Scientific Developments in Imaging and Dosimetry for Molecular Radiotherapy.

Molecular radiotherapy is a rapidly developing field with new vector and isotope combinations continually added to market. As with any radiotherapy treatment, it is vital that the absorbed dose and toxicity profile are adequately characterised. Methodologies for absorbed dose calculations for radiopharmaceuticals were generally developed to characterise stochastic effects and not suited to calculations on a patient-specific basis. There has been substantial scientific and technological development within the field of molecular radiotherapy dosimetry to answer this challenge. The development of imaging systems and advanced processing techniques enable the acquisition of accurate measurements of radioactivity within the body. Activity assessment combined with dosimetric models and radiation transport algorithms make individualised absorbed dose calculations not only feasible, but commonplace in a variety of commercially available software packages. The development of dosimetric parameters beyond the absorbed dose has also allowed the possibility to characterise the effect of irradiation by including biological parameters that account for radiation absorbed dose rates, gradients and spatial and temporal energy distribution heterogeneities. Molecular radiotherapy is in an exciting time of its development and the application of dosimetry in this field can only have a positive influence on its continued progression.

Homozygous human C3 deficiency. The role of C3 in antibody production, C-1s-induced vasopermeability, and cobra venom-induced passive hemolysis.

Studies of the family of a patient with marked deficiency of the third component of complement (C3) demonstrated that the patient was homozygous for a blank allele at the C3 locus, C3-. Metabolic studies with purified radiolabeled C3 in the patient revealed a mildly elevated fractional catabolic rate and a markedly reduced synthesis rate, consistent with a lack of C3 synthesis as the patient's primary defect. There was also a mild increase in the rate of conversion of purified C3 added to her serum and incubated at 37 degrees C in vitro. Major blood group-compatible erythrocytes from a patient with paroxysmal nocturnal hemoglobinuria had the same shortened survival in the C3-deficient patient as in a normal control. Although no leukocytosis developed in the patient in spontaneous infection by pyogenic organisms, there was a normal leukocytosis in response to the injection of thyphoid vaccine. The intradermal injection of C-1s, which produces a marked increase in vasopermeability in the skin of normal subjects, produced no definite change in the patient, possibly implicating C3 or a protein in the alternative pathway as the normal mediator of this response. The patient's serum exhibited near-normal immune adherence activity, confirming the lack of requirement of C3 for this function. C5 inactivation and passive hemolysis of unsensitized guinea pig erythrocytes occurred normally in C3-deficient serum on incubation with cobra venom factor, indicating that C3 is not required for these reactions. The patient's humoral antibody response to both protein and carbohydrate antigens was entirely normal, making it unlikely that C3 is required for antigen processing.

The application of polymer gel dosimeters to dosimetry for targeted radionuclide therapy.

There is a lack of standardized methodology to perform dose calculations for targeted radionuclide therapy and at present no method exists to objectively evaluate the various approaches employed. The aim of the work described here was to investigate the practicality and accuracy of calibrating polymer gel dosimeters such that dose measurements resulting from complex activity distributions can be verified. Twelve vials of the polymer gel dosimeter, 'MAGIC', were uniformly mixed with varying concentrations of P-32 such that absorbed doses ranged from 0 to 30 Gy after a period of 360 h before being imaged on a magnetic resonance scanner. In addition, nine vials were prepared and irradiated using an external 6 MV x-ray beam. Magnetic resonance transverse relaxation time, T2, maps were obtained using a multi-echo spin echo sequence and converted to R2 maps (where T2 = 1/R2). Absorbed doses for P-32 irradiated gel were calculated according to the medical internal radiation dose schema using EGSnrc Monte Carlo simulations. Here the energy deposited in cylinders representing the irradiated vials was scored. A relationship between dose and R(2) was determined. Effects from oxygen contamination were present in the internally irradiated vials. An increase in O2 sensitivity over those gels irradiated externally was thought to be a result of the longer irradiation period. However, below the region of contamination dose response appeared homogenous. Due do a drop-off of dose at the periphery of the internally irradiated vials, magnetic resonance ringing artefacts were observed. The ringing did not greatly affect the accuracy of calibration, which was comparable for both methods. The largest errors in calculated dose originated from the initial activity measurements, and were approximately 10%. Measured R2 values ranged from 5-35 s(-1) with an average standard deviation of 1%. A clear relationship between R2 and dose was observed, with up to 40% increased sensitivity for internally irradiated gels. Curve fits to the calibration data followed a single exponential function. The correlation coefficients for internally and externally irradiated gels were 0.991 and 0.985, respectively. With the ability to accurately calibrate internally dosed polymer gels, this technology shows promise as a means to evaluate dosimetry methods, particularly in cases of non-uniform uptake of a radionuclide.

Reversal in mortality trends: evidence from the Agincourt field site, South Africa, 1992-1995.

OBJECTIVE: To examine changes in mortality in rural South Africa over the period 1992-1995 by age, sex and cause of death. DESIGN: As with much of sub-Saharan Africa, South Africa lacks effective vital registration and information on mortality is lacking. The Agincourt demographic and health surveillance system was established to inform health policy and practice with regard to rural subdistrict populations. METHODS: Prospective community-based study involving annual update of a household census with enquiry into all birth, death and migration events. All reported deaths (n = 1001) are the subject of a verbal autopsy. RESULTS: An increasing trend in overall mortality relative to general population growth in the study area is apparent. There is evidence for a reversal in the previously declining trend in mortality among women 20-44 years. A comparison of 1992-1993 with 1994-1995 shows that most of the increase in mortality is concentrated in the younger adult (20-49 year) age group. AIDS and related diseases, particularly tuberculosis, appear primarily responsible. Injuries and violence (especially homicide) and circulatory disease are important, under-recognized causes of death, although their levels have remained constant over the period. CONCLUSIONS: Mortality from AIDS and related diseases appears responsible for the probable reversal in mortality emerging in South Africa's rural northeast. Findings carry implications for the emerging system of decentralized health care.

Correlation of the distribution of Rickettsia conorii, microscopic lesions, and clinical features in South African tick bite fever.

Three South African patients with severe Rickettsia conorii infection had complicated courses of illness with 2 fatal cases and 1 with gangrene of multiple digits. Immunofluorescent organisms of R. conorii were demonstrated in vascular endothelium of brain, leptomeninges, renal glomerular arterioles and capillaries, renal arteries and veins, myocardial capillaries and arteries, pulmonary alveolar capillaries, pancreatic septa, splenic arterioles, and dermis. Rickettsiae were also observed in hepatic sinusoidal lining cells, splenic and lymph node macrophages, and the blood vessels of the partially viable zone of the amputated digits. Pathologic lesions included cerebral and cerebellar perivascular mononuclear leukocytes, mild mononuclear leptomeningitis, glomerular arteriolitis, vascular and perivascular mononuclear cell-rich inflammatory foci in the kidney, pancreas, skin, and myocardium, hepatocellular necrosis, and pulmonary edema. The sites of lesions and rickettsiae showed strong topographical correlation. Thrombi and hemorrhage occurred in a minority of the sites of vascular injury. Rickettsiae were the apparent direct cause of meningoencephalitis, peripheral gangrene, and other foci of vascular injury. Fatal R. conorii infection with disseminated organ involvement emphasizes the pathogenic potential of this disease.

The clinical manifestations of Rhodesian trypanosomiasis: an account of cases contracted in the Okavango swamps of Botswana.

Over 100 years ago, David Livingstone reported the presence of tsetse flies in the Okavango swamps in northern Botswana. They have persisted in the region and recently have been responsible for many cases of Rhodesian sleeping sickness caused by Trypanosoma rhodesiense in visitors to the area. The clinical manifestations in illustrative cases of this disease are described. One patient who refused treatment died five months after being infected. One patient died of encephalopathy complicating treatment with Melarsoprol (Mel B) and one died in a hemorrhagic state associated with a heavy parasitemia early in his illness. Most patients treated early respond well to treatment with specific drugs, usually Suramin, and are cured. In those with involvement of the central nervous system the treatment required is more hazardous, but usually is effective in curing the patient.

Poliomyelitis outbreak in South Africa, 1982. II. Laboratory and vaccine aspects.

Between May and September 1982 an extensive epidemic of poliomyelitis occurred in Gazankulu in the north-eastern region of South Africa, with a total of 260 paralysed cases and 42 deaths. A three-part study was instituted, the first of which established the aetiological agent of the epidemic to be poliovirus type 1. This was determined initially by serology and later by isolation of the virus, chiefly from stool specimens. The potency of the trivalent oral polio vaccine manufactured at the National Institute for Virology, was evaluated in the second study by in vitro potency testing of samples recalled from the epidemic areas and also in vivo by determining the serological response of seronegative children immunized with fresh vaccine. Nearly half of the vaccine samples withdrawn from the field had sub-optimal titres whereas fresh vaccine produced a very satisfactory serological response. In order to plan immunization rationally, the third study, namely the determination of the immune status of the various populations throughout the country was instituted. This involved both serology, using a neutralization test on randomly collected sera and also an analysis of patient history and health card documentation. With the exception of the urban black area (Soweto), which had high levels of immunity both serologically (75%) and on history, other areas examined had poorer levels of immunity of approximately 52% on serological testing and 57% on history. It is clear that the epidemic was multifactorial in origin, with fall-offs in the level of immunization and evidence of breaks in the cold chain being the major factors.

Cerebellar stimulation in the management of cerebral palsy: clinical and physiological studies.

Cerebellar stimulators were inserted into seven children who had cerebral palsy and in whom extensive investigation, including computerized tomography, had revealed no structural brain abnormality. A team including physiotherapists, occupational therapists, speech pathologists, and respiratory physiologists assessed the children pre- and postoperatively; their somatosensory evoked potentials were also measured. The mean age at implantation was 8.6 yearsl follow-up has ranged from 8 to 23 months (mean, 17.3 months). No adverse effects of the cerebellar stimulation have been noted. Detailed case histories obtained from the parents, together with formal assessment scores, indicate good improvement in six patients and mild but significant improvement in the seventh. Clinically, there has been gradual improvement in all seven patients. The charge density range associated with clinical improvement was 0.8 to 2.1 muCi/cm2/phase. The stimulation equipment must be monitored very carefully to ensure that any variation from the desired output is acceptably small because it is probable that sizable deviation is a determining factor in lack of response to this therapy.

Effects of toluene exposure on the spontaneous cortical activity in rats.

Effects of toluene on the electroencephalogram (EEG) and its power spectra were measured during a 2-hr exposure in a dynamic inhalational chamber in rats. Rats were exposed to one of six graded concentrations (110.6, 162.5, 432, 676, 1558, 2730 ppm) of toluene on different days. It was found that the duration of waking (W) was increased with a decrease in duration of rapid eye movement (REM) sleep even at 110.6 ppm. Duration of nonrapid eye movement (NREM) sleep was decreased with an increase of W and a decrease of REM sleep at 162.5 ppm. Dose-related effects were noted in higher concentrations. The power of delta frequency band was increased with a decrease of theta frequency band power at hr 1 of exposure to 676 ppm during REM sleep recorded from the visual cortex. The power of theta frequency band was also decreased at hr 2 of exposure at 432 ppm. During W and NREM sleep power spectra were not changed significantly. Results indicate that the changes of EEG are a sensitive measure of the effects of toluene on the central nervous system (CNS).

Decrease in timed balance test scores with aging.

This study investigated whether 184 volunteers from 20 to 79 years of age could perform eight timed balance tests and examined the relationship between test performance and age. All subjects were able to balance with their feet together and eyes closed for 30 seconds. The ability to balance on the right and left legs did not differ significantly. Subjects over 60 years of age were unable to balance on one leg, particularly when their eyes were closed, for as long a period as younger subjects. The Pearson product-moment and Spearman correlations of age and duration of one-legged balance were -.65 and -.71 (eyes opened) and -.79 and -.75 (eyes closed). The findings suggest that when timed balance tests are performed as a part of a patient's neurologic examination, the results should be interpreted in light of the patient's age. Information is provided to assist in this interpretation.

Prednisone when used as treatment for rejection correlates with poor outcome.

Since January 1974, 195 of 202 (95%) renal transplants have been performed on blacks at the Howard University Hospital Transplant Center. Hypertension is the most common cause of end-stage renal disease (ESRD) at this center (57%). The immunosuppressive regimens utilized were divided into four eras. The first era (1974-1980) consisted of the prophylactic administration of prednisone, Imuran (AZA), and Minnesota antilymphocyte globulin (MAG) with high prednisone dosage used to treat rejection. One-year, two-year, and five-year patient survival rates were 59% 54%, and 41%, respectively. Graft survival rates for the same period were 53%, 47%, and 36%. In the second era (1980-1983), the same immunoprophylaxis was used but only MAG was used to reverse rejection. One-year and two-year patient survival rates were 90% and 84%. Graft survival rates for the same period were 72% and 64%. When era 1 is compared with era 2, statistically significant improvement in patient survival is evident (P less than 0.005). Graft survival rates are statistically significant for one-year graft survival (P less than 0.05). In the third era (1983-1986), cyclosporine was the principal immunosuppressive agent used along with prednisone. Rejection in this era was treated by adjusting the cyclosporine dose to keep the level between 100 ng to 150 ng per mL and in addition to high prednisone. One-year patient survival and graft survival rates were 83% and 55%, respectively. The fourth era began April 1986 and was initiated because of previous bad experiences with high doses of prednisone to treat rejection in era 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Streptococcus grouping latex kits: evaluation of five commercially available examples.

This study compares a recently introduced latex agglutination test for the serogrouping of beta-haemolytic streptococci against four internationally used commercial kits. The new kit is Prolex-Blue (Pro-Lab Diagnostics) and the comparators are Streptex (Murex), PathoDx (DPC), Streptococcus Grouping kit (Oxoid) and Prolex-White (Pro-Lab Diagnostics). A total of 302 consecutive clinical isolates are tested against all five kits, following the individual manufacturer's protocol, for both accuracy and speed. In addition, the data produced permits determination of the strengths or weaknesses of the kits against individual serotypes. Prolex-Blue proved to be both accurate and rapid, with a sensitivity of 99% and a specificity of 100%. Furthermore, average time to agglutination was substantially less than achieved by three of the other four kits evaluated.

Development of patient-specific molecular imaging phantoms using a 3D printer.

PURPOSE: The aim of the study was to investigate rapid prototyping technology for the production of patient-specific, cost-effective liquid fillable phantoms directly from patient CT data. METHODS: Liver, spleen, and kidney volumes were segmented from patient CT data. Each organ was converted to a shell and filling holes and leg supports were added using computer aided design software and prepared for printing. Additional fixtures were added to the liver to allow lesion inserts to be fixed within the structure. Phantoms were printed from an ultraviolet curable photopolymer using polyjet technology on an Objet EDEN 500V 3D printer. RESULTS: The final print material is a clear solid acrylic plastic which is watertight, rigid, and sufficiently durable to withstand multiple assembly and scanning protocols. Initial scans of the phantoms have been performed with Tc-99m SPECT and F-18 PET/CT. CONCLUSIONS: The organ geometry showed good correspondence with anatomical references. The methodology developed can be generally applied to other anatomical or geometrical phantoms for molecular imaging.

Monte Carlo verification of polymer gel dosimetry applied to radionuclide therapy: a phantom study.

This study evaluates the dosimetric performance of the polymer gel dosimeter 'Methacrylic and Ascorbic acid in Gelatin, initiated by Copper' and its suitability for quality assurance and analysis of I-131-targeted radionuclide therapy dosimetry. Four batches of gel were manufactured in-house and sets of calibration vials and phantoms were created containing different concentrations of I-131-doped gel. Multiple dose measurements were made up to 700 h post preparation and compared to equivalent Monte Carlo simulations. In addition to uniformly filled phantoms the cross-dose distribution from a hot insert to a surrounding phantom was measured. In this example comparisons were made with both Monte Carlo and a clinical scintigraphic dosimetry method. Dose-response curves generated from the calibration data followed a sigmoid function. The gels appeared to be stable over many weeks of internal irradiation with a delay in gel response observed at 29 h post preparation. This was attributed to chemical inhibitors and slow reaction rates of long-chain radical species. For this reason, phantom measurements were only made after 190 h of irradiation. For uniformly filled phantoms of I-131 the accuracy of dose measurements agreed to within 10% when compared to Monte Carlo simulations. A radial cross-dose distribution measured using the gel dosimeter compared well to that calculated with Monte Carlo. Small inhomogeneities were observed in the dosimeter attributed to non-uniform mixing of monomer during preparation. However, they were not detrimental to this study where the quantitative accuracy and spatial resolution of polymer gel dosimetry were far superior to that calculated using scintigraphy. The difference between Monte Carlo and gel measurements was of the order of a few cGy, whilst with the scintigraphic method differences of up to 8 Gy were observed. A manipulation technique is also presented which allows 3D scintigraphic dosimetry measurements to be compared to polymer gel dosimetry measurements without generating misleading errors due to the limited spatial resolution.