Early Onset Rapidly Progressive Osteoarthritis of the Hip in a Young Athlete.

We report and discuss a very rare case of early-stage rapidly progressive osteoarthritis (RPO) in a 33-year-old female athlete. The etiopathology of RPO remained unclear, although in this case mechanical overloading due to constant joint overuse appeared to be the only significant contributing factor to the very early development of RPO. Key words: rapidly progressive osteoarthritis, rapid destructive arthrosis, hip arthrosis, total hip arthroplasty, athlete, osteoarthritis.

Hyperthermia induces injury to the intestinal mucosa in the mouse: evidence for an oxidative stress mechanism.

Loss of the intestinal barrier is critical to the clinical course of heat illness, but the underlying mechanisms are still poorly understood. We tested the hypothesis that conditions characteristic of mild heatstroke in mice are associated with injury to the epithelial lining of the intestinal tract and comprise a critical component of barrier dysfunction. Anesthetized mice were gavaged with 4 kDa FITC-dextran (FD-4) and exposed to increasing core temperatures, briefly reaching 42.4°C, followed by 30 min recovery. Arterial samples were collected to measure FD-4 concentration in plasma (in vivo gastrointestinal permeability). The small intestines were then removed to measure histological evidence of injury. Hyperthermia resulted in a ≈2.5-fold elevation in plasma FD-4 and was always associated with significant histological evidence of injury to the epithelial lining compared with matched controls, particularly in the duodenum. When isolated intestinal segments from control animals were exposed to ≥41.5°C, marked increases in permeability were observed within 60 min. These changes were associated with release of lactate dehydrogenase, evidence of protein oxidation via carbonyl formation and histological damage. Coincubation with N-acetylcysteine protected in vitro permeability during hyperthermia and reduced histological damage and protein oxidation. Chelation of intracellular Ca(2+) to block tight junction opening during 41.5°C exposure failed to reduce the permeability of in vitro segments. The results demonstrate that hyperthermia exposure in mouse intestine, at temperatures at or below those necessary to induce mild heatstroke, cause rapid and substantial injury to the intestinal lining that may be attributed, in part, to oxidative stress.

The Trial-Ready Cohort for Preclinical/Prodromal Alzheimer's Disease (TRC-PAD) Project: An Overview.

The Trial-Ready Cohort for Preclinical/prodromal Alzheimer's Disease (TRC-PAD) project is a collaborative effort to establish an efficient mechanism for recruiting participants into very early stage Alzheimer's disease trials. Clinically normal and mildly symptomatic individuals are followed longitudinally in a web-based component called the Alzheimer's Prevention Trial Webstudy (APT Webstudy), with quarterly assessment of cognition and subjective concerns. The Webstudy data is used to predict the likelihood of brain amyloid elevation; individuals at relatively high risk are invited for in-person assessment in the TRC screeing phase, during which a cognitive battery is administered and Apolipoprotein E genotype is obtained followed by reassessment of risk of amyloid elevation. After an initial validation study, plasma amyloid peptide ratios will be included in this risk assessment. Based on this second risk calculation, individuals may have amyloid testing by PET scan or lumbar puncture, with those potentially eligible for trials followed in the TRC, while the rest are invited to remain in the APT Webstudy. To date, over 30,000 individuals have participated in the Webstudy; enrollment in the TRC is in its early stage.

Recruitment into the Alzheimer Prevention Trials (APT) Webstudy for a Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's Disease (TRC-PAD).

BACKGROUND: The Alzheimer Prevention Trials (APT) Webstudy is the first stage in establishing a Trial-ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD). This paper describes recruitment approaches for the APT Webstudy. OBJECTIVES: To remotely enroll a cohort of individuals into a web-based longitudinal observational study. Participants are followed quarterly with brief cognitive and functional assessments, and referred to Sites for in-clinic testing and biomarker confirmation prior to enrolling in the Trial-ready Cohort (TRC). DESIGN: Participants are referred to the APT Webstudy from existing registries of individuals interested in brain health and Alzheimer's disease research, as well as through central and site recruitment efforts. The study team utilizes Urchin Tracking Modules (UTM) codes to better understand the impact of electronic recruitment methods. SETTING: A remotely enrolled online study. PARTICIPANTS: Volunteers who are at least 50 years old and interested in Alzheimer's research. MEASUREMENTS: Demographics and recruitment source of participant where measured by UTM. RESULTS: 30,650 participants consented to the APT Webstudy as of April 2020, with 69.7% resulting from referrals from online registries. Emails sent by the registry to participants were the most effective means of recruitment. Participants are distributed across the US, and the demographics of the APT Webstudy reflect the referral registries, with 73.1% female, 85.0% highly educated, and 92.5% Caucasian. CONCLUSIONS: We have demonstrated the feasibility of enrolling a remote web-based study utilizing existing registries as a primary referral source. The next priority of the study team is to engage in recruitment initiatives that will improve the diversity of the cohort, towards the goal of clinical trials that better represent the US population.

The Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's Disease (TRC-PAD): Experience from the First 3 Years.

BACKGROUND: The Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD) aims to accelerate enrollment for Alzheimer's disease (AD) clinical trials by remotely identifying and tracking individuals who are at high risk for developing symptoms of AD, and referring these individuals to in-person cognitive and biomarker evaluation with the purpose of engaging them in clinical trials. A risk algorithm using statistical modeling to predict brain amyloidosis will be refined as TRC-PAD advances with a maturing data set. OBJECTIVES: To provide a summary of the steps taken to build this Trial-Ready cohort (TRC) and share results of the first 3 years of enrollment into the program. DESIGN: Participants are remotely enrolled in the Alzheimer Prevention Trials (APT) Webstudy with quarterly assessments, and through an algorithm identified as potentially at high risk, referred to clinical sites for biomarker confirmation, and enrolled into the TRC. SETTING: Both an online study and in-clinic non-interventional cohort study. PARTICIPANTS: APT Webstudy participants are aged 50 or older, with an interest in participation in AD therapeutic trials. TRC participants must have a study partner, stable medical condition, and elevated brain amyloid, as measured by amyloid positron emission tomography or cerebrospinal fluid analysis. Additional risk assessments include apolipoprotein E genotyping. MEASUREMENTS: In the APT Webstudy, participants complete the Cognitive Function Index and Cogstate Brief Battery. The TRC includes the Preclinical Alzheimer's Cognitive Composite, comprised of the Free and Cued Selective Reminding Test, the Delayed Paragraph Recall score on the Logical Memory IIa test from the Wechsler Memory Scale, the Digit-Symbol Substitution test from the Wechsler Adult Intelligence Scale-Revised, and the Mini Mental State Examination total score (1). RESULTS: During the first 3 years of this program, the APT Webstudy has 30,650 consented participants, with 23 sites approved for in person screening, 112 participants have been referred for in-clinic screening visits with eighteen enrolled to the TRC. The majority of participants consented to APT Webstudy have a family history of AD (62%), identify as Caucasian (92.5%), have over twelve years of formal education (85%), and are women (73%). Follow up rates for the first quarterly assessment were 38.2% with 29.5% completing the follow up Cogstate Battery. CONCLUSIONS: After successfully designing and implementing this program, the study team's priority is to improve diversity of participants both in the APT Webstudy and TRC, to continue enrollment into the TRC to our target of 2,000, and to improve longitudinal retention, while beginning the process of referring TRC participants into clinical trials.

Infrapopliteal transcatheter interventions for limb salvage in diabetic patients: importance of aggressive interventional approach and role of transcutaneous oximetry.

OBJECTIVES: This study sought to determine whether infrapopliteal transcatheter interventions can salvage ischemic limbs in diabetic patients referred for below the knee amputation at our institution. BACKGROUND: The value of transcatheter interventions in diabetic crural arteries is controversial. Tissue oxygen partial pressure (TCO2) levels < 40 mm Hg predict poor wound healing. METHODS: Percutaneous interventions were performed in 29 consecutive diabetic patients in need of limb salvage. Technical success was defined as < 20% residual vessel stenosis. Clinical success was defined as the avoidance of amputation and achievement of wound healing. At hospital discharge, patients were treated with Coumadin and aspirin. Ankle-brachial index (ABI) and TCO2 measurements were obtained before and after the intervention. RESULTS: After 12-month follow-up, six patients had presistent wounds, whereas 23 experienced wound healing. Forty of the 50 infrapopliteal arteries successfully dilated were occluded, with a mean (+/-SD) lesion length of 18.0 +/- 3.5 cm. After the procedure, TCO2 improved from 27.82 +/- 9.97 mm Hg (95% confidence interval [CI] 23.95 to 31.69) to 54.5 +/- 14.73 mm Hg (95% CI 48.79 to 60.21, p < 0.0001), whereas the ABI did not (p > 0.2). TCO2 predicted procedural and clinical success (p < 0.0182). CONCLUSIONS: Infrapopliteal transcatheter interventions in diabetic patients may salvage the majority of limbs doomed to amputation. Although TCO2 measurements are valuable in predicting wound healing and success after interventions, ABI measurements are not.

Superoxide scavengers augment contractile but not energetic responses to hypoxia in rat diaphragm.

Acute exposure to severe hypoxia depresses contractile function and induces adaptations in skeletal muscle that are only partially understood. Previous studies have demonstrated that antioxidants (AOXs) given during hypoxia partially protect contractile function, but this has not been a universal finding. This study confirms that specific AOXs, known to act primarily as superoxide scavengers, protect contractile function in severe hypoxia. Furthermore, the hypothesis is tested that the mechanism of protection involves preservation of high-energy phosphates (ATP, creatine phosphate) and reductions of P(i). Rat diaphragm muscle strips were treated with AOXs and subjected to 30 min of hypoxia. Contractile function was examined by using twitch and tetanic stimulations and the degree of elevation in passive force occurring during hypoxia (contracture). High-energy phosphates were measured at the end of 30-min hypoxia exposure. Treatment with the superoxide scavengers 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron, 10 mM) or Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride (50 microM) suppressed contracture during hypoxia and protected maximum tetanic force. N-acetylcysteine (10 or 18 mM) had no influence on tetanic force production. Contracture during hypoxia without AOXs was also shown to be dependent on the extracellular Ca(2+) concentration. Although hypoxia resulted in only small reductions in ATP concentration, creatine phosphate concentration was decreased to approximately 10% of control. There were no consistent influences of the AOX treatments on high-energy phosphates during hypoxia. The results demonstrate that superoxide scavengers can protect contractile function and reduce contracture in hypoxia through a mechanism that does not involve preservation of high-energy phosphates.

Unique in vivo applications of spin traps.

The ultimate goal of in vivo electron spin resonance (ESR) spin trapping is to provide a window to the characterization and quantification of free radicals with time within living organisms. However, the practical application of in vivo ESR to systems involving reactive oxygen radicals has proven challenging. Some of these limitations relate to instrument sensitivity and particularly to the relative stability of these radicals and their nitrone adducts, as well as toxicity limitations with dosing. Our aim here is to review the strengths and weaknesses of both traditional and in vivo ESR spin trapping and to describe new approaches that couple the strengths of spin trapping with methodologies that promise to overcome some of the problems, in particular that of radical adduct decomposition. The new, complementary techniques include: (i) NMR spin trapping, which monitors new NMR lines resulting from diamagnetic products of radical spin adduct degradation and reduction, (ii) detection of *NO by ESR with dithiocarbamate: Fe(II) "spin trap-like" complexes, (iii) MRI spin trapping, which images the dithiocarbamate: Fe(II)-NO complexes by proton relaxation contrast enhancement, and (iv) the use of ESR to follow the reactions of sulfhydryl groups with dithiol biradical spin labels to form "thiol spin label adducts," for monitoring intracellular redox states of glutathione and other thiols. Although some of these approaches are in their infancy, they show promise of adding to the arsenal of techniques to measure and possibly "image" oxidative stress in living organisms in real time.

Detection of free radicals in blood by electron spin resonance in a model of respiratory failure in the rat.

Previous work has suggested that a free radical mechanism is involved in some types of muscle fatigue and that there can be free radicals released extracellularly. Because muscle fatigue may be an important factor in respiratory failure, the authors tested the hypothesis that increased concentrations of free radicals could be detected in the blood of animals undergoing severe resistive loading to respiratory failure. An ex vivo spin trapping technique with alpha-phenyl-N-tert-butylnitrone (PBN) was used to investigate the possible formation of free radicals in systemic blood samples by electron spin resonance (ESR) spectrometry. After 2.5-3 h of severe inspiratory resistive loading with 70% supplemental inspired oxygen, free radical levels in the form of PBN-adducts were found to rise significantly over the control group breathing room air and the control group breathing 70% oxygen (p < 0.05, N = 8). There were no significant differences between control groups breathing room air and control groups breathing 70% oxygen. This study presents direct evidence that free radicals are produced ex vivo and that they can be detected in the systemic circulation due to excessive resistive loading of the respiratory muscles.

NMR spin trapping: detection of free radical reactions with a new fluorinated DMPO analog.

Electron spin resonance (ESR) and nuclear magnetic resonance (NMR) spin trapping were used for detection of free radical reactions utilizing a new fluorinated analog of DMPO, 4-hydroxy-5,5-dimethyl-2-trifluoromethylpyrroline-1-oxide (FDMPO). The parent FDMPO spin trap exhibits a single 19F-NMR resonance at -66.0 ppm. The signal to noise ratio improved 10.4-fold compared to 31P-NMR sensitivity of the phosphorus-containing spin trap, DEPMPO. The spin adducts of FDMPO with .OH, .CH3, and .CH2OH were characterized. Competitive spin trapping of FDMPO with DMPO showed that both have similar rates of addition of .OH and C-centered radicals. The corresponding paramagnetic spin adducts of FDMPO were extremely stable to degradation. In the presence of ascorbate, reaction products from C-centered radicals resulted in the appearance of two additional 19F-NMR signals at -78.6 and -80 ppm for FDMPO/ .CH(3) and at -74.6 and -76.75 ppm for FDMPO/ .CH(2)OH. In each case, these peaks were assigned to the two stereoisomers of their respective, reduced hydroxylamines. The identification of the hydroxylamines for FDMPO/ .CH3 was confirmed by EPR and 19F-NMR spectra of independently synthesized samples. In summary, spin adducts of FDMPO were highly stable for ESR. For NMR spin trapping, FDMPO showed improved signal to noise and similar spin trapping efficiency compared to DEPMPO.

Recurrent respiratory insufficiency and depressed ventilatory drive complicating mitochondrial myopathies.

Three patients with mitochondrial myopathies and progressive external ophthalmoplegia had repeated episodes of respiratory failure requiring assisted ventilation. Studies in these patients and asymptomatic family members, as well as a sporadic case of Kearns-Sayre syndrome, demonstrated markedly depressed ventilatory drive responses to hypoxia. In 2 patients, there was also decreased drive to hypercapnia. The reduced ventilatory drive appears to be due to an altered neural control system that may cause episodic life-threatening hypoventilation occurring especially in relation to surgery, sedation, or intercurrent infection.

Improved pulmonary function and exercise tolerance with inspiratory muscle conditioning in children with cystic fibrosis.

This study documented the effect of inspiratory muscle conditioning in children with cystic fibrosis. Subjects, ages 7 to 14 years, were divided into two groups. The experimental group (n = 10) trained at a high pressure load (> or = 29 cm H2O) and the control group (n = 10) trained at a minimal pressure load (< or = 15 cm H2O), using a threshold loading device. Subjects trained 30 min a day for 10 weeks. Pulmonary function, inspiratory muscle strength, and exercise tolerance were measured at the beginning and end of the training period. Pulmonary function was measured by body plethysmography. Inspiratory muscle strength was determined by standard measures of maximal inspiratory pressure against an occluded airway. Exercise tolerance was measured by the length of time subjects could walk on a treadmill. Findings indicated that the experimental group showed significant increases in inspiratory muscle strength, vital capacity, total lung capacity, and exercise tolerance in comparison to the control group.

Marked pulmonary function abnormalities in a case of HIV-associated pulmonary hypertension.

Recent reports have suggested an association between primary pulmonary hypertension and human immunodeficiency virus (HIV) infection. This appears to be an accelerated syndrome, associated with a relatively brief duration of symptoms, yet prominent right ventricular failure and severe pulmonary hypertension on presentation. We present a case of a primary pulmonary hypertension in a 35-year-old HIV-seropositive hemophiliac. His accelerated clinical course is consistent with previously reported cases of HIV-related pulmonary hypertension. However, this patient's pulmonary function tests revealed marked hyperinflation, a decreased diffusing capacity, and no airflow obstruction. To our knowledge, this very usual constellation of pulmonary function changes has not been described previously in this syndrome.

High- vs low-intensity inspiratory muscle interval training in patients with COPD.

This study determined the effect of a high vs low resistive inspiratory muscle interval training protocol on inspiratory muscle strength (PImax), incremental inspiratory threshold loading (Pitl), inspiratory muscle endurance (IE), and 12-minute distance test (12 MD) in severely impaired patients with COPD. We used a double-blind, two-group, repeated-measure design. Group 1 (n = 12) received supervised high resistive loading at approximately 52 percent PImax and group 2 (n = 8) received supervised low resistive loading at approximately 22 percent PImax. All subjects trained three times weekly (progressing from 5 min per session in week 1 to 18 min per session in week 12) for 12 weeks. After three practice sessions, measures of PImax, Pitl, IE, and 12 MD were taken at baseline, at 4-week intervals, and within 72 h of completing the protocol. Group 1 showed significant improvement in all four dependent variables while group 2 improved in Pitl, IE, and 12 MD. The results suggest there is no significant difference between high and low resistive interval training in more severely impaired patients with COPD.

Inspiratory muscle conditioning using a threshold loading device.

We demonstrate the effectiveness of a new conditioning technique for increasing the strength and endurance of the inspiratory muscles. The technique employs a threshold loading device which allows for maximization of exercise intensity with a minimum of exercise duration. After ten weeks, with approximately 25 minutes of exercise time per week, four test subjects showed an average increase in maximum inspiratory pressure (PImax) of 50 (+/- 9 SD) cm H2O (p less than 0.02), whereas four control subjects undergoing submaximal inspiratory muscle exercise showed no significant change. The time the test subjects could endure 65 percent of their prestudy PImax increased from an average of 3.58 +/- 1.65 SD min to over 10 min in all four subjects. No significant change was seen in control subjects. Further testing showed the test subjects could endure 100 percent of their prestudy PImax after conditioning for an average duration 5.15 +/- 1.65 min. This technique should be useful for conditioning the inspiratory muscles in subjects with pulmonary disease.

Alveolar fluid glutathione decreases in asymptomatic HIV-seropositive subjects over time.

BACKGROUND: Initial investigations demonstrated a deficiency of glutathione (GSH) in the epithelial lining fluid (ELF) of HIV-seropositive patients. In a recent study, our laboratory was unable to document such a deficiency. The current study was performed in an attempt to reconcile those disparate findings. STUDY OBJECTIVES: To determine if ELF GSH decreases over time in asymptomatic HIV-seropositive subjects. DESIGN: Prospective, longitudinal study. SETTING: Major university medical center. PATIENTS OR PARTICIPANTS: Thirty-three asymptomatic HIV-seropositive volunteers. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: BAL was performed on 33 asymptomatic HIV-seropositive subjects at baseline, 6 months later, and 12 months later. The volume of ELF and the concentration of GSH and oxidized GSH were determined. The concentration of total GSH in ELF was 689.0+/-100.4 microM. This significantly decreased when measured 6 and 12 months later (355.9+/-41.7 microM, and 397.9+/-52.7 microM, respectively, p=0.01, compared with baseline, both comparisons). Significant decreases were also noted in the HIV-seropositive subjects who smoked cigarettes (baseline--762.6+/-142.4 microM; 6 months--373.7+/-45.9 microM; 12 months--459.3+/-73.8 microM, p<0.03, for baseline vs 6 months, and baseline vs 12 months). In nonsmoking HIV-seropositive subjects, there was a decrease in ELF GSH over time, but it did not reach statistical significance (baseline--589.1+/-138.2 microM; 6 months--335.3+/-74.1 microM; 12 months--345.8+/-74.0 microM, p>0.1, all comparisons). The percentage of total GSH in the oxidized form was similar at all three time points (baseline--3.8+/-0.5%; 6 months--3.1+/-0.5%; 12 months--3.9+/-0.9%, p>0.1, all comparisons). CONCLUSIONS: The current study demonstrates that the GSH level in ELF is significantly decreased in HIV-seropositive subjects 6 and 12 months after the initial determination.

Fatigue of the inspiratory muscle pump in humans: an isoflow approach.

A new method is described for measurement of inspiratory muscle endurance in humans that is based on isokinetic principles of muscle testing (i.e., measurement of maximum force during a constant velocity of shortening). Subjects inspired maximally while their lungs were inflated at a constant rate during each breath for 10 min. Inspiratory and expiratory time, flow rate, tidal volume, and end-tidal CO2 were maintained constant. In each subject, maximum inspiratory mouth pressure exponentially decayed over the first few minutes to an apparent sustainable value. Repeated tests in experienced subjects showed high reproducibility of sustainable pressure measurements. To determine the effects of flow, endurance tests were repeated in four subjects at flows of 0.75, 1.0, and 1.25 l/s, with a constant duty cycle. As flow increased, the maximum pressures that could be attained at rest and the maximum sustainable pressures decreased. At each flow, the sustainable pressure remained a constant fraction of the maximum pressure attainable at rest. We interpret the decay in mouth pressure during isoflow endurance tests to directly reflect the loss of net inspiratory muscle force available by maximum voluntary activation of the inspiratory pump.

Accelerated decay of inspiratory pressure during hypercapnic endurance trials in humans.

Seven normal human subjects inspired a CO2-O2 mixture from a constant-flow generator while performing maximal inspiratory maneuvers from functional residual capacity. End-tidal CO2 (ETCO2) was maintained at either 5.5 (normocapnia), 3.5 (hypocapnia), or 7% (hypercapnia) on separate testing days. Subjects attained maximal mouth pressure (Pm) while breathing at either 1.25 or 1 l/s, utilizing a fixed breathing pattern (duty cycle 0.43) with an inspiratory time of 1.5 s. Maximal Pm was measured at rest and then during a 10-min endurance trial in which subjects repeated maximal voluntary inspirations with constant flow and breathing pattern. The endurance Pm data were fit to nonlinear exponential regression. The results indicated that 1) maximal Pm at rest was unaffected by changing ETCO2; 2) the rate of Pm decay over time was accelerated by hypercapnia, whereas hypocapnia showed no consistent effects; and 3) "sustainable" Pm, attained toward the end of the endurance trial, was not decreased; therefore sustainable force output was preserved in response to changing ETCO2.

Hyperoxia and moderate hypoxia fail to affect inspiratory muscle fatigue in humans.

Normal human subjects (n = 7) breathing 21% O2 (normoxia), 13% O2 (hypoxia), or 100% O2 (hyperoxia) performed repeated maximal inspiratory maneuvers (inspiratory duration = 1.5 s, total breath duration = 3.5 s) on an "isoflow" system, which delivered a constant mouth flow (1.25 or 1 l/s) while maintaining normocapnia (5.5% end-tidal CO2). Respective mean arterial O2 saturation values (ear lobe oximetry) were 98 +/- 1, 91 +/- 4 (P less than or equal to 0.01), and 99 +/- 1% (NS). Maximal mouth pressure (Pm) was measured during inspirations at rest and during a 10-min fatigue trial, and the Pm measurements obtained during the fatigue trials were fit to an exponential equation. The parameters of the equation included the time constant (tau), which describes the rate of decay of Pm from the initial pressure (Pi) to the asymptote, or "sustainable" pressure (Ps). The mean fraction of Pm remaining at the end of the fatigue trials (Ps/Pi) was 63 +/- 5%. No significant differences in Pi, Ps, or tau were observed between O2 treatments. This suggests that fatigue of the inspiratory muscles in normal humans occurs by a mechanism that is insensitive to changes in blood O2 content that occur during inspiration of O2 in the range of 13-100%.

Invited review: Adaptive responses of skeletal muscle to intermittent hypoxia: the known and the unknown.

Intermittent hypoxia (IH) describes conditions of repeated, transient reductions in O2 that may trigger unique adaptations. Rest periods during IH may avoid potentially detrimental effects of long-term O2 deprivation. For skeletal muscle, IH can occur in conditions of obstructive sleep apnea, transient altitude exposures (with or without exercise), intermittent claudication, cardiopulmonary resuscitation, neonatal blood flow obstruction, and diving responses of marine animals. Although it is likely that adaptations in these conditions vary, some patterns emerge. Low levels of hypoxia shift metabolic enzyme activity toward greater aerobic poise; extreme hypoxia shifts metabolism toward greater anaerobic potential. Some conditions of IH may also inhibit lactate release during exercise. Many related cellular phenomena could be involved in the response, including activation of specific O2 sensors, reactive oxygen and nitrogen species, preconditioning, hypoxia-induced transcription factors, regulation of ion channels, and influences of paracrine/hormonal stimuli. The net effect of a variety of adaptive programs to IH may be to preserve contractile function and cell integrity in hypoxia or anoxia, a response that does not always translate into improvements in exercise performance.