A mathematical model of optimized radioiodine-131 therapy of Graves' hyperthyroidism

Background

The current status of radioiodine-131 (RaI) dosimetry for Graves' hyperthyroidism is not clear. Recurrent hyperthyroidism and iatrogenic hypothyroidism are two problems which interact such that trying to solve one leads to exacerbation of the other. Optimized RaI therapy has therefore begun to be defined just in terms of early hypothyroidism (ablative therapy) as physicians have given up on reducing hypothyroidism.

Methods

Optimized therapy is evaluated both in terms of the greatest separation of cure rate from hypothyroidism rate (non-ablative therapy) or in terms of early hypothyroidism (ablative therapy) by mathematical modeling of outcome after radioiodine and critically discussing the three common methods of RaI dosing for Graves' disease.

Results

Cure follows a logarithmic relationship to activity administered or absorbed dose, while hypothyroidism follows a linear relationship. The effect of including or omitting factors in the calculation of the administered I–131 activity such as the measured thyroid uptake and effective half-life of RaI or giving extra compensation for gland size is discussed.

Conclusions

Very little benefit can be gained by employing complicated methods of RaI dose selection for non-ablative therapy since the standard activity model shows the best potential for cure and prolonged euthyroidism. For ablative therapy, a standard MBq/g dosing provides the best outcome in terms of cure and early hypothyroidism.     

Persistent tubular conduction in vacuolated amphibian skeletal muscle following osmotic shock

The transverse (T-)tubules primarily function in conducting the action potentials that initiate excitation– contraction coupling in skeletal muscle but may additionally subserve longer-term roles in volume regulation, membrane fusion and other trafficking processes. Osmotic shock thus both electrically detaches the T-tubules from surface membrane (‘detubulation’) and produces tubular vacuolation. The present experiments separated these effects. An established, reference osmotic shock protocol that exposed muscles to Ca²⁺/Mg²⁺-Ringer and gradual cooling to 10°C after 18 min in glycerol–Ringer accomplished significant detubulation (77.5 ± 13.15%, mean ± SEM; n = 4). In contrast, a test protocol conducted entirely at room temperature using Mg²⁺-rather than Ca²⁺/Mg²⁺-Ringer yielded reduced (P < 0.05, post hoc Duncan's multiple range test) detubulation indices (1.67 ± 1.67%, n = 6) statistically indistinguishable from findings in fibres spared osmotic shock. Yet both osmotic shocks caused a formation of closed vacuoles, demonstrated by Sulphorhodamine B trapping, that occupied statistically similar fractions of total fibre volume (reference procedure: 14.38 ± 2.7%, n = 6; test procedure: 13.36 ± 2.00%, n = 22) in turn higher than determinations in control fibres (P < 0.05). The findings reconcile reports associating detubulation with vacuolation in osmotically shocked muscle [S. Nik-Zainal et al. (1999) J Muscle Res Cell Motil 20: 45–53; K.N. Khan et al. (2000) J Muscle Res Cell Motil 21: 79–90] with the persistence of tubular electrical activity in extensively vacuolated amphibian fibres following fatigue [J. Lannergren and H. Westerblad (1987) Acta Physiol Scand 129: 311–318; J. Lannergren et al. (1999) J Muscle Res Cell Motil 20: 19–32]. Furthermore test protocols produced higher densities of open vacuoles (13.38 ± 2.33%, n = 9) than did reference protocols (6.66 ± 1.63%, n = 20) contrary to their possible involvement in the electrophysiological changes. Abolition of tubular electrophysiological activity thus either follows or is independent of tubular vacuolation whilst sharing some of its underlying osmotic mechanisms. This revised version was published online in July 2006 with corrections to the Cover Date.     

Melanotropic activity in extrahypophyseal regions of rodent brain: effect of age, hormones, and drugs.

Two or more melanotropic peptides are present in extrahypophyseal regions of mammalian brain. Previous studies showed that extrahypophyseal melanotropic activity is not influenced by hypophysectomy, adrenalectomy, or exogenous glucocorticoid. The present study investigated the possible influence of the following factors on the level of melanotropic activity in whole brain, cerebral cortex, cerebellum, midbrain, and brainstem of mouse and rat: age, sex, starvation; and of the following hormones or drugs administered by the intraperitoneal or intracerebral route: norepinephrine, dihydroxyphenylalanine, pargyline, 6-hydroxy-dopamine, alpha-methyltyrosine methyl ester, reserpine, acetylcholine, pilocarpine, atropine, serotonin, p-chlorophenylalanine, pentobarbital, pentylenetetrazol, insulin, melatonin, and cycloheximide. Only age influenced extrahypophyseal melanotropic activity. The activity per unit of tissue wet weight or of tissue protein increased in all regions progressively from birth to 1 yr of age. Extrahypophyseal melanotropic activities perunit wet weight of tissue at 50 wk averaged 4.3 times those at birth. When brain of adult rodents was fractionated by differential centrifugation, the major proportion of melanotropic activity was recovered in myelin (27-35 percent), nerve endings (20-22 percent), and mitochondria (25-30 percent). The lower activity in newborn brain resulted not onlyfrom absence of a myelin fraction, but also from lower activity at birth in nerve endings and mitochondria.     

Identification and characterization of aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus with partial vasopressin response

Congenital nephrogenic diabetes insipidus (NDI) is a rare disease caused most often by mutations in the vasopressin V2 receptor (AVPR2). We studied a family which included a female patient with NDI with symptoms dating from infancy. The patient responded to large doses of desmopressin (dDAVP) which decreased urine volume from 10 to 4 I/day. Neither the parents nor the three sisters were polyuric. The patient was found to be a compound heterozygote for two novel recessive point mutations in the aquaporin-2 (AQP2) gene: L22V in exon 1 and C181W in exon 3. Residue Cys181 in AQP2 is the site for inhibition of water permeation by mercurial compounds and is located near to the NPA motif conserved in all aquaporins. Osmotic water permeability (Pf) in Xenopus oocytes injected with cRNA encoding C181W-AQP2 was not increased over water control, while expression of L22V cRNA increased the Pf to approximately 60% of that for wild-type AQP2. Co-injection of the mutant cRNAs with the wild-type cRNA did not affect the function of the wild-type AQP2. Immunolocalization of AQP2-transfected CHO cells showed that the C181W mutant had an endoplasmic reticulum-like intracellular distribution, whereas L22V and wild-type AQP2 showed endosome and plasma membrane staining. Water permeability assays showed a high Pf in cells expressing wild-type and L22V AQP2. This study indicates that AQP2 mutations can confer partially responsive NDI.      

Reciprocal effect of Waardenburg syndrome mutations on DNA binding by the Pax-3 paired domain and homeodomain

The Pax-3 protein contains two DNA-binding domains, a paired domain and a homeodomain. Mutations in Pax-3 cause Waardenburg syndrome (WS) in humans and the mouse Splotch (Sp) phenotype. In the Sp-delayed mouse, a mutation in the Pax-3 paired domain (G9R) abrogates the DNA-binding activity of both the paired domain and the homeodomain, suggesting that they may functionally interact. To investigate this possibility further, we have analyzed the DNA-binding properties of additional point mutants in the Pax-3 paired domain and homeodomain that occur in WS patients (F12L, N14H, G15S, P17L, R23L, G48A, S51F and G66D in the paired domain, V47F and R53G in the homeodomain), the Pax-1 un mutation (G15A) and a substitution associated with Peters' anomaly in the PAX-6 gene (R23G). Within the paired domain, seven of 10 mutations were found to abrogate DNA-binding by the paired domain. Remarkably, these seven mutations also affected DNA binding by the homeodomain, causing either a complete loss (P17L and G66D), a reduction (R23G, R23L, G15S and G15A) or an increase in DNA-binding activity (N14H). In addition, the effect of paired domain mutations occurred at the level of monomer formation by the homeodomain, while the dimerization potential of this domain seemed unaffected in mutants where it could be analyzed. Furthermore, while both homeodomain mutations were found to abolish DNA binding by this domain, the R53G mutation also abrogated DNA binding by the paired domain. The important observation that independent mutations in either domain can affect DNA binding by the other in the intact Pax- 3 protein strongly suggests that the two domains are not functionally independent but bind DNA through cooperative interactions. Modeling the deleterlous mutations on the three-dimensional structure of the paired domain of Drosophila Prd shows that these mutations cluster at the DNA interface, thus suggesting that a series of DNA contacts are essential for DNA binding by both the paired domain and the homeodomain of Pax-3.      

Gastrointestinal imaging: a systems analysis comparing digital and conventional techniques

OBJECTIVE: The purpose of this study was to compare digital and conventional methods of gastrointestinal imaging based on the cost of image storage and estimated overall costs, radiation exposure to the patient, and duration of the examination. MATERIALS AND METHODS: Our study sample consisted of 128 patients who underwent conventional gastrointestinal studies (64 double-contrast upper gastrointestinal examinations and 64 double-contrast barium enemas) and 139 patients who underwent digital gastrointestinal studies (66 double-contrast upper gastrointestinal examinations and 73 double-contrast barium enemas). The number of images and films for each study was recorded, and the mean cost of image storage and the estimated overall costs for digital versus conventional studies were calculated. Both the duration of fluoroscopy and the time from start to completion of the study were obtained from our radiology information system. From these data, we calculated mean radiation exposure to the patient and the duration of the examination. Finally, referring physicians completed a questionnaire about their level of satisfaction with paper prints generated from digital gastrointestinal studies. RESULTS: When digital studies were compared with conventional studies, the mean cost of image storage decreased by 45% and the estimated overall 10-year costs decreased by 8%. The mean number of spot images increased by 8% for upper gastrointestinal examinations and by 25% for barium enema examinations, whereas the mean duration of fluoroscopy decreased by 4% and by 10%, respectively. As a result, radiation exposure to patients increased by only 2%, a difference that did not approach statistical significance. Finally, the mean duration of examinations decreased by 24% for upper gastrointestinal examinations and by 33% for barium enemas. Approximately 85% of the physicians who completed the questionnaires indicated that they reviewed the paper prints generated from digital studies and that they would like to continue receiving them. CONCLUSION: Digital gastrointestinal imaging systems are associated with higher initial costs than conventional systems, but the long-term costs of these digital imaging systems are slightly less because of the lower cost of image storage, and radiation exposure to patients is comparable. The shorter duration of digital examinations is a potential benefit of this technology, allowing improved patient throughput. Finally, referring physicians have a high level of satisfaction with paper prints generated from digital imaging.     

Neuromuscular transmission failure due to common krait (Bungarus caeruleus) envenomation

Neurophysiological studies were performed in 12 patients with neuromuscular paralysis due to envenomation by the common krait (Bungarus caeruleus). All patients presented with an acute, reversible, oculofaciobulbar paresis. In addition, 7 patients had weakness of the limb muscles and 4 required assisted mechanical ventilation. Neurophysiological abnormalities included: (1) a reduction in the amplitude of the median-elicited compound muscle action potential (CMAP) in 4 patients; and (2) a decremental response (>10%) to 3-Hz repetitive nerve stimulation (RNS) in 4 patients. With 1 exception, these abnormalities were noted only in clinically weak muscles. The administration of edrophonium to 6 patients produced an insignificant increase in CMAP amplitudes as well as partial (not significant) improvement in the decremental response to 3-Hz RNS. Neurophysiological studies were performed in 2 patients before and after the administration of 20 mL of polyvalent antivenom. A decrease in amplitude of the median-elicited CMAP amplitude occurred after the administration of antivenom. In 1 patient, administered 100 mL of antivenom, the median-elicited CMAP amplitude increased and the decrement to 3-Hz RNS decreased. Neurophysiological studies can provide useful information regarding the nature, severity, and therapy of the neuroparalytic syndrome of krait envenomation.     

PREVALENCE OF MICROALBUMINURIA IN NON-INSULIN-DEPENDENT DIABETES MELLITUS

The prevalence of microalbuminuria was assessed in 50 patients of non-insulin dependent diabetes mellitus. The mean age of patients was 52.1 ± 11.6 years and the duration of diabetes was 8.3 ± 6.8 years. Twenty (40%) patients had microalbuminuria. Microalbuminuria was more common in patients with a longer duration of diabetes (more than 5 years), a poor glycaemic control, and higher systolic blood pressure.KEY WORDS: Microalbuminuria, Diabetes mellitus, Diabetic nephropathy, Chronic renal failure