Dopamine depletion and in vivo binding of PET D1 receptor radioligands: implications for imaging studies in schizophrenia.

Recent positron emission tomography (PET) studies have assessed the level of dopamine (DA) D1 receptors in the prefrontal cortex (PFC) in patients with schizophrenia and have generated contradictory findings. In the PFC of patients with schizophrenia, the binding potential (BP) of [11C]NNC 112 has been reported as increased, while the BP of [11C]SCH 23390 was reported as decreased or unchanged. In this study, the effect of acute and subchronic DA depletion on the in vivo binding of [11C]NNC 112 and [3H]SCH 23390 was evaluated in rats. Acute DA depletion did not affect [11C]NNC 112 in vivo binding, but paradoxically decreased [3H]SCH 23390 in vivo binding. Subchronic DA depletion was associated with increased [11C]NNC 112 in vivo binding and decreased [3H]SCH 23390 in vivo binding. Together, these data demonstrate that the in vivo binding of these radiotracers is differentially affected by changes in endogenous DA tone, and suggest that alterations in the binding of these tracers in the PFC of patients with schizophrenia might reflect changes in D1 receptors secondary to sustained deficit in prefrontal DA function.     

Human biodistribution and dosimetry of iodine-123-fluoroalkyl analogs of β-CIT

Two new N-ω-fluoroalkyl analogs of [¹²³I]2β-carbomethoxy-3β-(4-iodophenyl)tropane ([¹²³I]β-CIT), the fluoroethyl and fluoropropyl compounds ([¹²³I]FE-CIT and [¹²³I]FP-CIT, respectively), have been shown to have faster kinetics and better selectivity for the dopamine transporter than [¹²³I]β-CIT. We examined the organ biodistribution and radiation safety of these two compounds in six healthy volunteers who received an injection with each of the two compounds 2 weeks apart. Data were obtained on the Strichman 860 whole-body scanner. Transmission scans were obtained in all subjects prior to the injection of the radiotracer with a line source and used to derive organ-specific attenuation correction factors. Whole-body planar images were acquired every hour for the first 6 h, and at 24 h. Attenuation-corrected regional conjugate counts were converted into units of activity using a calibration factor obtained for each subject by dividing whole-body conjugate decay-corrected counts from the first acquisition by the injected activity. Radiation dose estimates were on average higher for [¹²³I]CIT-FE than for [¹²³I]CIT-FP, with the lower large intestine receiving the highest exposure: 0.15±13% mGy/MBq (mean ±COV) and 0.12±14% mGy/MBq for [¹²³I]FE-CIT and [¹²³I]FP-CIT, respectively, followed by the upper large intestine and the spleen. Received 7 May and in revised form 7 August 1997     

Using sensitivity analysis to validate the predictions of a biomechanical model of bite forces.

Biomechanical modelling has become a very popular technique for investigating functional anatomy. Modern computer simulation packages make producing such models straightforward and it is tempting to take the results produced at face value. However the predictions of a simulation are only valid when both the model and the input parameters are accurate and little work has been done to verify this. In this paper a model of the human jaw is produced and a sensitivity analysis is performed to validate the results. The model is built using the ADAMS multibody dynamic simulation package incorporating the major occlusive muscles of mastication (temporalis, masseter, medial and lateral pterygoids) as well as a highly mobile temporomandibular joint. This model is used to predict the peak three-dimensional bite forces at each teeth location, joint reaction forces, and the contributions made by each individual muscle. The results for occlusive bite-force (1080N at M1) match those previously published suggesting the model is valid. The sensitivity analysis was performed by sampling the input parameters from likely ranges and running the simulation many times rather than using single, best estimate values. This analysis shows that the magnitudes of the peak retractive forces on the lower teeth were highly sensitive to the chosen origin (and hence fibre direction) of the temporalis and masseter muscles as well as the laxity of the TMJ. Peak protrusive force was also sensitive to the masseter origin. These result shows that the model is insufficiently complex to estimate these values reliably although the much lower sensitivity values obtained for the bite forces in the other directions and also for the joint reaction forces suggest that these predictions are sound. Without the sensitivity analysis it would not have been possible to identify these weaknesses which strongly supports the use of sensitivity analysis as a validation technique for biomechanical modelling.     

The treatment of self-injurious hand mouthing by using a multi-component intervention with individuals positioned in a small group

Hand mouthing is a common and often chronic behavior problem exhibited by individuals who have mental retardation. The prevalence of hand mouthing is highest among individuals who have profound multiple disabilities. Individuals with profound multiple disabilities also have extensive heath care needs. Treatment procedures designed to reduce rates of hand mouthing must be integrated with all other services care providers perform for these individuals. This study evaluated the effectiveness of a multi-component intervention designed to simultaneously increase the rate of engagement with alternative activities and reduce the rate of hand mouthing with a group of individuals who demonstrated chronic hand mouthing behavior. Two groups of three individuals who engaged in chronic hand mouthing served as participants. Results indicated that a single therapist could implement the intervention with up to three individuals simultaneously. Five of the six participants displayed reduced rates of hand mouthing and increased rates of engagement with alternative activities. These treatment effects were successfully maintained during daily treatment sessions conducted by direct care providers who were taught the intervention procedures. Usefulness of this strategy and future research needs are discussed.     

Augmentation of hypoxic pulmonary vasoconstriction by N-L-methyl-arginine in a rabbit model of thermal injury

We tested deeply anesthetized rabbits to determine if a burn acutely diminished the strength of hypoxic pulmonary vasoconstriction (HPV) and if this could be augmented by L-NMMA, a nitric oxide synthase inhibitor. We induced a burn using water heated to 75°C and assessed the strength of HPV as the difference in pulmonary vascular resistance during 100% and 13% O₂ ventilation. The rabbits then were randomized to receive 10 mg/kg L-NMMA (n = 8) or a placebo (n = 8). The strength of HPV decreased from 0.42 ± 0.11 mm Hg/mL/min preburn to 0.22 ± 0.11 mm Hg/mL/min postburn (P < .05). L-NMMA administration augmented HPV to a postburn value of 0.48 ± 0.014 mm Hg/mL/min (P < .05). We speculate that the loss of HPV following a burn could worsen ventilation to perfusion mismatch and thereby aggravate the hypoxia associated with burns. Augmentation of HPV might be a short-term goal during the acute stabilization of hypoxic burn patients.