External addition of pulses to fluid channels of body to release or suppress endothelial mediators and to determine effectiveness of such intervention

• US 7,090,648 B2
• Filed: 09/28/2001
• Issued: 08/15/2006
• Est. Priority Date: 09/28/2000
• Status: Expired due to Term

• Current Assignee: Non-Invasive Monitoring Systems, Inc.
• Original Assignee: Non-Invasive Monitoring Systems, Inc.
• Inventors: Sackner, Marvin A., Inman, D. Michael
• Primary Examiner(s): Bockelman, Mark
• Application Number:
  US09/967,422
• Publication Number:
  US 20020103454A1
• Time in Patent Office: 1,782 Days
• Field of Search: 600/300, 601/1, 601 23- 24, 601/89, 601/98, 601/100, 604/19
• US Class Current: 601/1
• CPC Class Codes: A61H 1/001 Apparatus for applying movements to the whole body
• CPC Class Codes: A61H 1/003 Rocking or oscillating around a horizontal axis transverse to the body
• CPC Class Codes: A61H 1/005 Moveable platforms, e.g. vibrating or oscillating platforms for standing, sitting, laying or leaning
• CPC Class Codes: A61H 9/0078 with intermittent or alternately inflated bladders or cuffs mattresses for preventing bed-sores with alternated pressurized chambers A61G7/05776
• CPC Class Codes: A61N 1/326 for promoting growth of cells, e.g. bone cells

Abstract

Methods of medical treatment and diagnosis using mediators released by endothelial cells stimulated by external addition of pulses to the circulation are disclosed. The external pulses produce circumferential shear stress in body fluid channels that subsequently stimulates the endothelial cells to produce mediators that become available for therapeutic and diagnostic purposes. The preferred means of adding external pulses is the mechanical inducement of periodic acceleration of the body or parts of the body by a reciprocating motion platform.

Claims

1. A method of medical treatment for a patient with a body, comprising the steps of:

providing a periodic acceleration means for periodically accelerating one of the body and at least one part thereof to externally and non-invasively add a pulse to the body'"'"'s fluid filled channels over the body'"'"'s own pulse; and

treating a disease, condition, or injury of the patient that is treatable by at least one endothelial released mediator by adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse, thereby stimulating endothelial release of beneficial mediators and suppressing non-beneficial mediators;

wherein the periodic acceleration means comprises a reciprocating movement platform which periodically accelerates the one of the body and at least one part thereof in a headwards-footwards direction at a frequency between about 1 Hz and about 6 Hz.

2. The method of medical treatment as recited claim 1, further comprising the step of:

using the periodic acceleration means to control the frequency and intensity of said pulses.

3. The method of medical treatment as recited claim 1, wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse comprises:

adding pulses, using the periodic acceleration means, over the body'"'"'s own pulse to at least one of the vascular circulation, heart, lymphatics, interstitial spaces, and bone interstices.

4. The method of medical treatment as recited in claim 1, further comprising the step of:

repeatedly adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse such that even during periods when pulses are not imparted, bioavailability of the beneficial mediators is greater than in the pretreatment period.

5. The method of medical treatment as recited in claim 1, wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse comprises the step of:

adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse, thereby stimulating endothelial release of at least one of nitric oxide, prostacyclin, tissue plasminogen activator (t-PA), endothelial dependent hyperpolarizing factor (EDHF), endothelial dependent relaxing factor, endothelial growth factors, and transcription genes.

6. The method of medical treatment as recited in claim 1, wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse comprises the step of:

modulating vascular endothelial growth factor (VEGF).

7. The method of medical treatment as recited in claim 1, wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse comprises the step of:

adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse, thereby suppressing at least one of endothelins, tissue plasminogen antigens, and tissue plasminogen inhibitors.

8. The method of medical treatment as recited in claim 1, wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse comprises the step of:

adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse, thereby stimulating endothelial release of at least one of Cu/Zn superoxide dismutase, prostacyclin synthesis-related enzymes cyclooxygenases (COX-1 and COX-2), prostacyclin synthase (PGS), and thromboxane synthase (TXS).

9. The method of medical treatment as recited in claim 1, wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse comprises the step of:

adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse, thereby stimulating endothelial release of at least one of metabolites prostaglandin (PGI(2)) and thromboxane (TXA(2)) in endothelial cells.

10. The method of medical treatment as recited in claim 1, wherein the step of providing a periodic acceleration means for periodically accelerating one of the body and at least one part thereof comprises the step of:

providing a periodic acceleration means for pulsing with a periodic acceleration up to about ±

0.6 g.

11. The method of medical treatment as recited in claim 10, wherein the step of providing a periodic acceleration means for periodically accelerating one of the body and at least one part thereof comprises the step of:

providing a periodic acceleration means for periodically accelerating one of the body and at least one part thereof to externally and non-invasively add a pulse to the body'"'"'s fluid filled channels over the body'"'"'s own pulse such that the added pulses are visible over the patient'"'"'s own pulse waveform on a vascular pulse waveform trace display.

12. The method of medical treatment as recited in claim 1, wherein the step of providing a periodic acceleration means for periodically accelerating one of the body and at least one part thereof comprises the step of:

providing a reciprocating movement platform for shifting the patient to and fro in headwards-footwards direction using a horizontal platform driven by a controllable fly wheel-motor mechanism.

13. The method of medical treatment as recited in claim 12, wherein the step of providing a periodic acceleration means for periodically accelerating one of the body and at least one part thereof comprises the step of:

providing a means for fixing the patient to the movement platform with a vertical foot-board along with attachments to immobolize at least one of the feet and legs such that movement which is transmitted by the platform is conveyed to the patient without substantial out-of-phase body movement relative to platform movement.

14. The method of medical treatment as recited in claim 1, wherein the step of providing a periodic acceleration means for periodically accelerating one of the body and at least one part thereof comprises the step of:

providing a seat within a wheel chair driven by an adjustable frequency movement means, wherein the adjustable frequency movement means comprises a cam adjustable for vertical displacement and one of a rotary motor mechanism and a flywheel drive motor assembly.

15. The method of medical treatment as recited in claim 1, wherein the step of providing a periodic acceleration means for periodically accelerating one of the body and at least one part thereof comprises the step of:

providing a means for shifting the patient'"'"'s legs up and down while the patient is seated, the means for shifting comprising an adjustable frequency, cam adjustable for vertical displacement, rotary motor mechanism.

16. The method of medical treatment as recited in claim 1, wherein the medical treatment is for a prospective donor of at least one organ for transplantation;

and wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse causes endothelial release of nitric oxide, prostacyclin, and tissue plasminogen activator and suppression of endothelin-1, tissue plasminogen inhibitor and antigen thereby helping to prevent graft rejection.

17. The method of medical treatment as recited in claim 16, further comprising the step of:

dosing the patient with phosphodiesterase inhibitors.

18. The method of medical treatment as recited in claim 16, further comprising the step of:

preserving the at least one organ after the donor dies.

19. The method of medical treatment as recited in claim 1, wherein the medical treatment is for depressive reactions, chronic fatigue syndrome, panic and generalized anxiety disorder, schizophrenia, conversion and somatoform pain disorder, and alcohol abuse and dependence.

20. The method of medical treatment as recited in claim 1, wherein the step of providing a periodic acceleration means for periodically accelerating one of the body and at least one part thereof comprises the step of:

providing a means to utilize high frequency oscillatory ventilation with bias flow and added apparatus dead space which adds pulses to the body'"'"'s fluid channels through the lungs.

21. The method of medical treatment as recited in claim 1, wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse comprises the step of:

adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse to thereby add pulses over the body'"'"'s own pulse to the body'"'"'s fluid filled channels, thereby stimulating endothelial release of beneficial mediators and suppress non-beneficial mediators, such that the pulses do not entrain to the patient'"'"'s own pulse wave.

22. The method of medical treatment as recited in claim 1, wherein the beneficial mediator is nitric oxide, further comprising the step of:

testing a response of the patient by at least one of analyzing a dicrotic notch present on a diastolic limb of an arterial pulse, analyzing an Augmentation Index of the patient'"'"'s arterial pulse, analyzing arterial pulse wave velocity, analyzing central venous pressure, analyzing E wave deceleration time, analyzing peripheral blood flow, utilizing biochemical markers, and utilizing blood coagulation tests.

23. The method of medical treatment as recited in claim 1, wherein the beneficial mediator is nitric oxide, further comprising the step of:

testing a response of the patient by utilizing biochemical markers, wherein the biochemical markers are released as products or metabolites from endothelial tissue and comprise at least one of serum nitric oxide, nitrite/nitrates, tissue plasminogen activator (tPA), and prostacycline.

24. The method of medical treatment as recited in claim 1, further comprising the step of:

dosing the patient with a drug;

wherein the combination of dosing and providing pulses is for at least one of potentiating an effect of the drug, limiting the dosing of the drug, minimizing unwanted side effects, and obtaining unique beneficial effects of a combination of dosing and pulsing.

25. The method of medical treatment as recited in claim 24, wherein the drug is at least one of L-Arginine, insulin, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker, Angiotensin-(1-7), aspirin, an iloprost, a beta blocker, a calcium antagonist that upregulate the activity of superoxide dismutase, statin, an estrogen, an atrial natriuretic peptide, an intravenous clot buster, phosphodiesterase inhibitor-3 or -4 or -5, a xanthine oxidase inhibitor, an endothelin receptor antagonist, SC52608 (a synthesized superoxidase dismutase mimic), a platelet aggregation inhibitor, a furoxins or S-nitrosothiol derivative that releases nitric oxide slowly, and a prostaglandin;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse, in conjunction with the step of dosing the patient with the drug, provides at least one of additive and synergistic vasodilator, antiplatelet aggregation and antileukocyte adhesion actions.

26. The method of medical treatment as recited in claim 25, wherein the calcium antagonist that upregulates the activity of superoxide dismutase is pranidipine.

27. The method of medical treatment as recited in claim 25, wherein the platelet aggregation inhibitor is YC-1.

28. The method of medical treatment as recited in claim 25, wherein the intravenous clot buster is recombinant tPA.

29. The method of medical treatment as recited in claim 24, wherein the drug is a statin;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse, in conjunction with the step of dosing the patient with the drug, provides at least one of additive and synergistic vasodilator, antiplatelet aggregation, antileukocyte adhesion actions and bone building.

30. The method of medical treatment as recited in claim 24, wherein the medical treatment is for Alzheimer'"'"'s disease and the drug is a monamine oxidase-B inhibitor, L-deprenyl.

31. The method of medical treatment as recited in claim 24, wherein the medical treatment is for at least one of acute brain injury and a chronic neurogenerative disease, and the drug is a nitric oxide synthase (NOS) inhibitor.

32. The method of medical treatment as recited in claim 31, wherein the acute brain injury comprises one of stroke and brain contusion.

33. The method of medical treatment as recited in claim 31, wherein the chronic neurodegenerative disease comprises one of Parkinson'"'"'s disease, Huntington'"'"'s disease, Alzheimer'"'"'s disease, amyotrophic lateral sclerosis, and multiple sclerosis.

34. The method of medical treatment as recited in claim 31, wherein the NOS inhibitor is one of macrophage or smooth muscle inducible NOS (iNOS) and neuronal NOS (nNOS) inhibitor.

35. The method of medical treatment as recited in claim 34, wherein the iNOS inhibitor is one of 1400 W, aminoguanidine, radicicol, L-NIL, and interferon-β

.

36. The method of medical treatment as recited in claim 34, wherein the nNOS inhibitor is one of ARR17338 and ARL17477.

37. The method of medical treatment as recited in claim 24, wherein the medical treatment is to prevent the inflammatory consequences of hemorrhagic shock, the drug is both a macrophage or smooth muscle inducible NOS (iNOS) inhibitor and a scavenger of peroxynitrate;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse, in conjunction with the step of dosing the patient with the drug, provides a useful adjunct to appropriate electrolyte and fluid balance.

38. The method of medical treatment as recited in claim 37, wherein the scavenger of peroxynitrate is mercaptoethylguanidine.

39. The method of medical treatment as recited in claim 24, wherein the medical treatment is for septic shock, and the drug is a macrophage or smooth muscle inducible NOS (iNOS) inhibitor;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse, in conjunction with the step of dosing the patient with the drug, provides lower pulmonary vascular resistance.

40. The method of medical treatment as recited in claim 1, wherein the medical treatment is for the treatment of heart diseases, heart conditions, and heart disorders.

41. The method of medical treatment as recited in claim 40, wherein the heart diseases, conditions, and disorders comprise one of left ventricular hypertrophy, cardiac allograft, heart failure, diastolic dysfunction, and intracardiac thrombosis.

42. The method of medical treatment as recited in claim 1, wherein the medical treatment is for impaired lymphatic drainage;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse causes sustained relaxation and dilation of lymph channels.

43. The method of medical treatment as recited in claim 42, further comprising the step of:

measuring volume changes by means of a limb plethysmograph in order to test the efficacy of the medical treatment.

44. The method of medical treatment as recited in claim 1, wherein the medical treatment is for promoting bone growth in states where mediator release is deficient;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse causes release of nitric oxide and prostacyclin from bone osteoblasts.

45. The method of medical treatment as recited in claim 44, wherein the state where mediator release is deficient is osteoporosis.

46. The method of medical treatment as recited in claim 1, wherein the medical treatment is to provide at least one of cerebrospinal fluid drainage, vasodilation, and increased blood flow;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases mediators from endothelial pia matter.

47. The method of medical treatment as recited in claim 1, wherein the medical treatment is for chronic heart failure;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial nitric oxide synthase (eNOS) basal activity to release greater amounts of nitric oxide from dysfunctioning endothelium.

48. The method of medical treatment as recited in claim 1, wherein the medical treatment is for acute myocardial infarction;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial nitric oxide synthase (eNOS) basal activity to release greater amounts of nitric oxide for at least one of coronary vasodilation, stimulating release of tPA from the endothelium to enhance myocardial reperfusion, and suppressing release of tPA inhibitors and antigens.

49. The method of medical treatment as recited in claim 1, wherein the medical treatment is for vasopathic angina;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates coronary vascular endothelial nitric oxide synthase (eNOS) to release nitric oxide thereby diminishing the frequency and intensity of coronary spasm episodes.

50. The method of medical treatment as recited in claim 1, wherein the medical treatment is for one of coronary atherosclerosis and asymptomatic coronary artery disease.

51. The method of medical treatment as recited in claim 1, wherein the medical treatment is for diastolic dysfunction;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial nitric oxide synthase (eNOS) in myocytes and endocardial endothelium to release nitric oxide thereby improving diastolic function.

52. The method of medical treatment as recited in claim 1, wherein the medical treatment is for systemic hypertension;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse downregulates endothelial release of endothelin-1 and upregulates endothelial nitric oxide synthase (eNOS) in endothelium to increase at least one of basal production of nitric oxide and genes that increase prostacyclin and tissue plasminogen activator (t-PA).

53. The method of medical treatment as recited in claim 1, wherein the medical treatment is for pulmonary hypertension;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse stimulates endothelial release of nitric oxide, prostacylin, and tissue plasminogen activator (t-PA), while suppressing endothelin-1 and tissue plasminogen inhibitor, in order to bring pulmonary arterial pressures down toward normal levels and inhibit thrombus formation.

54. The method of medical treatment as recited in claim 1, wherein the medical treatment is for Raynaud'"'"'s phenomenon;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse stimulates endothelial release of nitric oxide, prostacyclin, and tissue plasminogen activator (t-PA), and suppresses endothelin-1 release.

55. The method of medical treatment as recited in claim 1, wherein the medical treatment is for proliferative retinopathy;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial nitric oxide synthase (eNOS) in endothelium and downregulates release of vascular endothelial growth factor from vascular endothelium.

56. The method of medical treatment as recited in claim 1, wherein the medical treatment is for insulin resistance syndrome;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates beneficial mediator release from vascular endothelium.

57. The method of medical treatment as recited in claim 1, wherein the medical treatment is for wide-angle glaucoma;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates beneficial mediator release from vascular endothelium.

58. The method of medical treatment as recited in claim 1, wherein the medical treatment is for macular degeneration;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates eNOS thereby effecting an increase of choroidal blood flow through the nitric oxide pathway.

59. The method of medical treatment as recited in claim 1, wherein the medical treatment is for angina pectoris;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial nitric oxide synthase (eNOS) of epicardial arteries and endothelial dependent hyperpolarizing factor release.

60. The method of medical treatment as recited in claim 1, wherein the medical treatment is for acute myocardial infarction and restenosis;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse stimulates endothelium to release nitric oxide, prostacyclin, and tissue plasminogen activator (t-PA);

suppresses tissue plasminogen inhibitor; and

inhibits activation of platelet fibrinogen receptors because of nitric oxide and prostacycline, thereby resulting in an action that is counter to thrombosis formation and propagation.

61. The method of medical treatment as recited in claim 60, further comprising:

dosing the patient with Platelet Glycoprotein GPIIb-IIIa Complex inhibitor.

62. The method of medical treatment as recited in claim 1, wherein the medical treatment is for a vasospastic angina;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates release of endothelial nitric oxide synthase (eNOS) of epicardial arteries, endothelial dependent hyperpolarizing factor, and tissue plasminogen activator (t-PA) in vasospastic arteries.

63. The method of medical treatment as recited in claim 1, wherein the medical treatment is for preparing the myocardium for redo coronary bypass graft surgery;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates release of endothelial nitric oxide synthase (eNOS), endothelial dependent hyperpolarizing factor, and tissue plasminogen activator (t-PA) in coronary arteries.

64. The method of medical treatment as recited in claim 1, wherein the medical treatment is for graft failure in coronary revascularization procedures;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial nitric oxide synthase (eNOS) for release of nitric oxide from endothelium as well as endothelial dependent hyperplolarizing factor and tissue plasminogen activator (t-PA) to prevent venous graft failure by maintaining patency.

65. The method of medical treatment as recited in claim 1, wherein the medical treatment is for type-2 diabetes mellitus;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse stimulates endothelial release of nitric oxide, prostacyclin, and tissue plasminogen activator (t-PA) thereby improving the patient'"'"'s coagulation profile.

66. The method of medical treatment as recited in claim 1, wherein the medical treatment is for preconditioning the patient'"'"'s heart to minimize reperfusion injury in case myocardial ischemia or cardiac arrest should take place;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial nitric oxide synthase (eNOS).

67. The method of medical treatment as recited in claim 1, wherein the medical treatment is for myocardial ischemia;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse induces beneficial hibernation of the myocardium, thereby reducing myocardial oxygen consumption and improving regional myocardial function for any given level of myocardial blood flow, oxygen consumption and energetics.

68. The method of medical treatment as recited in claim 1, wherein the medical treatment is for obesity related hypertension;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial release of nitric oxide and prostacyclin.

69. The method of medical treatment as recited in claim 1, wherein the medical treatment is for renal failure complicated by arterial stiffness;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial release of nitric oxide, prostacyclin, and endothelial dependent hyperpolarizing factor, all of which diminish arterial stiffness, and increases renal blood flow, which has a diuretic effect.

70. The method of medical treatment as recited in claim 1, wherein the medical treatment is for chronic atrial fibrillation;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial release of nitric oxide, prostacyclin, endothelial dependent hyperpolarizing factor and tissue plasminogen activator (tPA) from endothelium, all of which have fibrinolytic properties.

71. The method of medical treatment as recited in claim 1, wherein the medical treatment is for ischemic stroke;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse increases cerebral blood flow through release of nitric oxide from vascular endothelium as well as prostacyclin and tissue plasminogen activator (tPA).

72. The method of medical treatment as recited in claim 1, wherein the medical treatment is for subarachnoid hemorrhage;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases nitric oxide from vascular endothelium thereby relieving cerebral vasospasm.

73. The method of medical treatment as recited in claim 1, wherein the medical treatment is of a neonatal patient with neonatal pulmonary hypertension caused by a genetic deficiency of endothelial nitric oxide synthase (eNOS);

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse helps to restore eNOS and releases endothelial prostacylin, thereby reducing pulmonary hypertension and promoting closure of the patent ductus arteriosus.

74. The method of medical treatment as recited in claim 1, wherein the medical treatment is for bronchopulmonary dysplasia;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial release of nitric oxide and prostacyclin thereby alleviating secondary pulmonary hypertension.

75. The method of medical treatment as recited in claim 1, wherein the medical treatment is for pulmonary embolism;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases nitric oxide, prostacyclin, tissue plasminogen activator (tPA) and endothelial dependent hyperpolarizing factor.

76. The method of medical treatment as recited in claim 1, wherein the medical treatment is for portal hypertension;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial nitric oxide synthase (eNOS) in portal venous endothelium.

77. The method of medical treatment as recited in claim 76, further comprising:

dosing the patient with inducible nitric oxide synthase (iNOS) inhibitors.

78. The method of medical treatment as recited in claim 1, wherein the medical treatment is for venous stasis;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial release of nitric oxide, prostacyclin and tissue plasminogen activator (tPA) from venous endothelium and increases venous return, thereby mitigating risk of venous thrombosis.

79. The method of medical treatment as recited in claim 1, wherein the medical treatment is for a patient with one of deep venous thrombosis and a high risk of deep venous thrombosis;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial release of nitric oxide, prostacycline, and tissue plasminogen activator (tPA) while suppressing tissue plasminogen inhibitor.

80. The method of medical treatment as recited in claim 79, further comprising the step of:

dosing the patient with one of heparin, a heparin-like product, a recombinant tissue plasminogen activator, and a streptokinase in order to provide one of additive and synergistic action.

81. The method of medical treatment as recited in claim 1, wherein the medical treatment is for endothelial dysfunction caused by peripheral arterial occlusive disease;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse restores endothelial function by upregulating basal synthesis of nitric oxide, prostacyclin, and tissue plasminogen activator (tPA) and downregulating basal synthesis of endothelin-1 and tissue plasminogen inhibitor.

82. The method of medical treatment as recited in claim 1, wherein the medical treatment is for dysmenorrhea;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases endothelial nitric oxide thereby relieving symptoms of dysmenorrhea.

83. The method of medical treatment as recited in claim 1, wherein the medical treatment is for preeclampsia;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse promotes endothelial release of nitric oxide thereby relieving manifestations of preeclampsia.

84. The method of medical treatment as recited in claim 1, wherein the medical treatment is for preterm cervical dilitation;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse promotes endothelial release of nitric oxide thereby delaying onset of labor.

85. The method of medical treatment as recited in claim 1, wherein the medical treatment is for Alzheimer'"'"'s disease;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases endothelial nitric oxide, increases cerebral blood flow, improves cerebral vessel endothelial function and suppresses formation of Interleukin-6.

86. The method of medical treatment as recited in claim 85, further comprising the step of:

dosing the patient with at least one of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) inhibitors.

87. The method of medical treatment as recited in claim 1, wherein the medical treatment is for Parkinson'"'"'s disease;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases endothelial nitric oxide, increases cerebral blood flow, and improves cerebral vessel endothelial function.

88. The method of medical treatment as recited in claim 87, further comprising the step of:

dosing the patient with at least one of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) inhibitors.

89. The method of medical treatment as recited in claim 1, wherein the medical treatment is for multiple sclerosis;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases endothelial nitric oxide promoting vasodilation in areas of the central nervous system.

90. The method of medical treatment as recited in claim 89, further comprising the step of:

dosing the patient with at least one of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) inhibitors.

91. The method of medical treatment as recited in claim 1, wherein the medical treatment is for traumatic brain injury;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases endothelial nitric oxide thereby increasing cerebral blood flow to damaged areas of the central nervous system.

92. The method of medical treatment as recited in claim 91, further comprising the step of:

dosing the patient with at least one of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) inhibitors.

93. The method of medical treatment as recited in claim 92, further comprising the step of:

dosing the patient with a narcotic.

94. The method of medical treatment as recited in claim 1, wherein the medical treatment is for pain management;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse promotes endothelial release of nitric oxide.

95. The method of medical treatment as recited in claim 1, wherein the medical treatment is for depressive reactions;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases endothelial nitric oxide thereby increasing hippocampal blood flow, and releases endothelial brain-derived neurotrophic factor (BDNF).

96. The method of medical treatment as recited in claim 1, wherein the medical treatment is for sleep deprivation and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases endothelial nitric oxide thereby promoting NREM sleep.

97. The method of medical treatment as recited in claim 1, wherein the medical treatment is for one of sudden deafness and Meniere'"'"'s disease;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial nitric oxide synthase (eNOS) in the cochlear arterial endothelium.

98. The method of medical treatment as recited in claim 1, wherein the medical treatment is for lymphatic damage;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases mediators that promote lymphatic drainage.

99. The method of medical treatment as recited in claim 98, wherein the lymphatic damage is caused by at least one of Milroy'"'"'s lymphedema, lymphedema precox, lymphedema tarda, lymphangitis, neoplastic lymphatic invasion, irradiation induced narrowing of lymphatic channels, post-traumatic injury to lymphatic channels, chronic heart failure, lymphangiospasm, causalgia, and the surgical resection of lymph nodes and lymph channels.

100. The method of medical treatment as recited in claim 1, wherein the medical treatment is for one of adult respiratory distress syndrome and meconium aspiration syndrome;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases nitric oxide and suppresses endothelin-1 from pulmonary vascular endothelium thereby reducing pulmonary hypertension.

101. The method of medical treatment as recited in claim 1, wherein the medical treatment is for osteoporosis;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse causes nitric oxide release and upregulation of endothelial nitric oxide synthase (eNOS) which is transmitted to fluid channels of bone, thereby increasing bone mineral density and diminishing bone fracture risk.

102. The method of medical treatment as recited in claim 1, wherein the medical treatment is for bone fractures;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases endothelial nitric oxide from bone blood vessels and osteoblasts in the bone fractures.

103. The method of medical treatment as recited in claim 1, wherein the medical treatment is for rheumatoid and juvenile arthritis;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases nitric oxide and prostacyclin from vascular endothelium thereby suppressing the inflammatory response.

104. The method of medical treatment as recited in claim 103, further comprising the step of:

dosing the patient with iNOS inhibitors.

105. The method of medical treatment as recited in claim 1, wherein the medical treatment is for osteoarthritis;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases nitric oxide and prostacyclin from vascular endothelium thereby suppressing the inflammatory response.

106. The method of medical treatment as recited in claim 105, further comprising the step of:

dosing the patient with iNOS inhibitors.

107. The method of medical treatment as recited in claim 1, wherein the medical treatment is for fibromyalgia;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases nitric oxide and prostacyclin from vascular endothelium thereby providing benefits analogous to benefits from exercise.

108. The method of medical treatment as recited in claim 1, wherein the medical treatment is for wounds;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse increases endothelial release of nitric oxide thereby facilitating wound healing through increased blood flow and laying down of reparative wound collagen.

109. The method of medical treatment as recited in claim 108, further comprising the step of:

providing one of light and laser therapy to provide one of additive and synergistic actions in the promotion of wound healing.

110. The method of medical treatment as recited in claim 1, wherein the medical treatment is for bed sores;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse increases endothelial release of nitric oxide thereby facilitating healing.

111. The method of medical treatment as recited in claim 1, wherein the medical treatment is for anal fissure;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse stimulates endothelial release of nitric oxide thereby providing pain relief and facilitated healing.

112. The method of medical treatment as recited in claim 1, wherein the medical treatment is for tendon damage;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse causes endothelial release of nitric oxide thereby facilitating tendon healing.

113. The method of medical treatment as recited in claim 1, wherein the medical treatment is for acute gastric injury;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases nitric oxide from endothelium.

114. The method of medical treatment as recited in claim 1, wherein the medical treatment is for HIV-1 infection;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse releases endothelial nitric oxide.

115. The method of medical treatment as recited in claim 1, wherein the medical treatment is for erectile dysfunction;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial nitric oxide synthase (eNOS) and prostacyclin synthesis in endothelium.

116. The method of medical treatment as recited in claim 1, wherein the medical treatment is for cancer;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse increases endothelial release of nitric oxide thereby inhibiting growth of tumors.

117. The method of medical treatment as recited in claim 1, wherein the medical treatment is for prostate cancer with an overexpression of endothelin-1;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse increases endothelial release of nitric oxide thereby inhibiting growth of the prostate cancer.

118. The method of medical treatment as recited in claim 114, further comprising the step of:

dosing the patient with cisplatin.

119. The method of medical treatment as recited in claim 1, wherein the medical treatment is for a patient with hepatic veno-occlusive disease who is undergoing hematopoetic stem cell transplantation;

and

wherein the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse upregulates endothelial storage and release of tissue plasmiogen activator and suppresses tissue plasminogen inhibitor.

120. The method of medical treatment as recited in claim 1, wherein the medical treatment is for the improvement of memory and cognitive function.

121. A method of medical treatment for a patient with a body, comprising the steps of:

providing a pulse means for externally and non-invasively pulsing one of the body and at least one part thereof; and

treating a disease, condition, or injury of the patient that is treatable by at least one endothelial released mediator by adding pulses, using the pulse means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse, said added pulses not being synchronized with the body'"'"'s own pulse, thereby stimulating endothelial release of beneficial mediators and suppressing non-beneficial mediators;

wherein the periodic acceleration means comprises a reciprocating movement platform which periodically accelerates the one of the body and at least one part thereof in a headwards-footwards direction at a frequency between about 1 Hz and about 6 Hz.

122. The method of medical treatment as recited in claim 121, wherein the step of providing a pulse means for externally and non-invasively pulsing one of the body and at least one part thereof comprises the step of:

providing a compression means for providing external intermittent compression of at least one of the legs, thighs, and buttocks.

123. The method of medical treatment as recited in claim 122, further comprising the step of:

providing at least one of air and liquid filled bladders, the at least one bladder attached to reservoirs and pumps, and placed around at least one of legs, thighs, and buttocks.

124. The method of medical treatment as recited in claim 122, further comprising the step of:

exercising, by the patient, on a treadmill within a lower body negative pressure chamber in order to maintain bone, neuromuscular and cardiovascular fitness on long space flights in microgravitational fields.

125. A method of medical diagnosis for a subject with a body, comprising the steps of:

providing a periodic acceleration means for periodically accelerating one of the body and at least one part thereof;

treating a disease, condition, or injury of the patient that is treatable by at least one endothelial released mediator by adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse to thereby add pulses over the body'"'"'s own pulse to the body'"'"'s fluid filled channels; and

testing a physiological response of the subject either during or immediately after the step of adding pulses, using the periodic acceleration means, to the body'"'"'s fluid filled channels over the body'"'"'s own pulse;

wherein the periodic acceleration means comprises a reciprocating movement platform which periodically accelerates the one of the body and at least one part thereof in a headwards-footwards direction at a frequency between about 1 Hz and about 6 Hz.

126. The method of medical diagnosis as recited claim 125, wherein the periodic acceleration means controls the frequency and intensity of said pulses.

127. The method of medical diagnosis as recited in claim 125, wherein the testing step comprises the step of:

analyzing a dicrotic notch present on a diastolic limb of an arterial pulse;

wherein an amount of downward descent of the dicrotic notch is a function of nitric oxide released and absent or diminished descent of dicrotic notch relative to response of normally functioning endothelium is caused by endothelial dysfunction.

128. The method of medical diagnosis as recited in claim 127, wherein the testing step comprises:

computing a b/a ratio, wherein the b/a ratio is the height of the dicrotic notch upward inflection point from its location on arterial pulse to the end-diastolic level (b) divided by total pulse amplitude height (a).

129. The method of medical diagnosis as recited in claim 127, wherein the dicrotic notch is determined using non-invasive sensors, wherein the non-invasive sensors are placed on at least one of thumbs or fingers, toes, neck and skin or over at least one of radial, brachial, carotid, subclavian, and femoral arteries.

130. The method of medical diagnosis as recited in claim 129, wherein the non-invasive sensors comprise a digital inductive plethysmograph.

131. The method of medical diagnosis as recited in claim 129, wherein the non-invasive sensors comprise at least one of oscillometric plethysmographs, piezoelectric sensors, mercury in rubber or silastic strain gauges, photoelectric plethysmographs, pulse oximeters, impedance plethysmographs, capacitance condenser microphones, and electronic pneumoplethysmographs.

132. The method of medical diagnosis as recited in claim 125, wherein the testing step comprises:

computing dose response curves by plotting frequency, amplitude of added pulses, and peak acceleration of the externally added pulses against a b/a ratio, wherein the b/a ratio is the height of a dicrotic notch upward inflection point from its location on arterial pulse to the end-diastolic level (b) divided by total pulse amplitude height (a); and

comparing the computed dose response curves to control dose response curves.

133. The method of medical diagnosis as recited in claim 132, wherein the control dose response curves comprise one of dose response curves of the subject after applying a nitric oxide donor drug that relaxes vascular smooth muscle independent of endothelial participation and dose response curves of a normal population.

134. The method of medical diagnosis as recited in claim 125, further comprising the steps of:

displaying on a display the arterial pulse of the subject during external addition of pulses; and

removing device driven, externally added pulses from the display of the arterial pulse.

135. The method of medical diagnosis as recited in claim 134, wherein the step of removing external pulses from the display comprises the step of:

using triggered electrocardiographic R-wave ensemble-averaging in order to remove device driven, externally added pulses from the display of the arterial pulse and to display an averaged vascular pulse.

136. The method of medical diagnosis as recited in claim 134, wherein the step of removing external pulses from the display comprises the steps of:

triggered ensemble-averaging of input from at least one of linear displacement, velocity, or acceleration sensors mounted either to the means for externally and non-invasively adding external pulses into the body'"'"'s fluid filled channels or the subject to obtain an averaged externally added pulse output; and

subtracting the averaged externally added pulses output from an averaged vascular pulse output while accounting for differences of phase and gain characteristics between the two outputs.

137. The method of medical diagnosis as recited in claim 134, further comprising the step of:

displaying at least one of an averaged vascular pulse, an averaged mathematical first derivative from the averaged vascular pulse, and an averaged mathematical second derivative from the averaged vascular pulse, along with an averaged electrocardiographic waveform for timing purposes.

138. The method of medical diagnosis as recited in claim 125, wherein the testing step comprises the step of:

analyzing an Augmentation Index of the subject'"'"'s arterial pulse, wherein the Augmentation Index is a ratio of the amplitude of pressure wave between its initial systolic shoulder to the peak divided by the pulse amplitude;

wherein an increase in a baseline of the Augmentation Index relative to a response of normally functioning endothelium is caused by endothelial dysfunction.

139. The method of medical diagnosis as recited in claim 125, wherein the testing step comprises the step of:

analyzing arterial pulse wave velocity, wherein arterial pulse wave velocity is computed by dividing the distance between two remote arterial sites by difference in time of onset of two remote arterial waveforms;

wherein an increase in arterial pulse wave velocity relative to a response of normally functioning endothelium is caused by endothelial dysfunction.

140. The method of medical diagnosis as recited in claim 125, wherein the testing step comprises the step of:

analyzing central venous pressure;

wherein a decrease in central venous pressure is caused by normal endothelial function and little or no change occurs in the presence of endothelial dysfunction.

141. The method of medical diagnosis as recited in claim 140, wherein a means for measuring the central venous pressure is a neck inductive plethysmograph.

142. The method of medical diagnosis as recited in claim 125, wherein the testing step comprises the step of:

analyzing E wave deceleration time, wherein E wave deceleration time is computed from the mathematical derivative of the left ventricular volume curve;

wherein, because of endothelial dysfunction of the heart corresponding to diastolic dysfunction, the E wave deceleration time during the addition of external pulses is substantially unchanged relative to a response of normally functioning endothelium.

143. The method of medical diagnosis as recited in claim 142, wherein a means for measuring the left ventricular volume curve is a thoracic inductive inductive plethysmograph (thoracocardiograph).

144. The method of medical diagnosis as recited in claim 125, wherein the testing step comprises the step of:

analyzing blood flow of the subject;

wherein, during the addition of external pulses, a lesser increase in blood flow relative to a response of normally functioning endothelium is caused by endothelial dysfunction.

145. The method of medical diagnosis as recited in claim 144, wherein a means for measuring the blood flow comprises one of venous occlusion plethysmography with a limb inductive plethysmograph, mercury on rubber or silastic strain gauges, and doppler ultrasound imaging.

146. The method of medical diagnosis as recited in claim 125, wherein the testing step comprises the step of:

utilizing biochemical markers to test the response of the subject.

147. The method of medical diagnosis as recited in claim 146, wherein the biochemical marker comprises a marker of one of urinary serum, blood serum, plasma nitrite/nitrate, or nitric oxide.

148. The method of medical diagnosis as recited in claim 146, wherein, during the addition of external pulses, the extent of the change, if any, in levels of the biochemical object of the biochemical marker is indicative of endothelial function.

149. The method of medical diagnosis as recited in claim 146, wherein the biochemical marker comprises at least one of L-citrulline, prostacyclin, and tissue plasminogen activator (t-PA), and wherein, during the addition of external pulses, the at least one of L-citrulline, prostacyclin, and tissue plasminogen activator (t-PA) remains substantially unchanged relative to a response of normally functioning endothelium because of endothelial dysfunction and rises relative to a response of normally functioning endothelium because of normal endothelial function.

150. The method of medical diagnosis as recited in claim 125, wherein the testing step comprises the step of:

utilizing a blood coagulation test;

wherein, during the addition of external pulses, a decrease in fibrinogen or increase in fibrinogen degradation products is a response of normally functioning endothelium whereas little or no change in fibrinogen or fibrinogen degradation products occurs in the presence of endothelial dysfunction.

151. The method of medical diagnosis as recited in claim 125, wherein at least one of the following conditions is being tested for:

atherosclerosis, hypertriglyeridemia, systemic hypertension, hypercholesterolemia, insulin resistance syndrome, arterial smooth muscle dysfunction, microvascular cerebrovascular disorders, and normal pressure glaucoma.

152. The method of medical diagnosis as recited in claim 125, wherein the testing step comprises the step of:

analyzing baroceptor sensitivity as a plot of RR intervals of an electrocardiogram against a rate of arterial distension from a thumb or finger inductive plethysmograph.

153. The method of medical diagnosis as recited in claim 152, wherein at least one of the following conditions is being screened for:

atherosclerosis, diabetes, and chronic heart failure.

154. The method of medical diagnosis as recited in claim 125, wherein the periodic acceleration means comprises running or jumping by the subject.

155. The method of medical diagnosis as recited in claim 125, wherein the subject is a baby and wherein the periodic acceleration means comprises a carriage which is pushed back and forth by a caregiver.

156. The method of medical diagnosis as recited in claim 125, wherein the periodic acceleration means comprises running or jumping by the subject.