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Radioisotope therapy in bone and joint disease.

The short range tissue destruction of beta-emitting radioisotopes can be utilized in painful metastatic disease of the skeleton by employing a radionuclide that is specifically metabolized in or adjacent to these lesions. Sodium phosphate P 32 has been used for this purpose for the past 25 yr. It uptake in skeletal tumor and in osteoblastic new bone adjacent to tumor can be markedly increased by pharmacologic stimulation using androgenic steroids, or during rebound deposition after a course of parathyroid hormone. Although efficacy in terms of subjective pain relief is high, more objective signs of success are often lacking, and survival, while more confortable, is not prolonged. Marrow depression is the most significant side effect. A beta-emitting, bone-seeking isotope, 89Sr, may have a better therapeutic/toxic ratio, and should receive further trial. Radiation-induced necrosis has also been applied, though more hesitantly, to the proliferative, destructive, but nonmalignant synovium in rheumatoid disease. Here, a number of colloidal preparations, most commonly 198Au, have been employed. Again, relief of symptoms, particularly recurrent joint effusions, is quite high, although the basic disease process is not reversed. The major hazard here appears to be leakage of material to regional lymph nodes, resulting in irradiation of circulating lymphocytes. Although chromosomal damage can be detected when such cells are then cultured, the actual consequences of this, if any, are not presently known. Both shorter-lived (165Dy) and longer-lived (32P) larger-size colloids are being evaluated, which may prove safer in this regard than 198Au.

Bone Marrow↗

Microdosimetric measurements of ionization by some radioisotopes.

Microdosimetry has been a fast growing field in dosimetry during the last years. We have measured and calculated microdosimetric quantities which are important in correlation between the energy deposited in microscopic volumes and the biological effect. We have measured the energy distribution spectra in volumes with diameters of 1 and 2 mum and calculated the dose mean of specific energy and the mean event number per unit absorbed dose for the radioisotopes: 60Co, 137Cs, 99Tcm, 125J and the beta emitter 90Sr.

Cesium Radioisotopes↗

Bone marrow necrosis. Diagnosis and assessment of extent of involvement by radioisotope studies.

In two patients with extensive marrow necrosis, the diagnosis of marrow necrosis was established by morphologic and radioisotopic studies, and the extent of involvement was accurately assessed by marrow scanning with technetium Tc 99m sulfur colloid while the patients were still alive. The literature on marrow necrosis was briefly reviewed and the clinical features of this condition were characterized. It was found that patients with this condition often have malignancies, underlying marrow disorders, sepsis, bone pain, and pancytopenia. Their marrow is often difficult to aspirate and they may require frequent transfusions to maintain a stable hemoglobin level. Radioisotopic studies are useful in the diagnosis and assessment of extent of involvement of this condition. They should be used in patients with clinical findings suggestive of marrow necrosis.

Bone Marrow Diseases↗

Leukocyte adherence inhibition as measured by a radioisotopic technique for detection of cell-mediated tumor immunity.

It has been previously reported that cell-mediated tumor immunity may be detected by leukocyte adherence inhibition (LAI) as determined by a visual counting technique in the presence of soluble tumor antigen. In the present experiments leukocyte adherence was measured by a radioisotopic technique. Peripheral blood mononuclear cells from Wistar/Fu rats and lymph-node cells (LNC) from C3H/J mice were labelled with Technetium 99m (99mTc) and incubated with medium alone and with medium containing tumor antigens (high dilutions of dialyzed tumor homogenates) in the wells of plastic tissue-culture plates. After incubation, fluid and non-adherent cells were removed. The ratio of residual radioactivity in wells with antigen to that in wells without antigen was determined. Adherence of blood mononuclear cells from rats bearing syngeneic transplants of a polyoma-virus-induced tumor was inhibited by dialyzed homogenates of this tumor. Adherence of blood mononuclear cells from normal rats was not inhibited. Adherence of LNC from mice bearing syngeneic transplants of a 3-methylcholanthrene (3-MCA)-induced fibrosarcoma was inhibited by dialyzed homogenates of this tumor. Adherence of LNC from normal mice or from mice or from mice bearing a different 3-MCA-induced tumor was not inhibited. These results support the use of LAI as a simple test for cell-mediated tumor immunity. Measuring relative leukocyte adherence with the radioisotope 99mTc eliminates possible bias in counting and permits multiple replicate determinations with a small number of leukocytes.

Animals↗

Novel approach for classifying chemicals according to skin sensitizing potency by non-radioisotopic modification of the local lymph node assay.

The murine local lymph node assay (LLNA) is currently recognized as a stand-alone sensitization test for determining the sensitizing potential of chemicals, and it has the advantage of yielding a quantitative endpoint that can be used to predict the sensitization potency of chemicals. The EC3 has been proposed as a parameter for classifying chemicals according to the sensitization potency. We previously developed a non-radioisotopic endpoint for the LLNA based on 5-bromo-2'-deoxyuridine (BrdU) incorporation (non-RI LLNA), and we are proposing a new procedure to predict the sensitization potency of chemicals based on comparisons with known human contact allergens. Nine chemicals (i.e. diphencyclopropenone, p-phenylenediamine, glutaraldehyde, cinnamicaldehyde, citral, eugenol, isopropyl myristate, propyleneglycol and hexane) categorized as human contact allergen classes 1-5 were tested by the non-RI LLNA with the following reference allergens: 2,4-dinitrochlorobenzene (DNCB) as a class 1 human contact allergen, isoeugenol as a class 2 human contact allergen and alpha-hexylcinnamic aldehyde (HCA) as a class 3 human contact allergen. Consequently, nine test chemicals were almost assigned to their correct allergen class. The results suggested that the new procedure for non-RI LLNA can provide correct sensitization potency data. Sensitization potency data are useful for evaluating the sensitization risk to humans of exposure to new chemical products. Accordingly, this approach would be an effective modification of LLNA with regard to its experimental design. Moreover, this procedure can be applied also to the standard LLNA with radioisotopes and to other modifications of the LLNA.

Allergens↗

Estimation of the neurovirulence of poliovirus by non-radioisotope molecular analysis to quantify genomic changes.

Mutant analysis by polymerase chain reaction and restriction enzyme cleavage (MAPREC) has been developed for poliovirus to determine quantitatively for the presence of genomic changes in particular nucleotide sequences correlate with the characteristic of neurovirulence for monkeys. Currently the MAPREC is scheduled to be used as a routine safety test for oral poliomyelitis vaccine (OPV). Radioisotopes (RI) are used in MAPREC for quantitative determinations, a circumstance likely to limit its use. We investigated the possibility of developing a modified MAPREC, which did not require the use of radioisotopes, and developed a procedure designated NON-RI MAPREC. Conventional MAPREC and NON-RI MAPREC were then used in a series of studies in which analyses were performed on Sabin type 1 and Sabin type 3 attenuated vaccine polioviruses prepared under various conditions. Under the experimental conditions used, the stability of the genome of type 1 virus was shown to be markedly greater than that of the type 3 virus, and the frequency of mutants was observed to vary in relation to both the virus strain and the virus inoculum used. The results of the studies relating to the two analytical procedures used indicated that the reproducibility of both methods was of a similarly high order, but that MAPREC had a somewhat broader range of sensitivity than NON-RI MAPREC. As the quantity of genomic changes in OPV relating to neurovirulent properties are within the range of detection by NON-RI MAPREC, this procedure can be used as a quality control test for OPV.

Animals↗

The radioisotope stent for the prevention of restenosis.

The use of intracoronary stenting has revolutionized catheter-based revascularization of obstructive coronary artery disease. These devices provide excellent scaffolding, predictable immediate success with the creation of a large, dissection-free luminal cross-section and improved long-term outcomes, when compared to "plain old balloon angioplasty". Despite these improvements restenosis still occurs at unacceptable rate, particularly in smaller vessels and in longer lesions. In this article we review the concept of using a stent implanted with low activities of radioisotope as a means to inhibit the proliferative process that is believed to initiate in-stent restenosis. The potential advantages, as well as the limitations of this means of intravascular brachytherapy are reviewed. This approach has been shown to be effective in certain animal models of restenosis. The initial clinical results with the Phase I safety trials will be summarized. Future directions for this technology, including the evaluation of new stent designs and new radioisotopes will be discussed. The early clinical results with more than 170 implants of low activity 32P Palmaz-Schatz and BX radioactive stents have demonstrated excellent procedural and 30-day event-free survival. Further dose finding safety trials are anticipated in 1998. Implementation of a large scale randomized clinical trial will commence if and when early safety and efficacy data suggest a therapeutic effect from this technology. Thus, future studies will focus on optimal stent design and will evaluate alternative isotopes and dosing strategies.

Angioplasty, Balloon, Coronary↗

Role of radioisotope penile plethysmography in the evaluation of penile hemodynamics in impotent patients.

Nineteen impotent patients were included in the study. Radioisotope penile plethysmography using technetium-99m-labelled RBC was performed on each patient before and after intracavernosal injection of prostaglandin E1 (PGE1) for quantitating the penile hemodynamic change. The peak penile blood flow (PPF) and penile blood volume change (dPV) were evaluated. The results revealed that (a) the PPF values (mean 2.24 +/- 1.38 ml/min) of all patients were lower than that of the patients with no arterial changes previously reported, and (b) there was good correlation between PPF and dPV (r = 0.75). We conclude that quantitative radioisotope penile plethysmography coupled with intracavernosal injection of PGE1 is a valuable method for the objective evaluation of the penile erectile response of impotent patients, and that the PPF values of the impotent patients with arterial insufficiency might be a reliable parameter of penile volume change.

Alprostadil↗

Brain death in children: clinical, neurophysiological and radioisotopic angiography findings in 125 patients.

The objective of this study was to determine the main clinical, neurophysiological and angiographic findings in brain death (BD) in children seen at the Instituto Nacional de Pediatría, a third-level facility in Mexico City, between 1991 and 1996. The following variables were retrospectively analyzed: sex, age, etiology, associated morbidity, duration of stay in hospital, and the results of two of three confirmatory studies (electroencephalogram, evoked potentials, radioisotopic angiography). In all, 125 patients were studied 78 male, median age 2 years (range: 18 days to 17 years)[. The most frequent etiology was infection (34%); 57% of the children developed associated morbidity. In 111 of 122 patients electrocerebral silence was observed; 100 of 107 had brain stem and somatosensory evoked potentials affording conclusive evidence of BD; and 83 of 90 patients had a positive radioisotopic angiography indicating BD. In 76 patients all three confirmatory studies were performed: for 15 there was at least one false-negative test result. Our age cohort showed a predominance of children less than 2 years old. BD etiologies in developing countries differ from those reported in developed countries.

Adolescent↗

Radioisotope penogram in diagnosis of vasculogenic impotence.

A radioisotope technique to estimate penile blood flow is described. The radioisotope penogram is noninvasive and gives a dynamic evaluation of the arterial supply, venous drainage, and blood flow in the corporeal bodies. The penogram is a valuable adjunct in evaluation of patients with vasculogenic impotence.

Adolescent↗

The use of radioisotopes in haematology.

Radioisotopes used in haematology may be divided into four groups: 1. those used for in vivo studies, involving the labelling of cells in the blood or bone marrow and the use of labelled plasma albumin; 2. investigations involving surface counting over organs such as the bone marrow, spleen, liver and heart; 3. in vitro use of radioisotopes in the haematology laboratory and 4. isotopes used as part of imaging procedures. The shorter the half life of the isotope, the more limited patient exposure to radioactivity will be, but the greater the problems of starting and completing the investigation before the isotope has decayed. Isotopes studies should not be carried out in children or pregnancy unless there are exceptional clinical indications.

Absorption↗

A modification of the local lymph node assay for contact allergenicity screening: measurement of interleukin-2 as an alternative to radioisotope-dependent proliferation assay.

The local lymph node assay is an effective prediction method for contact allergenicity, but employs radioisotopes. We investigated whether measurement of interleukin-2 (IL-2) production by lymph node cells could be used instead to predict contact allergenicity of chemicals. Test chemicals were applied for three consecutive days to both ears of Balb/c mice and the auricular lymph nodes were obtained on either the fourth or fifth day after the first application. Both IL-2 concentration in supernatant of the suspension and proliferative activity of lymph node cells were determined after 24-, 48-, 72-h cell culture in RPMI-1640 medium by ELISA and by measuring [3H]methylthymidine incorporation, respectively. These two methods detected allergenicity similarly except in the case of TNCB and oxazolone, which showed excessive proliferation-inducing capacity as compared to IL-2 release-increasing effect. Flow cytometry showed that these two chemicals also increased the percentage of Iad-positive cells in the lymph nodes, suggesting that these chemicals might induce not only cellular immunity but also humoral immunity. We conclude that interleukin-2 assay is a convenient and dependable method for screening strong contact allergens without using radioisotopes.

Allergens↗

Automatic ventricular edge detection for determination of left ventricular volumes, ejection fraction and regional ejection fractions from first pass radioisotope angiography.

An automated method for detection of left ventricular (LV) outline (including the aortic and mitral valve planes) was developed for measurements of end-diastolic volume (EDV), end-systolic volume (ESV), global ejection fraction (EF), and regional EFs from first pass radioisotope ventriculography. The procedure includes: (1) interpolative background subtraction, (2) construction of gradient images, (3) automatic detection of valve planes, and (4) automatic radial search of LV outlines. The correlation between contrast angiography and Tc-99m first pass study was r = 0.84 (SEE = 23.4) for EDV, r = 0.93 (SEE = 12.8) for ESV, r = 0.84 (SEE = 6.91) for EF (via counts) and r = 0.80 (SEE = 8.56) for EF (via area-length method). Tests of intra-observer, inter-observer and inter-study variability revealed low level of variability. The results showed the potential of the automation of data processing for first pass radioisotope ventriculography.

Cardiac Volume↗

Diagnostic value of the radioisotope erection penogram for vasculogenic impotence.

Radioisotope erection penography of 113 consecutive impotent patients (41 with psychogenic and 72 with vasculogenic impotence) and 15 normal potent men were obtained. Twenty minutes after intracavernous injection of 99mtechnetium-pertechnetate 40 mg. papaverine hydrochloride were administered into the corpus cavernosum to induce erection. A gamma camera with a pinhole collimator was used to monitor the radioactivity. Various penogram indexes were calculated from the time activity curve and their usefulness was evaluated. Index A1 was useful to differentiate vasculogenic and psychogenic importance. Indexes V1 and V2 were useful to differentiate arteriogenic and venogenic impotence. The radioisotope erection penogram is a simple, less invasive and valuable screening test in the identification of vasculogenic impotence, and is effective in differentiating arteriogenic and venogenic impotence.

Adult↗

Radioisotope bone scanning characteristics of metastatic skeletal deposits of prostatic adenocarcinoma.

Radioisotopic bone scans and metastatic bone surveys were conducted on patients with endocrine-unresponsive prostatic adenocarcinoma undergoing multiple drug chemotherapy. Three types of bone scans were observed--type I scans were characterized by asymmetric radioisotope activity and normal renal imaging, type II was characterized by symmetrical skeletal uptake and faint or absent renal imaging and type III showed symmetrical skeletal uptake with normal renal imaging and was interpreted as normal, although the bone surveys showed diffuse osteoblastic disease. The appearance of a type II scan was a grave prognostic indicator.

Adenocarcinoma↗

The first attempt at radioisotopic evaluation of the integrity of the nose-brain barrier.

The first attempt at radioisotopic assessment of the integrity of the nose-brain barrier was performed on an anosmic patient by spraying an aliquot of a mixture of 99mTc-DTPA and hyaluronidase onto the olfactory mucosa with the patient's head positioned vertically and subsequently measuring the cerebral radioactivity. A significant rise in cerebral radioactivity was observed 5 minutes after introduction of the radioisotope. This simple technique will aid in assessing olfactory impairment from selected etiologies and also in testing the integrity of the nose-brain barrier. In view of the study of diseases such as viral encephalitis and Alzheimer's disease, the clinical implications of this method cannot be overemphasized. This principle may also facilitate developing novel pharmaceuticals for some brain diseases.

Aged↗

Novel non-radioisotope immunoprecipitation studies indicate involvement of pemphigus vulgaris antigen in paraneoplastic pemphigus.

We have developed two different novel immunoprecipitation assays in which radioisotopes are not used, and have examined antigens for four cases of paraneoplastic pemphigus (PNP) including three new patients. The PNP sera showed a clear reactivity with transitional epithelia of rat urinary bladder by immunofluorescence, and reacted with a characteristic doublet of the 210 and 190 kD proteins by immunoblotting of normal human epidermal extract, confirming the diagnosis of PNP. In addition, by immunoprecipitation using silver-stain to detect immunoprecipitated proteins, the PNP sera detected the 250, 210 and 190 kD proteins, while control bullous pemphigoid sera detected only the 230 kD bullous pemphigoid antigen. Furthermore, with another immunoprecipitation using cell surface biotinylation, three of the four PNP sera specifically reacted with the 130 kD pemphigus vulgaris antigen (Dsg3), indicating that pemphigus vulgaris antigen may be involved in PNP. This reactivity was further suggested by the immunoblot analysis using recombinant pemphigus vulgaris antigen. In future, these non-radioisotope immunoprecipitation assays should become a useful tool not only to unravel the complex situation for the PNP antigens, but also to study antigens in other autoimmune bullous skin diseases.

Animals↗

A new method of measuring renal function in conscious rats without the use of radioisotopes.

The purpose of the current experiment was to develop fast and accurate assays for measuring glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). An enzymatic method was developed for the determination of inulin, and a colorimetric method was developed for determination of p-aminohippurate (PAH) in the plasma and urine of rats. These assays are easily automated and do not require the use of radioisotopes or corrosive chemicals. Glomerular filtration rate was measured by the clearance of inulin, and effective renal plasma flow was measured by the clearance of PAH. Blood pressure, heart rate, and renal function (urine volume, electrolytes, GFR, and ERPF) were measured in conscious rats for 1.5 h prior to drug treatment and for 3 h after treatment. Baseline renal function was compared to historical data. Acute changes in GFR and ERPF following administration of the vasoconstrictor peptide endothelin-1 (ET-1) were accurately measured with results similar to those obtained with older methodologies. These new methods offer many advantages over previously described methods by eliminating the use of radioisotopes and harsh chemicals. In addition, these methods can be used with an automated instrument with high accuracy and precision. Therefore, these new methods can be used to accurately determine GFR and ERPF and are sensitive enough to detect acute changes in GFR and ERPF in conscious animals.

Animals↗