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Risk prediction through integration of clinical variables and imaging data into a prognostic model can able to identify those factors with a high impact on patient outcome. The development of a prognostic model traditionally includes the evaluation of the independent contribution of variables with consideration of covarying factors that may confound risk stratification. Several methods and metrics are available to assess the performance of a prediction model. Traditional measures for binary and survival outcomes include the concordance (C) statistic for discriminative ability, and goodness-of-fit statistics for calibration. Different prognostic approaches, including variants of the C statistic for survival data, reclassification tables, net reclassification improvement, and integrated discrimination improvement have been recently proposed to evaluate the contribution of new markers when they are added to a defined risk model and to evaluate how these variables are able to change the class of risk of the patient and the resulting diagnostic and therapeutic managements. Moreover, decision-analytic measures including decision curves analysis have been introduced to assess the net benefit obtained by making clinical decisions based on model predictions. This review provides an overview of various metrics available for risk stratification using nuclear cardiology procedures, underlying the need of choosing the appropriate prognostic model in order to justify the referral decision.

BACKGROUND: Congenital hypothyroidism (CH) is a common endocrine disease that occurs in about 1:3000 newborns. In 80-85% of the cases, CH is presumably secondary to thyroid dysgenesis (TD), a defect in the organogenesis of the gland leading to an ectopic (30-45%), absent (agenesis, 35-40%) or hypoplastic (5%) thyroid gland. The pathogenesis of TD is still largely unknown. Most cases of TD are sporadic, although familial occurrences have occasionally been described. Recently, mutations in the PAX8 transcription factor have been identified in patients with TD. OBJECTIVE: Our aim was to identify and functionally characterize novel PAX8 mutations with autosomal dominant transmission responsible for TD. DESIGN: The PAX8 gene was sequenced in a mother and child both suffering from congenital hypothyroidism (CH) because of thyroid hypoplasia. Subsequently, expression vectors encoding the mutated PAX8 were generated, and the effects of the mutation on both the DNA-binding capability and the transcriptional activity were evaluated. RESULTS: PAX8 gene sequencing revealed a heterozygous mutation that consists of the substitution of a histidine residue with a glutamine at position 55 of the PAX8 protein (H55Q). When tested in cotransfection experiments with a thyroglobulin promoter reporter construct, the mutant protein turned out to be still able to bind DNA in Electrophoretic Mobility Shift Assay assays but transcriptionally inactive. CONCLUSIONS: Our findings confirm the important role of PAX8 in normal thyroid development and support the evidence that in humans haploinsufficiency of PAX8 is associated with TD.

CONTEXT:Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3000- 4000 newborns. In 80-85% of cases, CH is caused by defects in thyroid organogenesis, resulting in absent, ectopically located, and/or severely reduced gland, all conditions indicated as "thyroid dysgenesis" (TD). A higher prevalence of congenital heart diseases has been documented in children with CH compared to the general population. This association suggests a possible pathogenic role of genes involved in both heart and thyroid development. Among these, it can be included Isl1, a transcription factor containing a LIM homeodomain that is expressed in both thyroid and heart during morphogenesis. OBJECTIVE: In the present study, we investigate the role of ISL1 in the pathogenesis of TD. SETTINGS AND PATIENTS: By single stranded conformational polymorphism, we screened for mutations the entire ISL1 coding sequence in 96 patients with TD and in 96 normal controls. RESULTS: No mutations have been found in patients and controls. CONCLUSION: Our data indicate that, despite the relevant role of ISL1 in thyroid and heart morphogenesis, mutations in its coding region are not associated with TD in our group of patients.

Background: We evaluated the warranty period of a normal stress myocardial perfusion single-photon emission computed tomography (MPS) in hypertensive patients. Methods and Results: A total of 471 consecutive hypertensive patients with suspected coronary artery disease and normal perfusion at stress MPS were followed for a mean of 76 ± 21 months. Endpoint events were cardiac death or nonfatal myocardial infarction. With Cox analysis, age (hazard ratio 1.1, P < .005) and stress test type (hazard ratio 2.7, P < .005) were independent predictors of events. With parametric Weibull analysis, patients ≤60 years old undergoing exercise stress test remained at low risk for the entire length of follow-up, while the highest probability of events and the major risk acceleration were observed in those > 60 years old who underwent pharmacologic stress test. In patients undergoing exercise test, peak systolic blood pressure (BP; hazard ratio 1.1, P < .005) emerged as predictor of events, and only subjects with peak systolic BP < 160 mmHg remained at low risk for the entire length of follow-up. In contrast, for patients with peak systolic BP ≥180 mmHg, the time to achieve a cumulative cardiac risk level of 3% was 18 months. Conclusions: In hypertensive patients, the warranty period of a normal stress MPS varies according to stress type and peak systolic BP. A normal stress MPS can be considered reassuring in subjects ≤60 years old who performed exercise stress test and a peak systolic BP < 160 mmHg.

Progranulin gene (GRN) mutations are among the leading causes of frontotemporal lobar degeneration, a group of neurodegenerative diseases characterized by remarkable clinical heterogeneity. In this article, we report the new GRN 708+4A>T splicing mutation, identified in 2 siblings of a family with several members affected by cognitive, behavioral, and motor disorders. Plasma progranulin dosage and GRN expression analysis, together with in silico prediction studies, supported the pathogenicity of the mutation. Both the patients displayed a clinical syndrome in which language impairment was largely predominant. However, motor speech deficits were the major feature in one case, diagnosed as progressive nonfluent aphasia, whereas marked semantic alterations were present in the other, whose clinical phenotype was in favor of a mixed aphasia. The profile of neuroanatomical alterations from imaging studies was in line with the clinical phenotypes. Therefore, also this novel GRN mutation is associated with haploinsufficiency and phenotypic heterogeneity, which are both typical features of progranulinopathies.

The emerging role of molecular imaging has made possible to evaluate and quantify biochemical changes of molecular targets in specific neurochemical systems involved in movement disorders, providing neurochemical information of clinical changes before the pathological features occurred. In detail, radionuclides imaging techniques are frequently used for the in vivo study of neurotransmitter and receptor function, alterations in cerebral blood flow and metabolic activity, abnormal protein deposition, and inflammation, with a central role in molecular imaging for preclinical and clinical studies. The present chapter represents an overview of main use of single-photon emission computed tomography (SPECT) in movement disorders, with a focal attention on specific radiotracers used, recent advances in SPECT technology and reconstruction algorithm and added specific value of semiquantitative methods for images analysis. Finally, a brief paragraph is dedicated to description of SPECT/CT devices and advantages of using hybrid technology.

BACKGROUND AND AIMS: Despite an extensive use of stress myocardial perfusion single-photon emission computed tomography (MPS), no study addressed the role of perfusion imaging in diabetic patients with abnormal resting electrocardiogram (ECG). We compared analytical approaches to assess the added value of stress MPS variables in estimating coronary heart disease outcomes in diabetic patients with abnormal resting ECG. METHODS AND RESULTS: A total of 416 patients with diabetes and abnormal resting ECG who underwent stress MPS were prospectively followed up after the index study. The end point was the occurrence of a major cardiac event, including cardiac death and nonfatal myocardial infarction. At the end of follow-up (median 58 months), 42 patients experienced events. MPS data increased the predictive value of a model including traditional cardiovascular risk factors and left ventricular (LV) ejection fraction (likelihood ratio ?² from 17.54 to 24.15, p < 0.05, with a C statistic of 0.72, 95% confidence interval: 0.65-0.79). The addition of MPS data resulted in reclassification of 25% of the sample with a net reclassification improvement of 0.20 (95% confidence interval: 0.05-0.36). Overall, 63 patients were reclassified to a lower risk category, with a 5-year event rate of 3.5%, and 40 patients were reclassified to a higher risk category, with a 5-year event rate of 20%. CONCLUSION: The addition of MPS findings to a model based on traditional cardiovascular risk factors and LV ejection fraction improves risk classification for incident cardiac events in diabetic patients with abnormal resting ECG.

Malignant pheochromocytomas respond to chemotherapy with a reduction in tumor size and catecholamine secretion. We investigated the usefulness of molecular imaging with meta-iodobenzylguanidine (MIBG) for evaluating the effects of chemotherapy in patients with malignant pheochromocytoma. Six patients were studied before and after 6 ± 4 months of combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine. Urinary catecholamines, metanephrines, and vanillylmandelic acid (VMA) levels were measured before and after chemotherapy. [131I]MIBG uptake was calculated for each tumor lesion on images before and after chemotherapy. An intensity ratio (IR) of abnormal to normal tissue count density was used to evaluate the change in lesion activity with therapy. Urinary catecholamines, metanephrines, and VMA significantly decreased with chemotherapy. MIBG uptake decreased in most lesions and the reduction in overall IR correlated with the reduction in urinary VMA. However, the change in individual lesions was variable and MIBG IR did not change or increased in a number of lesions. In conclusion, MIBG imaging is useful in the evaluation of patients with malignant pheochromocytoma who are receiving chemotherapy. It can provide not only a measure of overall effectiveness of treatment but also allows a lesion-by-lesion evaluation of the heterogeneity of response to chemotherapy.

Stress myocardial perfusion single-photon emission computed tomography (MPS) variables are robust estimators of prognosis. No data are available on the comparative ability of stress MPS risk markers using varied iterative and risk classification approaches in asymptomatic diabetic patients. We compared analytical approaches to estimate the added value of MPS variables in estimating coronary artery disease (CAD) outcomes in asymptomatic diabetic patients. We also evaluated the temporal characteristics of cardiac risk according to MPS findings.A total of 436 consecutive asymptomatic diabetic patients who underwent stress-rest gated MPS were prospectively enrolled. Multivariable Cox proportional hazards model was employed to estimate cardiac death and nonfatal myocardial infarction (MI). Risk reclassification was calculated and parametric survival analysis was used to predict time to events.At multivariable analysis, post-stress left ventricular ejection fraction (LVEF) and stress MPS ischemia were independent predictors of CAD death or MI (both p0.01). The net reclassification improvement by adding MPS results to a model including pre-test CAD likelihood was 0.25 (95% confidence interval 0.06-0.44; p0.01). Parametric survival analysis showed the highest probability of CAD death or MI and the major risk acceleration in time in patients with stress MPS ischemia and post-stress LVEF ≤45%.In asymptomatic diabetic patients, analytical approaches that establish the reclassification of events may serve for estimation of improved outcomes for stress MPS. Post-stress LVEF and stress-induced ischemia by gated MPS influence the temporal characteristic of the patient's risk at long-term follow-up.

Aim: In 80–85% of cases, congenital hypothyroidism is associated with thyroid dysgenesis (TD), but only in a small percentage of cases mutations in thyroid transcription factors (NKX2.1, PAX8, FOXE1, and NKX2.5) have been associated with the disease. Several studies demonstrated that the activity of the transcription factors can be modulated by the interaction with other proteins, such as coactivators and co-repressors, and TAZ (transcriptional co-activator with PDZ-binding motif or VVWTR1) is a co-activator interacting with both NKX2.1 and PAX8. In the present study we investigate the role of TAZ in the pathogenesis of TD. Material and methods: By Single Stranded Conformational Polymorphism, we screened the entire TAZ coding sequence for mutations in 96 patients with TD and in 96 normal controls. Results: No mutations were found in patients and controls, but we found several polymorphisms in both groups. No significant differences could be demonstrated in the prevalence of the mutations between patients and controls. Conclusions: Our data indicate that TAZ mutations are not a cause of TD in the series of patients studied.

We studied a boy with congenital hypothyroidism, benign hereditary chorea, and respiratory distress. His mother and his grandfather were affected by hypothyroidism with a late onset and benign hereditary chorea. The aim of this study was to establish the genetic defects that cause that phenotype and study the molecular mechanisms of the pathology.NKX2.1, PAX8, NKX2.5, and TAZ genes were sequenced.Direct sequencing of the NKX2.1 gene showed, in all the affected, a new heterozygous mutation from cytosine to adenine in the second base of the triplet encoding for the amino acid at position 145. The mutation (C609A) is responsible for a change from serine to a stop codon (S145X). We also demonstrated that the mutant protein is predominantly in the cytoplasm and unable to translocate into the nucleus. Of note, the S145X mutation produces variable phenotypes in the affected members of the family. No mutations have been identified in the NKX2.5, PAX8, and TAZ genes.Our study extends the knowledge of the functional effect of NKX2.1 mutations and further highlights the complexities of genotype-phenotype correlation in the NKX2.1 deficiency syndromes.