persisted during the recovery period. The H-reflex amplitude concomitantly increased or remained unchanged. Thus, hypoxia seems to directly alter muscle spindle reactivity. Such alterations of sensorimotor control may occur in patients suffering from respiratory or circulatory insufficiency and may contribute to their exercise limitation.