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.     

Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand

Benign intracranial hypertension (BIH) is reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (rhGH). Three males and one female, aged between 10.5 and 14.2 y, developed intracranial hypertension within 2 weeks to 3 months of starting treatment. A national database, OZGROW, has been prospectively collecting data on all 3332 children treated with rhGH in Australia and New Zealand from January 1986 to 1996. The incidence of BIH in children treated with growth hormone (GH) is small, 1.2 per 1000 cases overall, but appears to be greater with biochemical GHD (<10IUml ^-1), i.e. 6.5/1000 (3 in 465 cases), relative risk 18.4, 95% confidence interval 1.9-176.1, than in all other children on the database. The incidence in patients with Turner's syndrome was 2.3/1000 (1 in 428 cases). No cases in patients with partial GHD (10–20 IUml ^-1) or chronic renal failure were identified. Possible causative mechanisms are discussed. The authors'practice is now to start GH replacement at less than the usual recommended dose of 14IUm-² week^-1 in those children considered to be at high risk of developing BIH. Ophthalmological evaluation is recommended for children before and during the first few months following commencement of rhGH therapy and is mandatory in the event of peripheral or facial oedema, persistent headaches, vomiting or visual symptoms. The absence of papilledema does not exclude the diagnosis.     

O,O′-二烷基-O″-(5-取代-3-苯并噻吩乙腈肟)磷酸酯及硫代磷酸酯的合成

合成了18个O,O′-二烷基-O″-(5-取代-3-苯并噻吩乙腈肟)磷酸酯及硫代磷酸酯类化合物(Ⅰ_1～18)。初步杀螺试验结果表明,其中5个化合物,即Ⅰ_2,3,7,11,12有明显的杀螺增效作用。     

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.