166Ho-DOTMP radiation-absorbed dose estimation for skeletal targeted radiotherapy.

166Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonate (DOTMP) is a tetraphosphonate molecule radiolabeled with 166Ho that localizes to bone surfaces. This study evaluated pharmacokinetics and radiation-absorbed dose to all organs from this beta-emitting radiopharmaceutical. METHODS: After two 1.1-GBq administrations of 166Ho-DOTMP, data from whole-body counting using a gamma-camera or uptake probe were assessed for reproducibility of whole-body retention in 12 patients with multiple myeloma. The radiation-absorbed dose to normal organs was estimated using MIRD methodology, applying residence times and S values for 166Ho. Marrow dose was estimated from measured activity retained after 18 h. The activity to deliver a therapeutic dose of 25 Gy to the marrow was determined. Methods based on region-of-interest (ROI) and whole-body clearance were evaluated to estimate kidney activity, because the radiotracer is rapidly excreted in the urine. The dose to the surface of the bladder wall was estimated using a dynamic bladder model. RESULTS: In clinical practice, gamma-camera methods were more reliable than uptake probe-based methods for whole-body counting. The intrapatient variability of dose calculations was less than 10% between the 2 tracer studies. Skeletal uptake of 166Ho-DOTMP varied from 19% to 39% (mean, 28%). The activity of 166Ho prescribed for therapy ranged from 38 to 67 GBq (1,030-1,810 mCi). After high-dose therapy, the estimates of absorbed dose to the kidney varied from 1.6 to 4 Gy using the whole-body clearance-based method and from 8.3 to 17.3 Gy using the ROI-based method. Bladder dose ranged from 10 to 20 Gy, bone surface dose ranged from 39 to 57 Gy, and doses to other organs were less than 2 Gy for all patients. Repetitive administration had no impact on tracer biodistribution, pharmacokinetics, or organ dose. CONCLUSION: Pharmacokinetics analysis validated gamma-camera whole-body counting of 166Ho as an appropriate approach to assess clearance and to estimate radiation-absorbed dose to normal organs except the kidneys. Quantitative gamma-camera imaging is difficult and requires scatter subtraction because of the multiple energy emissions of 166Ho. Kidney dose estimates were approximately 5-fold higher when the ROI-based method was used rather than the clearance-based model, and neither appeared reliable. In future clinical trials with 166Ho-DOTMP, we recommend that dose estimation based on the methods described here be used for all organs except the kidneys. Assumptions for the kidney dose require further evaluation.     

Hypercalcemia associated with dysregulation of 1,25-dihydroxyvitamin D in arthritis.

We describe an elderly man who presented with hypercalcemia associated with suppressed intact parathyroid hormone (PTH) levels. Despite renal insufficiency the circulating 1,25-dihydroxyvitamin D (1,25(OH)2D) was in the upper part of the normal range. Known causes of hypercalcemia were absent and mild hypercalcemia with suppression of intact PTH persisted until after bilateral hip replacement for severe arthritis (1 year after presentation). After hip replacement the ionized calcium normalized, intact PTH normalized, and 1,25(OH)2D decreased markedly. We believe the abnormalities in mineral homeostasis were related to production of 1,25(OH)2D by inflammatory mononuclear cells associated with arthritis.     

Deleterious effects of oxygen during extracorporeal circulation for the microcirculation in vivo.

OBJECTIVE: Clinical complications arising from extracorporeal circulation (ECC) have been linked to disturbances in the microcirculation. Hyperoxia, a mainstay of supportive treatment, is clinically used for a variety of pathological states. In previous in vivo animal experiments we found increased leukocyte/endothelial (L/E) cell interaction following ECC due to oxygen derived free radicals. This study was carried out to investigate the link between arterial pO2 during ECC and the potential damage to the microcirculation, supposedly caused by oxygen derived radicals. METHODS: Intravital fluorescence microscopy was used on the dorsal skinfold chamber preparation in syrian golden hamsters. ECC was introduced via a micro-rollerpump (0.7 ml/min) and a 60 cm silicon tube (1 mm inner diameter) shunted between the carotid artery and the jugular vein after application of 300 IE Heparin/kg/bw. Experiments were performed in chronically instrumented, awake animals (age: 10-14 weeks, weight: 65-75 g). Control inspired room air, experimental group 1 inspired 100% oxygen, group 2 received 100% oxygen and 2000 IE of Heparin i.v. (n=7/group), that releases endothelial bound superoxide dismutase, a natural scavenger of oxygen derived free radicals in the hamster. Results: Normobaric inhalation of 100% oxygen increased arterial pO2 from 64+/-8.1 mmHg to 512+/-124 mmHg (P<0.05 vs. baseline). ECC under 100% oxygen reduced functional capillary density (FCD) to 70% of baseline values 8 h after ECC (P<0.05). Adherent leukocytes in postcapillary venules and arterioles increased significantly (P<0.05). 2000 IE Heparin prevented the reduction in FCD and decreased the number of adherent leukocytes. CONCLUSIONS: Reduction in FCD, increased leukocyte adherence to the microvascular endothelium of postcapillary venules and arterioles under hyperoxia compared to ECC under room air conditions, demonstrates harmful effects of oxygen during ECC in vivo. A high dose of Heparin enhances functional capillary density, thus attenuating the microvascular dysfunction/damage in the period after ECC.     

Behavioural Problems in Children with Infantile Hydrocephalus

The occurrence of behavioural problems in a population-based series of children with infantile hydrocephalus (non-spina bifida) was analysed, using parent questionnaires. Children with both infantile hydrocephalus and mental retardation had significantly more behavioural problems compared with those with no mental retardation and controls. Inattentiveness and hyperactivity were particularly typical. No differences were found between children with infantile hydrocephalus and no mental retardation and the control group.     

Combined chemotherapy with m-amsacrine in high-risk patients with acute non-lymphocytic leukemia

Thirteen patients (7 male, 9 female) aged 22-71 years (means = 55 years) with acute non-lymphocytic leukemia and contraindications for anthracyclin therapy were treated with combined chemotherapy using m-amsacrine primarily or in relapse. The main reasons for avoiding cardiotoxic substances were overt cardiac insufficiency and former administration of daunorubicin with more than 540 mg/m2 body surface area. Amsacrine was combined with 6-thioguanine, VP 16-213 and cytosine arabinoside in conventional or high dosage. Eight out of 13 patients (62%) achieved complete remission after one or two courses of chemotherapy. One patient showed partial remission and could be brought into complete remission with another chemotherapy using high-dose ara-C and mitoxantrone. Three patients died in aplasia after chemotherapy and 1 other patient had to be regarded as a complete non-responder. Remission duration and survival time for the 8 successfully-treated patients so far is 1-12 months; however, medians have not yet been reached, since only one of the eight patients relapsed after 6 months of complete remission. These data indicate a high efficacy of m-amsacrine in combined chemotherapy for acute non-lymphocytic leukemia in high-risk patients with contraindications for anthracyclins.     

Different types of aortic stenosis and simulation of their morphological-hydrodynamic interdependence--in vitro study with allografts and stenotic valve models

Biological valves display a dependence of valve resistance and valve area on flow and a phase shift between systolic flow through the valves and pressure difference across the valves. The pressure-flow relations of stenosed valves raise questions about the "best measure of stenosis". There is a need for quantitative evaluation of the hydrodynamic performance of homografts and allografts. In the present paper, we report on in vitro studies of the hydrodynamic behavior of homografts from human donors, allografts from different animal species as well as three valve models. Valve model I was designed to simulate flow-dependence of valve area, valve model II was designed to simulate restricted valve opening independent of flow, and valve model III was designed to simulate a flow-dependent movement of valve root in flow direction. Among other aspects, the effect of increased viscosity of the test fluid on the pressure difference and the effects of water absorption by valve tissue on valve characteristics were investigated. The results of the present studies clearly indicate that any biological valve may be modelled as a serial connection of a model I type valve and a model II type valve. From the results, the dependence of the characteristic pressure-flow relationship of a valve on valve size and valve distensibility can be clearly seen and the clinical significance of the characteristic coefficients of the pressure-flow relationship of a valve can be elucidated. Further, it was shown that the characteristic phase shift between flow and pressure difference displayed by biological valves is due to their movable valve plane similar to that of valve model III.     

Survival of Acinetobacter baumannii on dry surfaces.

Acinetobacter spp. have frequently been reported to be the causative agents of hospital outbreaks. The circumstances of some outbreaks demonstrated the long survival of Acinetobacter in a dry, inanimate environment. In laboratory experiments, we compared the abilities of five Acinetobacter baumannii strains, three Acinetobacter sp. strains from the American Type Culture Collection (ATCC), one Escherichia coli ATCC strain, and one Enterococcus faecium ATCC strain to survive under dry conditions. Bacterial solutions of the 10 strains were inoculated onto four different material samples (ceramic, polyvinyl chloride, rubber, and stainless steel) and stored under defined conditions. We investigated the bacterial counts of the material samples immediately after inoculation, after drying, and after 4 h, 1 day, and 1, 2, 4, 8, and 16 weeks of storage. A statistical model was used to distribute the 40 resulting curves among four types of survival curves. The type of survival curve was significantly associated with the bacterial strain but not with the material. The ability of the A. baumannii strains to survive under dry conditions varied greatly and correlated well with the source of the strain. Strains isolated from dry sources survived better than those isolated from wet sources. An outbreak strain that had caused hospital-acquired respiratory tract infections survived better than the strains from wet sources, but not as well as strains from dry sources. Resistance to dry conditions may promote the transmissibility of a strain, but it is not sufficient to make a strain an epidemic one. However, in the case of an outbreak, sources of Acinetobacter must be expected in the dry environment.