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.     

Effect of High Doses of Radiation on Human Neutrophil Chemotaxis, Phagocytosis and Morphology

Human neutrophils were exposed to varying amounts of ionizing radiation up to 1,000,000 rad and evaluated as to their ability to respond to chemotactic stimuli and phagocytize and kill bacteria. Striking morphologic and functional resistance to radiation was apparent. At doses up to 5,000 rad there was little or no impairment of chemotaxis. As the dosage increased to 50,000 rad, chemotaxis decreased to approximately 50% of nonirradiated control values. At very high doses of radiation (250,000 to 1,000,000 rad) neutrophils failed to respond significantly to chemotactic stimuli. Effects of radiation as measured by phagocytosis and the degree of ultrastructural change paralleled the chemotaxis results.     

Brain natriuretic peptide and HIV-related cardiomyopathy

The brain natriuretic peptide (BNP) assay is a new, relatively inexpensive, and simple test that has the potential to be an early, cost-effective, and reliable marker for HIV-related cardiomyopathy. We report 1 case of HIV-related cardiomyopathy and 10 cases of of HIV infection with unknown heart disease in which we measured BNP levels and performed echocardiography. We found a significant inverse relationship between BNP and left ventricular function in these patients. Further basic and epidemiologic research on BNP measurement for the detection of HIV-related cardiomyopathy is needed to support these findings, which if confirmed, could have important clinical and public health implications.     

LH syndrome and brain catecholamine levels after lesions of the nigrostriatal bundle

Lesions of the nigrostriatal bundle (NSB), whose fibers pass through the medial portions of the internal capsule and the immediately adjacent lateral hypothalamus (LH), produced a more severe aphagia, adipsia, and disturbance of water regulation than did lesions of the medial forebrain bundle (MFB). When deprived of food, animals with NSB lesions drank significantly less than controls and animals with MFB lesions. NSB lesions also produced greater decreases in telencephalic content of the catecholamines than MFB lesions, while the reverse was true for serotonin. Water intake during food deprivation was highly correlated with telencephalic catecholamine levels in animals with NSB lesions. Thus, the inability to regulate water intake in the absence of food, one of the characteristic and long lasting effects of the LH syndrome, appears to be due to destruction of the NSB and the consequent decline in telencephalic content of catecholamines.     

Endocrinology and paracrinology: Roles of growth factors during peri-implantation development

Several growth factor ligand and receptor gene products havebeen shown to play roles during preimplantation mammalian development.Genes for insulin-like growth factors (IGFs), transforming growthfactors (TGFs), fibroblast growth factor (FGF), platelet-derivedgrowth factor (PDGF) and receptors for insulin, IGF, PDGF, TGFand epidermal growth factor (EGF) are expressed by early embryosof several species including mouse, rat, cow and sheep. Rolesof growth factors during early development have been demonstratedby addition of purified growth factors to culture medium orby molecular genetic techniques that interfere with gene expression.In this way, it has been shown that successful development ofthe blastocyst is dependent on the action of epidermal growthfactor (EGF) and leukaemia inhibitory factor (LIF). Recent experimentsshow that both LIF and EGF stimulate secretion of urokinase-typeplasminogen activator (uPA) and gelatinase B/ matrix metalloproteinase-9(MMP-9) in day 7 mouse blastocyst outgrowths. At the same time,tissue inhibitors of MMPs (TIMPs) are also expressed by embryonic,decidual and uterine tissues during the implantation process.It appears that LIF may act directly or indirectly, by inducingthe expression of other cytokines, to regulate the temporaland spatial production and activity of proteases and proteaseinhibitors to create a favourable environment for implantation.     

Diagnostic specificity of a sandwich ELISA for Aspergillus-related diseases

A sandwich ELISA with specificity for a major antigen (Ag 7) of Aspergillus fumigatus has been compared with indirect ELISAs with use of crude antigenic (culture filtrate) extracts and found to have a sensitivity of 100% and specificity of 92.3% for antibody detection in sera of patients with allergic bronchopulmonary aspergillosis (ABPA) and aspergilloma. In the Ag 7 ELISA, all sera from groups with ABPA (21) and aspergilloma (15) had positive titers, and mean values for both these groups were significantly higher (p less than 0.001) than control levels. By comparison, in the indirect ELISAs, most sera of patients with ABPA were positive; the sensitivity was 81% to 90%, and the specificity was 87%. Sera from other disease groups including sera from 13 patients with farmer's lung, 16 with tuberculosis, and 10 individuals with positive prick test to either A. fumigatus or Alternaria alternata were also tested by both types of assay. Up to five of these sera elicited significant positive results in the indirect ELISA, and although two sera were also positive in the Ag 7-specific ELISA, these latter titers were both below the range of values for the sera from patients with ABPA. With the use of an IgG calibration curve, the sensitivity of the assay was determined as within the range of 1 to 10 microgram of specific IgG antibody per milliliter. The Ag 7-specific ELISA is therefore a highly specific, sensitive assay for antibody detection in Aspergillus-related diseases.     

Thalamocortical specificity and the synthesis of sensory cortical receptive fields

A persistent and fundamental question in sensory cortical physiology concerns the manner in which receptive fields of layer-4 neurons are synthesized from their thalamic inputs. According to a hierarchical model proposed more than 40 years ago, simple receptive fields in layer 4 of primary visual cortex originate from the convergence of highly specific thalamocortical inputs (e.g., geniculate inputs with on-center receptive fields overlap the on subregions of layer 4 simple cells). Here, we summarize studies in the visual cortex that provide support for this high specificity of thalamic input to visual cortical simple cells. In addition, we review studies of GABAergic interneurons in the somatosensory "barrel" cortex with receptive fields that are generated by a very different mechanism: the nonspecific convergence of thalamic inputs with different response properties. We hypothesize that these 2 modes of thalamocortical connectivity onto subpopulations of excitatory and inhibitory neurons constitute a general feature of sensory neocortex and account for much of the diversity seen in layer-4 receptive fields.     

Dental abnormalities in individuals with pathogenic germline variation in DICER1

Pathogenic germline variation in the microRNA processing gene DICER1 gives rise to an autosomal dominant, tumor‐predisposition disorder. Conditional deletion of Dicer1 in murine dental epithelium shows that it controls tooth patterning, size, number, and shape. The human dental phenotype of people with germline pathogenic variation in DICER1 is unknown. DICER1‐carriers (n = 57) and family controls (n = 55) were evaluated at the NIH Clinical Center dental clinic as part of a comprehensive medical evaluation. Digital panoramic radiographs, bite‐wing radiographs, and oral photographs were collected. A single observer, blind to DICER1 status, reviewed the dental records and determined the presence or absence of 11 dental characteristics as described in the clinic notes, radiographs, or oral photographs. Subjective phenotypes were reviewed on radiographs by two examiners (blind to DICER1 status) for the presence or absence of the dental characteristics to reduce inconsistencies. By simple association, bulbous crown, periodontitis, and taurodontism were all significant (p < .05). Logistic regression with chi‐square maximum likelihood estimates showed that bulbous crown and periodontitis remained significant. Recognition of these phenotypes may aid identification of individuals and families at risk for DICER1‐associated neoplasms. These findings may also guide dental care for individuals with germline DICER1 pathogenic variation.