A computational model of intracellular oxygen sensing by hypoxia-inducible factor HIF1alpha.

J Cell Sci, Vol. 119, No. Pt 16. (15 August 2006), pp. 3467-3480.

Hypoxia-inducible factor-1, HIF1, transcriptionally activates over 200 genes vital for cell homeostasis and angiogenesis. We developed a computational model to gain a detailed quantitative understanding of how HIF1 acts to sense oxygen and respond to hypoxia. The model consists of kinetic equations describing the intracellular variation of 17 compounds, including HIF1, iron, prolyl hydroxylase, oxygen, ascorbate, 2-oxoglutarate, von Hippel Lindau protein and associated complexes. We tested an existing hypothesis of a switch-like change in HIF1 expression in response to a gradual decrease in O(2) concentration. Our model predicts that depending on the molecular environment, such as intracellular iron levels, the hypoxic response varies considerably. We show HIF1-activated cellular responses can be divided into two categories: a steep, switch-like response to O(2) and a gradual one. Discovery of this dual response prompted comparison of two therapeutic strategies, ascorbate and iron supplementation, and prolyl hydroxylase targeting, to predict under what microenvironments either effectively increases HIF1alpha hydroxylation. Results provide crucial insight into the effects of iron and prolyl hydroxylase on oxygen sensing. The model advances quantitative molecular level understanding of HIF1 pathways - an endeavor that will help elucidate the diverse responses to hypoxia found in cancer, ischemia and exercise.

AA Qutub

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Toward a core nutraceutical program for cancer management.

Integr Cancer Ther, Vol. 5, No. 2. (June 2006), pp. 150-171.

As previously suggested, it may be feasible to impede tumorevoked angiogenesis with a nutraceutical program composed of glycine, fish oil, epigallocatechin-3-gallate, selenium, and silymarin, complemented by a low-fat vegan diet, exercise training, and, if feasible, a salicylate and the drug tetrathiomolybdate. It is now proposed that the scope of this program be expanded to address additional common needs of cancer patients: blocking the process of metastasis; boosting the cytotoxic capacity of innate immune defenses (natural killer [NK] cells); preventing cachexia, thromboembolism, and tumor-induced osteolysis; and maintaining optimal micronutrient status. Modified citrus pectin, a galectin-3 antagonist, has impressive antimetastatic potential. Mushroombeta-glucans and probiotic lactobacilli can amplify NK activity via stimulatory effects on macrophages. Selenium, beta-carotene, and glutamine can also increase the number and/or cytotoxic activity of NK cells. Cachectic loss of muscle mass can be opposed by fish oil, glutamine, and beta-hydroxy-beta-methylbutyrate. Fish oil, policosanol, and vitamin D may have potential for control of osteolysis. High-dose aspirin or salicylates, by preventing NF-B activation, can be expected to aid prevention of metastasis and cachexia while down-regulating osteolysis, but their impacts on innate immune defenses will not be entirely favorable. A nutritional insurance formula crafted for the special needs of cancer patients can be included in this regimen. To minimize patient inconvenience, this complex core nutraceutical program could be configured as an oil product, a powder, and a capsule product, with the nutritional insurance formula provided in tablets. It would be of interest to test this program in nude mouse xenograft models.

MF McCarty

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Is the chronic fatigue syndrome an exercise phobia? A case control study

Journal of Psychosomatic Research, Vol. 58, No. 4. (April 2005), pp. 367-373.

Objective The aim of this study was to test whether patients with chronic fatigue syndrome (CFS) have an exercise phobia, by measuring anxiety-related physiological and psychological reactions to ordinary activity and exercise.Methods Patients and healthy but sedentary controls were assessed over 8 h of an ordinary day, and before, during and after an incremental exercise test on a motorised treadmill. To avoid confounding effects, those with a comorbid psychiatric disorder were excluded. Heart rate, galvanic skin resistance (GSR) and the amount of activity undertaken were measured, along with state and trait measures of anxiety.Results Patients with CFS were more fatigued and sleep disturbed than were the controls and noted greater effort during the exercise test. No statistically significant differences were found in either heart rate or GSR both during a normal day and before, during and after the exercise test. Patients with CFS were more symptomatically anxious at all times, but this did not increase with exercise.Conclusion The data suggest that CFS patients without a comorbid psychiatric disorder do not have an exercise phobia.

AM Gallagher

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The Effects of Lingual Exercise in Stroke Patients With Dysphagia

Arch. Phys. Med. Rehabil., Vol. 88, No. 2. (2007), pp. 150-158.

Robbins JA, Kays SA, Gangnon RE, Hind JA, Hewitt AL, Gentry LR, Taylor AJ. The effects of lingual exercise in stroke patients with dysphagia. Objective: To examine the effects of lingual exercise on swallowing recovery poststroke. Design: Prospective cohort intervention study, with 4- and 8-week follow-ups. Setting: Dysphagia clinic, tertiary care center. Participants: Ten stroke patients (n=6, acute: ?3mo poststroke; n=4, chronic: >3mo poststroke), age 51 to 90 years (mean, 69.7y). Intervention: Subjects performed an 8-week isometric lingual exercise program by compressing an air-filled bulb between the tongue and the hard palate. Main Outcome Measures: Isometric and swallowing lingual pressures, bolus flow parameters, diet, and a dysphagia-specific quality of life questionnaire were collected at baseline, week 4, and week 8. Three of the 10 subjects underwent magnetic resonance imaging at each time interval to measure lingual volume. Results: All subjects significantly increased isometric and swallowing pressures. Airway invasion was reduced for liquids. Two subjects increased lingual volume. Conclusions: The findings indicate that lingual exercise enables acute and chronic dysphagic stroke patients to increase lingual strength with associated improvements in swallowing pressures, airway protection, and lingual volume. © 2007 American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation.

J Robbins

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