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.     

Development of rostrocaudal dendritic bundles in rat thoracic spinal cord: analysis of cholinergic sympathetic preganglionic neurons.

Using monoclonal antibodies to choline acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP), we have analyzed the development of the dendritic bundles formed by cholinergic sympathetic preganglionic neurons (SPNs) in relationship to changes in the organization of glial fibers. In adult rat thoracic spinal cord, SPNs in the intermediolateral (IML) and central autonomic (CA) regions extend dendrites in both the mediolateral and rostrocaudal directions, forming a ladder-like pattern in horizontal sections of thoracic spinal cord. We report that, while the mediolateral dendrites form prenatally, the rostrocaudal dendritic bundles are not detected until at least a week later, during early postnatal life. The rostrocaudal dendrites develop rapidly during the first postnatal week, and achieve an adult-like pattern by postnatal day 14. The observed ontogenetic arrangements of dendritic bundles were correlated with the developing organization of astroglial processes with which they are intimately associated. While the appearance of mediolateral dendrites is consistent with the radial organization of glial in the embryonic spinal cord, the developmental time course of the rostrocaudal dendritic bundles coincides with the transformation of glial cells from this predominantly radial or transverse orientation to the randomly-oriented, stellate pattern of mature astrocytes. This temporal association suggests that ontogenetic changes in the organization of glial cells may contribute to the differential development of mediolateral and rostrocaudal dendritic patterns in the spinal cord.     

Relation between toxicity and carcinogenesis in the kidney: an heuristic hypothesis

Cellular toxicity and cellular carcinogenesis are closely linked. In the kidney, this relationship has been emphasized by the recent discovery of a number of putatively non-mutagenic chemicals that result in acute and chronic toxicity and ultimately in carcinogenesis, especially in the male rat. Many, but not all such compounds, result in renal PTE phagolysosomal overload. At the same time, known metabolites of other carcinogens, e.g., HCBD and FBPA, result in acute renal injury and/or necrosis, followed by chronic tubular disease, interstitial nephritis, and ultimately carcinogenesis. A series of cell mechanisms have been suggested that lead from acute cell injury to altered control of cell division. These mechanisms appear to involve ion deregulation, (especially [Ca2+]i) resulting from a variety of continued injuries, (e.g., oxidative stress from inflammatory cells) and ultimately leading to altered gene expression.     

Recruiting future neuroscientists: what asking the recruits can teach us.

Many different strategies are used to recruit students into scientific research careers, including neuroscience research. These strategies are rarely based on knowledge about students; instead, activities are selected based on their ease of implementation. The goal of the LEARN Project is to encourage high school students into mental health science research using the theme of learning and memory. One intervention the authors developed is five Web-based biographies introducing students to contemporary neuroscientist role models studying learning and memory. To guide the design of this intervention, the authors created a survey to determine where students obtain career information and who and what influences their career selection. In a convenience sample of 124 students, the authors found that almost all students use the Internet for information about careers, in addition to consulting family members and teachers. Students' career selections are influenced most by family members, teachers, and people already in the field. The most important factors students look for in their future career are money, fun, and a good match between current interests and future careers. The data affirm the value of outreach efforts that go beyond students to include a broader audience of parents and teachers who play a critical role in career selection.     

Dentists evaluate their patients: An empirical investigation of preferences

Dental treatment is a dyadic encounter. Yet research on the dentist-patient dyad has tended to focus on patient perceptions of dentist, to the neglect of dentist perceptions of patient. Previous theoretic and qualitative work on caregiver perceptions of patients suggested three dimensions of evaluation. Dentists (N=618) rated their patients on items taken from two prior studies. Dentists' responses were subjected to confirmatory factor analysis. The analysis substantiated the existence of three evaluative dimensions: compliance, tractability, and likability. Further analysis showed that the three dimensions formed a Guttman simplex, revealing a second-order factor of selectivity and allowing a classification of dentists on the basis of patient selectivity.This study was funded by a grant from the University of Connecticut Research Foundation.     

Preventive care: do we practice what we preach?

We used insurance claims from enrollees in the Rand Health Insurance Experiment to determine the amount of selected components of preventive care received by a representative sample of the non-aged population in the United States and to determine whether insurance coverage was an important determinant of that amount. Only 45 percent of infants received timely immunization for DPT and polio; 93 per cent received some well child care by 18 months of age. In the three-year experimental period, only 4 per cent of adults had a tetanus shot, 66 per cent of women aged 17-44 and 57 per cent aged 45-65 received a Pap smear, and 2 per cent of women aged 45-65 had a mammogram. Cost sharing was associated with even less preventive care: 60 per cent of children on the free plan and 49 per cent on cost sharing plans received preventive care of any type. For adults, women on the free plan received more preventive care of several kinds, and those aged 45-65 received more Pap smears than those on cost-sharing plans. Even with free care, most enrollees did not receive adequate preventive care. Thus, free care alone, while significant, is not a sufficient incentive to providing recommended levels of preventive care. The average per person insurance charge for increasing the amount of preventive care to a level consistent with that recommended would be $22 for a complete set of immunizations by age 18 months, $9 for a Pap smear every three years, and $97 for a Pap test and mammogram every three years.     

Local cerebral glucose metabolic rates in obsessive-compulsive disorder. A comparison with rates in unipolar depression and in normal controls

We studied 14 patients with obsessive-compulsive disorder (OCD) by positron emission tomography and the fluorodeoxyglucose method, looking for abnormalities in local cerebral metabolic rates for glucose in brain structures that have been hypothesized to function abnormally in OCD. These patients were compared with 14 normal controls and 14 patients with unipolar depression. The patients with unipolar depression and OCD did not differ in levels of anxiety, tension, or depression. In OCD, metabolic rates were significantly increased in the left orbital gyrus and bilaterally in the caudate nuclei. This was apparent on all statistical comparisons with both controls and unipolar depression. The right orbital gyrus showed at least a trend to an increased metabolic rate in all comparisons. The metabolic rate in the left orbital gyrus, relative to that in the ipsilateral hemisphere (orbital gyrus/hemisphere ratio), was significantly elevated compared to controls and subjects with unipolar depression, and stayed high even with successful drug treatment. Though it was in the normal range in the morbid state, with improvement in OCD symptoms after drug treatment, the caudate/hemisphere metabolic ratio increased uniformly and significantly bilaterally. This ratio did not increase in patients who did not respond to treatment. Thus, OCD showed cerebral glucose metabolic patterns that differed from controls in both the symptomatic and recovered states.