Standardisation of 11C.

The increasing use of positron emission tomography for medical imaging and the availability of short-lived positron emitters has raised concerns about the accuracy of calibration of secondary standard measurement systems and the viability of using a single long-lived positron emitter as a reference calibration source for all positron emitters. Potential problems arise because the 511 keV quanta arising from positron annihilation are not generally produced at the same point as the original disintegration. In addition, the secondary standard may also be responsive to the associated bremsstrahlung radiation. The magnitude of both effects depends on the positron end-point energy. In order to resolve these problems, it is necessary to produce absolute standards of these positron-emitting radionuclides and the work presented here details the results of such work with 11C.

1,5-Bis(4-amidinophenoxy)pentane (pentamidine) is a potent inhibitor of [3H]idazoxan binding to imidazoline I2 binding sites.

The aromatic diamidine 1,5-bis(4-amidinophenoxy)pentane (pentamidine) is used for treatment and prophylaxis of Pneumocystis carinii pneumonia in patients with Acquired Immune Deficiency Syndrome. Clinical use of pentamidine has been restricted by significant toxicity, that includes hypotension, and hypoglycemia. Although clinical toxicity is well described, the mechanisms are still poorly understood. Competitive binding analyses using [3H]idazoxan as the radioligand, and cirazoline to define non-specific binding, demonstrate that pentamidine binds to an imidazoline I2 binding site on rat liver membranes with a Ki of 1.4+/-0.22 nM. The Ki indicates that pentamidine inhibits radioligand binding at imidazoline I2 sites with an affinity approximating the most potent known ligands and may be related to pentamidine toxicity. Moreover, pentamidine analogs inhibit radioligand binding with a range of affinities that vary according to their structure. Two candidate drugs, Compounds 5 and 6, are more active than pentamidine in the corticosteroid-suppressed rat model of P. carinii pneumonia, yet have different affinities for the imidazoline I2 site (Ki 5 = 50.1+/-1.06 nM and Ki 6 = approximately 3500 nM). Affinity for this site does not correlate with antimicrobial activity (r = 0.60; p = 0.09) or the calculated log of the octanol:water partition coefficient (ClogP) (r = -0.38; p = 0.22).

Long-term mortality and cancer risk in irradiated rhesus monkeys.

Continuous, 24-year observations on a group of 358 rhesus monkeys reveal that life shortening from exposure to protons in the energy range encountered in the Van Allen belts and solar proton events is influenced primarily by the dose rather than by the energy of radiation. Life shortening in groups exposed to similar surface doses of 138- to 2300-MeV and 32- to 55-MeV protons are not significantly different, but the low-energy protons are associated with more deaths in the early years, while the high-energy protons contribute more to mortality in later years. In males, the most significant cause of life shortening is nonleukemia cancers. In females, radiation increased the risk of endometriosis (an abnormal proliferation of the lining of the uterus) which resulted in significant mortality in the years before early detection and treatment methods were employed. Animals exposed to 55-MeV protons had a high incidence of malignant brain tumors with latent periods ranging from 13 months to 20 years. The first fatal cancer among nonirradiated controls occurred 18 years after the study began. Analysis of the dose-response data supports the 1989 guidelines of the NCRP for maximum permissible radiation exposures in astronauts (NCRP, Guidance on Radiation Received in Space Activities, Report No. 98, National Council on Radiation Protection and Measurements, Bethesda, MD, 1989).

Late cataractogenesis caused by particulate radiations and photons in long-lived mammalian species.

Radiation cataractogenesis induced by small acute doses of particulate radiations and photons in the New Zealand white (NZW) rabbit (Oryctolagus cuniculus), the beagle dog (Canis familiaris) and the rhesus monkey (Macaca mulatta) is discussed in the context of the use of animal models to assess the radiation hazards faced by humans during lengthy sojourns in deep space. Attention is paid to: 1) the importance of lifespan studies with long-lived species--the above animals have median lifespans in captivity of 5-7, 13-14 and approximately 25 years, respectively; 2) the magnitudes of possible dose thresholds for cataractogenesis from sparsely ionizing radiations and the modifications of those thresholds by the late degenerative phase of the phenomenon.

Endometriosis: clinical and pathologic findings in 70 rhesus monkeys.

Endometriosis was histologically confirmed in 70 female rhesus monkeys (Macaca mulatta). Severity of endometriosis was staged as minimal (14% of the monkeys), moderate (20%), or massive (66%). Clinical examination indicated masses in the abdomen and/or pelvic cavity palpable abdominally (64% of the monkeys) or rectally (93%), constipation (29%), anorexia (39%), irregular menses (17%), and radiographic evidence of abdominal soft tissue masses (38%). Pathologic findings were of intra-abdominal endometrial cyst formation (73% of the monkeys), and adhesions involving the ureters (51%), colon (66%), urinary bladder (50%), or ovaries (81%). Metastatic growth of endometrial tissue was found in 4 (6%) of the monkeys.

Surgical treatment of endometriosis in 50 rhesus monkeys.

Surgical treatment of endometriosis was attempted in 50 female rhesus monkeys (Macaca mulatta). Endometriosis was clinically staged as minimal (8% of the monkeys), moderate (18%), or massive (74%). Elective euthanasia was performed in 15 (30%) of the monkeys. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed in 30 (60%) of the monkeys, and bilateral salpingo-oophoretomy alone was performed in 5 (10%) monkeys. Statistical differences were not found in Kaplin-Meier survival curves between the different stages of endometriosis (P = 0.6297).

Vasopressor responses and hypoxemia with acutely increased intracranial pressure.

We studied anesthetized dogs subjected to graded increases in intracranial pressure (ICP) to assess the role of the systemic vasopressor (Cushing) response in the arterial hypoxemia associated with increased ICP. The arterial PO2 decrement was significantly greater with rapidly increased ICP compared to slowly increased ICP (P less than 0.01). Systemic vasopressor responses generated in cats by direct electrical stimulation of the vasomotor center resulted in arterial hypoxemia during controlled ventilation. Therefore, arterial hypoxemia was coincident with increased systemic blood pressure produced by either elevation of ICP or electrical stimulation of the vasomotor center.

Occurrence of brain tumors in rhesus monkeys exposed to 55-MeV protons.

Twenty-year observation of monkeys exposed to single doses of high energy protons simulating solar particles revealed that the most prevalent fatal cancers were brain tumors in the group of animals exposed to 55-MeV protons. Of 72 animals (50 males and 22 females) receiving 0.25 to 8.0 Gy total body surface dose, nine developed fatal tumors classified as grade IV astrocytoma or glioblastoma multiforme. The latent period for tumor development ranged from 14 months to 20 years, with a median of 5 years. Doses associated with the tumors were 4.0 to 8.0 Gy. Eight males and one female were affected. Depth-dose determinations suggest that the high incidence of cerebral neoplasia is associated with the Bragg Peak energy distribution of the 55-MeV protons. Comparison of the tumor incidence with that in humans with brain exposures incidental to radiotherapy indicates a high biological effectiveness compared with gamma radiation. Studies are in progress to attempt to replicate the results in rodents and establish a dose-response curve for proton-induced brain tumors.

Use of primary cell cultures to measure the late effects in the skins of rhesus monkeys irradiated with protons.

Previous pilot investigations of the uses of primary cell cultures to study late damage in stem cells of the skin of the New Zealand white (NZW) rabbit and the rhesus monkey, have been extended to individual monkeys exposed to 55 MeV protons. Protons of this energy have a larger range in tissue of (approximately 2.6 cm) than the 32 MeV protons (approximately 0.9 cm) to which the animals in our earlier studies had been exposed. Although the primary emphases in the current studies were improvement and simplification in the techniques and logistics of transportation of biopsies to a central analytical facility, comparison of the quantitative measurements obtained thus far for survival of stem cells in the skins from animals irradiated 21 years ago reveals that the effects of both proton energies are similar.

Animal studies of life shortening and cancer risk from space radiation.

The U.S. Air Force study of the delayed effects of single, total body exposures to simulated space radiation in rhesus monkeys is now in its 21st year. Observations on 301 irradiated and 57 age-matched control animals indicate that life expectancy loss from exposure to protons in the energy range encountered in the Van Allen belts and solar proton events can be expressed as a logarithmic function of the dose. The primary causes of life shortening are cancer and endometriosis (an abnormal proliferation of the lining of the uterus in females). Life shortening estimates permit comparison of the risk associated with space radiation exposures to be compared with that of other occupational and environmental hazards, thereby facilitating risk/benefit decisions in the planning and operational phases of manned space missions. Calculations of the relative risk of fatal cancers in the irradiated subjects reveal that the total body surface dose required to double the risk of death from cancer over a 20-year post exposure period varies with the linear energy transfer (LET) of the radiation. The ability to determine the integrated dose and LET spectrum in space radiation exposures of humans is, therefore, critical to the assessment of lifetime cancer risk.

Amelioration of hypoxemia by neuromuscular blockade following brain injury.

Brain injury has been commonly associated with respiratory failure and uncontrolled skeletal muscle activity. In the present study, neuromuscular (NM) blockade induced by injection of succinylcholine hydrochloride was used to block uncontrolled muscle contractions in dogs with brain injury caused by rapid elevation of intracranial pressure (ICP). Decerebrate posturing, a decrease in value (mean +/- SEM) of arterial oxygen tension (Pa02) of 26 +/- 1 torr, and an increase in arterial carbon dioxide tension (PaCO2) of 11 +/- 1 torr occurred in the dogs, which were supported by mechanical ventilation. The arterial hypoxemia developed independently of the decerebration; however, dogs that demonstrated decerebrate posturing exhibited significantly larger decreases in Pa02 than dogs that did not (P less than 0.01). NM blockade ameliorated the effects of elevated ICP on the arterial blood gases; i.e., the amount of hypoxemia in decerebrate dogs was significantly less in dogs subjected to NM blockade than in dogs not subjected to NM blockade. It is concluded that uncontrolled skeletal muscle activity that exacerbates arterial hypoxemia associated with brain injury is ameliorated by use of NM blockade as a therapeutic adjunct to mechanical ventilation.

Seventeen-year mortality experience of proton radiation in Macaca mulatta.

This is an interim report on the lifetime study of chronic mortality and its causes under investigation in 31 control (20 males, 11 females) and 217 survivors (124 males, 93 females) of an acute 90-day experiment in rhesus monkeys. Single acute whole-body exposures were made using 32-, 55-, 138-, 400-, and 2300-MeV protons in 1964-1965. Doses ranged from 25 to 800 rad and dose rates from 12.5 and 100 rad per minute. Tissue depths of partially penetrating 32- and 55-MeV particles were approximately 1 and approximately 2.5 cm, respectively, and depth doses at the respective distances were 115 and 122% of surface doses. Protons with energies greater than or equal to 138 MeV were totally penetrating and the depth doses were essentially homogenous. For pooled data: (1) mortality was significantly higher (P less than 0.01) in irradiated animals (48%) than in controls (19%); (2) mortality in animals exposed to partially penetrating 55-MeV protons (53%) was essentially similar to those given totally penetrating 138- (53%), 400- (49%), and 2300-MeV (44%) exposures; (3) proton energies and doses that were effective in producing life shortening were greater than or equal to 55 MeV and greater than or equal to 360-400 rad, respectively; (4) death rates for irradiated animals compared to controls began to increase after approximately 8 years, approximately 2 years, and approximately 1 year for those exposed to 360-400, 500-650, and 800 rad, respectively; (5) of the nine probable causes of death reported, the leading causes were primary infections in both irradiated (31%) and control (50%) animals, endometriosis (25% vs 0%, respectively), neoplasms (17% vs 0%), and organ degeneration (17% vs 33%); and (6) if endometriosis is included with the neoplastic group, deaths from all forms of neoplasms would be 42% in irradiated animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Paralysis due to a glomangioma in a Macaca mulatta.

A glomangioma at the 6-7 thoracic intervertebral space caused compression of the spinal cord with posterior paralysis in an irradiated 20-year-old female rhesus monkey (Macaca mulatta). Glomangiomas are tumors of arterial-venous shunts, are rare and have only been reported in irradiated rhesus monkeys.