Diagnostic performance of artificial intelligence for pediatric pulmonary nodule detection on chest computed tomography: comparison of simulated lower radiation doses.

The combination of low dose CT and AI performance in the pediatric population has not been explored. Understanding this relationship is relevant for pediatric patients given the potential radiation risks. Here, the objective was to determine the diagnostic performance of commercially available Computer Aided Detection (CAD) for pulmonary nodules in pediatric patients at simulated lower radiation doses. Retrospective chart review of 30 sequential patients between 12-18 years old who underwent a chest CT on the Siemens SOMATOM Force from December 20, 2021, to April 12, 2022. Simulated lower doses at 75%, 50%, and 25% were reconstructed in lung kernel at 3 mm slice thickness using ReconCT and imported to Syngo CT Lung CAD software for analysis. Two pediatric radiologists reviewed the full dose CTs to determine the reference read. Two other pediatric radiologists compared the Lung CAD results at 100% dose and each simulated lower dose level to the reference on a nodule by nodule basis. The sensitivity (Sn), positive predictive value (PPV), and McNemar test were used for comparison of Lung CAD performance based on dose. As reference standard, 109 nodules were identified by the two radiologists. At 100%, and simulated 75%, 50%, and 25% doses, lung CAD detected 60, 62, 58, and 62 nodules, respectively; 28, 28, 29, and 26 were true positive (Sn = 26%, 26%, 27%, 24%), 30, 32, 27, and 34 were false positive (PPV = 48%, 47%, 52%, 43%). No statistically significance difference of Lung CAD performance at different doses was found, with p-values of 1.0, 1.0, and 0.7 at simulated 75%, 50%, and 25% doses compared to standard dose. CONCLUSION: The Lung CAD shows low sensitivity at all simulated lower doses for the detection of pulmonary nodules in this pediatric population. However, radiation dose may be reduced from standard without further compromise to the Lung CAD performance. WHAT IS KNOWN: • High diagnostic performance of Lung CAD for detection of pulmonary nodules in adults. • Several imaging techniques are applied to reduce pediatric radiation dose. WHAT IS NEW: • Low sensitivity at all simulated lower doses for the detection of pulmonary nodules in our pediatric population. • Radiation dose may be reduced from standard without further compromise to the Lung CAD performance.

Diagnostic performance of artificial intelligence for pediatric pulmonary nodule detection in computed tomography of the chest.

PURPOSE: To test the performance of a commercially available adult pulmonary nodule detection artificial intelligence (AI) tool in pediatric CT chests. METHODS: 30 consecutive chest CTs with or without contrast of patients ages 12-18 were included. Images were retrospectively reconstructed at 3 mm and 1 mm slice thickness. AI for detection of lung nodules in adults (Syngo CT Lung Computer Aided Detection (CAD)) was evaluated. 3 mm axial images were retrospectively reviewed by two pediatric radiologists (reference read) who determined the location, type, and size of nodules. Lung CAD results at 3 mm and 1 mm slice thickness were compared to reference read by two other pediatric radiologists. Sensitivity (Sn) and positive predictive value (PPV) were analyzed. RESULTS: The radiologists identified 109 nodules. At 1 mm, CAD detected 70 nodules; 43 true positive (Sn = 39 %), 26 false positive (PPV = 62 %), and 1 nodule which had not been identified by radiologists. At 3 mm, CAD detected 60 nodules; 28 true positive (Sn = 26 %), 30 false positive (PPV = 48 %) and 2 nodules which had not been identified by radiologists. There were 103 solid nodules (47 measuring < 3 mm) and 6 subsolid nodules (5 measuring < 5 mm). When excluding 52 nodules (solid < 3 mm and subsolid < 5 mm) based on algorithm conditions, the Sn increased to 68 % at 1 mm and 49 % at 3 mm but there was no significant change in the PPV measuring 60 % at 1 mm and 48 % at 3 mm. CONCLUSION: The adult Lung CAD showed low sensitivity in pediatric patients, but better performance at thinner slice thickness and when smaller nodules were excluded.

Joint EANM/SIOPE/RAPNO practice guidelines/SNMMI procedure standards for imaging of paediatric gliomas using PET with radiolabelled amino acids and [18F]FDG: version 1.0.

Positron emission tomography (PET) has been widely used in paediatric oncology. 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is the most commonly used radiopharmaceutical for PET imaging. For oncological brain imaging, different amino acid PET radiopharmaceuticals have been introduced in the last years. The purpose of this document is to provide imaging specialists and clinicians guidelines for indication, acquisition, and interpretation of [18F]FDG and radiolabelled amino acid PET in paediatric patients affected by brain gliomas. There is no high level of evidence for all recommendations suggested in this paper. These recommendations represent instead the consensus opinion of experienced leaders in the field. Further studies are needed to reach evidence-based recommendations for the applications of [18F]FDG and radiolabelled amino acid PET in paediatric neuro-oncology. These recommendations are not intended to be a substitute for national and international legal or regulatory provisions and should be considered in the context of good practice in nuclear medicine. The present guidelines/standards were developed collaboratively by the EANM and SNMMI with the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group and the Response Assessment in Paediatric Neuro-Oncology (RAPNO) working group. They summarize also the views of the Neuroimaging and Oncology and Theranostics Committees of the EANM and reflect recommendations for which the EANM and other societies cannot be held responsible.

Ileocolic intussusception in pediatric SARS-CoV-2 patients: experience at a tertiary pediatric center.

PURPOSE: COVID-19 disease can manifest with intussusception in pediatric patients, but prevalence of abnormalities on ultrasounds performed for intussusception is uncertain. We aim to report our experience in children with COVID-19 presenting with suspected intussusception imaged with ultrasound. METHODS: Children under 18 years who had an ultrasound for possible intussusception underwent retrospective analysis and were tested for COVID-19 between April 1 and December 14, 2020. Patients' demographic, clinical, radiological and surgical characteristics were reviewed. RESULTS: Twenty-four COVID-19-positive patients were identified; 19 boys with mean age 3 years (range: 3 months-18 years). Ultrasound was abnormal in 11 patients (11/24, 46%). Sonographic features of enterocolitis were documented in seven children (7/24, 29%). Three boys (3/24, 13%) were found to have ileocolic intussusception on ultrasound and underwent air enema with failed reduction (3/3, 100%), precipitating surgical reductions, all with favorable outcomes. One patient (1/24, 4%) was found to have a long segment of persistent small bowel-small bowel intussusception which was surgically repaired. CONCLUSION: Given the known association between failed reduction at air enema and delayed presentation, heightened awareness for intussusception in the setting of COVID-19 should be maintained, though more often, the etiology was attributed to other GI manifestations of COVID-19.

Acute appendicitis and SARS-CoV-2 in children: imaging findings at a tertiary children's hospital during the COVID-19 pandemic.

BACKGROUND: Evidence suggests severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may be associated with appendicitis or clinical symptoms that mimic appendicitis, but it is not clear if the findings or utility of imaging in pediatric patients with suspected appendicitis have changed since the onset of the coronavirus disease 2019 (COVID-19) pandemic. OBJECTIVE: To evaluate for potential differences in SARS-CoV-2 positive and SARS-CoV-2 negative pediatric patients imaged for suspected appendicitis to determine the reliability of the existing medical imaging approach for appendicitis in a population that contains both SARS-CoV-2 positive and SARS-CoV-2 negative pediatric patients. MATERIALS AND METHODS: Patients imaged for suspected appendicitis Apr. 1, 2020, to Dec. 31, 2020, were identified via an electronic medical records search. Differences in ultrasound (US) diagnostic performance, use of computed tomography (CT) following US, rates of appendicitis, imaging findings of appendicitis and perforation were compared between SARS-CoV-2 positive and SARS-CoV-2 negative tested patients, using pathology and surgery as reference standards for appendicitis and perforation, respectively. Fisher exact test and Student's t-test were used for statistical analysis. RESULTS: One thousand, six hundred and ninety-three patients < 18 years old met inclusion criteria, with 46% (772/1,693) female, 11 imaged with only CT and 1,682 with US. Comparing SARS-CoV-2 positive and SARS-CoV-2 negative patients, no statistically significant differences in sensitivity or specificity of US (P = 1 and P = 1, respectively), or in the US (P-values ranging from 0.1 to 1.0) or CT imaging findings (P-values ranging from 0.2 to 1.0) in appendicitis were found. Perforation rates were similar between SARS-CoV-2 positive (20/57, 35.1% perforated) and SARS-CoV-2 negative (359/785, 45.7% perforated) patients with appendicitis (P = 0.13). Use of CT following first-line US was similar, with 7/125 (5.6%) of SARS-CoV-2 positive imaged with CT after US and 127/1,557 (8.2%) of SARS-CoV-2 negative imaged with CT after US (P = 0.39). CONCLUSION: In pediatric patients with suspected appendicitis, no significant difference was found in the diagnostic performance of US, CT usage or perforation rates between SARS-CoV-2 positive and SARS-CoV-2 negative patients.

CT imaging of esophageal foreign bodies in children: a pictorial essay.

Foreign body (FB) ingestion is common in children, particularly from 6 months to 3 years of age. As young children may be unable to provide a clinical history and the ingestion is often unwitnessed, imaging plays an important role in diagnosis, predicting outcomes and detecting complications that require surgical intervention. Since 2015, our institution's diagnostic algorithm for suspected airway foreign bodies has included a noncontrast airway FB CT (FB-CT) with the z-axis coverage spanning from the larynx to the proximal segmental bronchi of the lower lung zones. The effective dose of radiation from this FB-CT airway protocol is typically less than 1 mSv, compared to an effective dose of just under 1 mSv to up to 3 mSv for a fluoroscopic esophagram in children under 10 years of age and 1-3 mSv for a routine pediatric CT chest. In using the FB-CT airway protocol at our institution, we observed that esophageal rather than airway FBs were sometimes encountered on these exams. However, the confidence among radiologists for definitively diagnosing an esophageal foreign body on noncontrast CT was variable. Consequently, we created a teaching module of positive cases for our group of 21 pediatric body radiologists to increase their diagnostic confidence. This pictorial essay illustrates our institutional experience and can help others to confidently diagnose esophageal foreign bodies using a dedicated CT foreign body imaging protocol. At a similar radiation dose to a fluoroscopic esophagram, CT provides the additional advantage of an expedited diagnosis without the need for a radiologist on site.

SULT1A1 and SULT1A2 Associated Extensive Prolapse-Type Inflammatory Polyposis in Crohn's Colitis.

Mucosal prolapse syndrome most commonly involves the rectum and presents as solitary rectal ulcer syndrome and proctitis cystica profunda. Symptoms and endoscopic appearances are nonspecific. Histologically, mucosal prolapse is characterized by fibromuscular obliteration of the lamina propria, and displacement of crypts into submucosa and muscularis mucosae. Mucosal prolapse presenting as polyposis is rare and has only been reported involving the rectosigmoid colon. In this report, we describe a case of mucosal prolapse syndrome presenting as diffuse polyposis and colitis cystica profunda involving the hepatic, splenic flexures and descending colon in a teenage boy suffering from refractory fibrostenosing Crohn's disease. This patient was found to have possibly deleterious homozygous single nucleotide polymorphisms in both SULT1A1 and SULT1A2 genes within a unique polygenic variation of altered cell adhesion.

Peptide receptor radionuclide therapy for treatment of metastatic neuroendocrine tumors in children.

Neuroendocrine tumors (NETs) of the pancreas and midgut are extremely rare in children, and patients presenting with metastatic disease have poor survival. Given this rarity, treatments are extrapolated from guidelines for adults with NET. Recent clinical trials in adults with NETs have shown that the addition of peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTATATE resulted in a disease control rate of nearly 80%, with minimal side effects. We report our experience using 177 Lu-DOTATATE to treat two pediatric patients with metastatic NET.

Testicular Myofibroma in Children: A Case Report and Review of the Literature.

Testicular tumors are rare in the prepubertal population and often are germ cell tumors. Myofibroma is a rare spindle cell neoplasm composed of myofibroblasts, which are intermediate cells between fibroblasts and smooth muscle cells. Only two prepubertal testicular myofibromas have been previously reported. While cryptorchidism is a risk factor for testicular germ cell tumors, the exact etiology of testicular myofibroma is unknown. We report a case of testicular myofibroma in a six-year-old male with a history of undescended testes, as well as a review of the literature. This case suggests a possible connection between undescended testes and testicular myofibroma.

SNMMI Procedure Standard/EANM Practice Guideline on Pediatric 18F-FDG PET/CT for Oncology 1.0.

PREAMBLEThe Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote the science, technology, and practical application of nuclear medicine. The European Association of Nuclear Medicine (EANM) is a professional nonprofit medical association founded in 1985 to facilitate communication worldwide among individuals pursuing clinical and academic excellence in nuclear medicine. SNMMI and EANM members are physicians, technologists, and scientists specializing in the research and practice of nuclear medicine.The SNMMI and EANM will periodically put forth new standards/guidelines for nuclear medicine practice to help advance the science of nuclear medicine and improve service to patients. Existing standards/guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated. Each standard/guideline, representing a policy statement by the SNMMI/EANM, has undergone a thorough consensus process, entailing extensive review. The SNMMI and EANM recognize that the safe and effective use of diagnostic nuclear medicine imaging requires particular training and skills, as described in each document. These standards/guidelines are educational tools designed to assist practitioners in providing appropriate and effective nuclear medicine care for patients. These guidelines are consensus documents, and are not inflexible rules or requirements of practice. They are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, the SNMMI and the EANM cautions against the use of these standards/guidelines in litigation in which the clinical decisions of a practitioner are called into question.The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals taking into account the unique circumstances of each case. Thus, there is no implication that action differing from what is laid out in the standards/guidelines, standing alone, is below standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the standards/guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to publication of the standards/guidelines.The practice of medicine involves not only the science, but also the art of dealing with the prevention, diagnosis, alleviation, and treatment of disease. The variety and complexity of human conditions make it impossible for general guidelines to consistently allow for an accurate diagnosis to be reached or a particular treatment response to be predicted. Therefore, it should be recognized that adherence to these standards/guidelines will not ensure a successful outcome. All that should be expected is that the practitioner follows a reasonable course of action, based on their level of training, the current knowledge, the available resources, and the needs/context of the particular patient being treated.PET and computerized tomography (CT) have been widely used in oncology. 18F-FDG is the most common radiotracer used for PET imaging. The purpose of this document is to provide imaging specialists and clinicians guidelines for recommending, performing, and interpreting 18F-FDG PET/CT in pediatric patients in oncology. There is not a high level of evidence for all recommendations suggested in this paper. These recommendations represent the expert opinions of experienced leaders in this field. Further studies are needed to have evidence-based recommendations for the application of 18F-FDG PET/CT in pediatric oncology. These recommendations should be viewed in the context of good practice of nuclear medicine and are not intended to be a substitute for national and international legal or regulatory provisions.

Pediatric applications of Dotatate: early diagnostic and therapeutic experience.

In recent years, new somatostatin receptor agents (SSTRs) have become available for diagnostic imaging and therapy in neuroendocrine tumors. The novel SSTR ligand DOTA-DPhel-Tyr3-octreotate (Dotatate) in particular can be linked with 68Gallium for diagnostic imaging purposes, and with the ß-emitter 177Lutetium for radiotherapy in the setting of neuroendocrine tumors. Dotatate imaging offers distinct advantages in the evaluation of neuroendocrine tumors compared to standard techniques, including greater target-to-background ratio and lesion conspicuity, high sensitivity/specificity, improved spatial resolution with positron emission tomography (PET)/CT or PET/MR, and decreased radiation exposure. Although currently off-label in pediatrics, Dotatate theranostics in children are being explored, most notably in the setting of neuroblastoma and hereditary neuroendocrine syndromes. This article provides a multicenter case series of Dotatate imaging and therapy in pediatric patients in order to highlight the spectrum of potential clinical applications.

Current trends in pediatric nuclear medicine: a Society for Pediatric Radiology membership survey.

BACKGROUND: Pediatric nuclear medicine is evolving, and its practice patterns are uncertain. Knowledge of the current trends in pediatric nuclear medicine might be helpful to direct local decisions, including expectations for patient care, needs for capital acquisitions, and staffing recruitment strategies. OBJECTIVE: To provide data regarding the current practice of pediatric nuclear medicine via a Society for Pediatric Radiology (SPR) membership survey. MATERIALS AND METHODS: The SPR emailed our 25-question survey to all 1,847 SPR members in August 2018 and we accepted responses until April 2019. Questions focused on nuclear medicine staffing, positron emission tomography (PET) utilization, and radiotherapy availability. Respondents could indicate their affiliated hospital, which we used for data cataloguing only. Analysis of survey responses was blinded to reported institution. We analyzed response data using contingency tables. Independence testing between categorical variables based on proportions of physicians with additional nuclear medicine board certification was performed on a subset of questions regarding PET and therapy practices. RESULTS: Sixty-seven people from at least 29 hospitals responded to the survey, including all 10 of the 2018-2019 U.S. News & World Report best children's hospitals. The majority (48/67, 71.6%) of respondents indicated that pediatric nuclear medicine examinations were interpreted in the pediatric radiology department by pediatric radiologists and that most physicians interpreting the exams (43/67, 64.2%) did not have subspecialty certification in nuclear medicine or nuclear radiology. Most facilities offered PET/CT (57/67, 85.1%); few offered PET/MRI (12/67, 17.9%). Most facilities offered radiotherapies (57/67, 85.1%) but at most of these facilities (30/57, 52.6%), fewer than half the physicians who cover nuclear medicine were approved to administer therapies. In the subset analyses based on proportion of physicians with additional nuclear medicine board certification, there were statistically significant differences between the groups in availability of PET/MRI, lutetium-177 dotatate therapy programs, and percentages of physicians approved to administer therapies. CONCLUSION: Pediatric nuclear medicine is largely practiced by pediatric radiologists without subspecialty certification. Staffing, PET practices and therapies vary among practices, in part associated with the number of radiologists with nuclear medicine board certification.

Neuroblastoma of the Bone and Bone Marrow Without an Apparent Primary Site: Report of 4 Cases With Long-term Follow-up.

Children with neuroblastoma rarely present with metastatic disease without identifiable primary tumors. We describe the clinical and histopathologic characteristics of 4 patients aged 1, 7, 7, and 11 years with neuroblastoma involving bone or bone marrow without an apparent primary site. One patient presented with a periorbital bone lesion, 1 presented with a distal femoral lesion, and 2 presented with diffuse bone marrow involvement. All tumors were negative for MYCN amplification. All patients were alive without evidence of disease 5 years after completion of multimodality therapy. Patients with neuroblastoma of the bone and bone marrow without an apparent primary site may constitute a unique group characterized by older age at diagnosis, nonamplified MYCN tumors, and good response to treatment.

Comparison of the diagnostic accuracy of PET/MRI to PET/CT-acquired FDG brain exams for seizure focus detection: a prospective study.

BACKGROUND: There is great interest in positron emission tomography (PET)/magnetic resonance (MR) as a clinical tool due to its capacity to provide diverse diagnostic information in a single exam. OBJECTIVE: The goal of this exam is to compare the diagnostic accuracy of PET/MR-acquired [F-18]2-fluoro-2-deoxyglucose (FDG) brain exams to that of PET/CT with respect to identifying seizure foci in children with localization-related epilepsy. MATERIALS AND METHODS: Institutional Review Board approval and informed consent were obtained for this Health Insurance Portability and Accountability Act-compliant, prospective study. All patients referred for clinical FDG-PET/CT exams of the brain at our institution for a diagnosis of localization-related epilepsy were prospectively recruited to undergo an additional FDG-PET acquisition on a tandem PET/MR system. Attenuation-corrected FDG images acquired at PET/MR and PET/CT were interpreted independently by five expert readers. Readers were blinded to the scanner used for acquisition and attenuation correction as well as all other clinical and imaging data. A Likert scale scoring system (1-5) was used to assess image quality. The locale of seizure origin determined at multidisciplinary epilepsy surgery work rounds was considered the reference standard. Non-inferiority testing for paired data was used to compare the diagnostic accuracy of PET/MR to that of PET/CT. RESULTS: The final study population comprised 35 patients referred for a diagnosis of localization-related epilepsy (age range: 2-19 years; median: 11 years; 21 males, 14 females). Image quality did not differ significantly between the two modalities. The accuracy of PET/MR was not inferior to that of PET/CT for localization of a seizure focus (P=0.017). CONCLUSION: The diagnostic accuracy of FDG-PET images acquired on a PET/MR scanner and generated using MR-based attenuation correction was not inferior to that of PET images processed by traditional CT-based correction.

Assessment of Sequential PET/MRI in Comparison With PET/CT of Pediatric Lymphoma: A Prospective Study.

OBJECTIVE: The objective of our study was to compare the diagnostic performance of sequential (18)F-FDG PET/MRI (PET/MRI) and (18)F-FDG PET/CT (PET/CT) in a pediatric cohort with lymphoma for lesion detection, lesion classification, and disease staging; quantification of FDG uptake; and radiation dose. SUBJECTS AND METHODS: For this prospective study of 25 pediatric patients with lymphoma, 40 PET/CT and PET/MRI examinations were performed after a single-injection dual-time-point imaging protocol. Lesions detected, lesion classification, Ann Arbor stage, and radiation dose were tabulated for each examination, and statistical evaluations were performed to compare the modalities. Quantification of standardized uptake values (SUVs) was performed for all lesions. All available examinations and clinical history were used as the reference standard. RESULTS: No statistically significant differences between PET/MRI and PET/CT were observed in lesion detection rates, lesion classification, or Ann Arbor staging. Fifty-four regions of focal uptake were observed on PET/MRI compared with 55 on PET/CT. Both modalities accurately classified 82% of the lesions relative to the reference standard. Disease staging based on PET/MRI was correct for 35 of the 40 studies, and disease staging based on PET/CT was correct for 35 of the 40 studies; there was substantial agreement between the modalities for disease staging (κ = 0.684; p < 0.001). PET SUVs were strongly correlated between PET/CT and PET/MRI (ρ > 0.72), although PET/MRI showed systematically lower SUV measurements. PET/MRI offered an average 45% reduction in radiation dose relative to PET/CT. CONCLUSION: In a pediatric cohort with lymphoma, sequential PET/MRI showed lesion detection, lesion classification, and Ann Arbor staging comparable to PET/CT. PET/MRI quantification of FDG uptake strongly correlated with PET/CT, but the SUVs were not interchangeable. PET/MRI significantly reduced radiation exposure and is a promising new alternative in the care of pediatric lymphoma patients.

cAMP-activated protein kinase-independent potentiation of insulin secretion by cAMP is impaired in SUR1 null islets.

Whereas the loss of ATP-sensitive K(+) channel (K(ATP) channel) activity in human pancreatic beta-cells causes severe hypoglycemia in certain forms of hyperinsulinemic hypoglycemia, similar channel loss in sulfonylurea receptor-1 (SUR1) and Kir6.2 null mice yields a milder phenotype that is characterized by normoglycemia, unless the animals are stressed. While investigating potential compensatory mechanisms, we found that incretins, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), can increase the cAMP content of Sur1KO islets but do not potentiate glucose-stimulated insulin release. This impairment is secondary to a restriction in the ability of Sur1KO beta-cells to sense cAMP correctly. Potentiation does not appear to require cAMP-activated protein kinase (PKA) because H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide) and KT5720, inhibitors of PKA, do not affect stimulation by GLP-1, GIP, or exendin-4 in wild-type islets, although they block phosphorylation of cAMP-response element-binding protein. The impaired incretin response in Sur1KO islets is specific; the stimulation of insulin release by other modulators, including mastoparan and activators of protein kinase C, is conserved. The results suggest that the defect responsible for the loss of cAMP-induced potentiation of insulin secretion is PKA independent. We hypothesize that a reduced release of insulin in response to incretins may contribute to the unexpected normoglycemic phenotype of Sur1KO mice versus the pronounced hypoglycemia seen in neonates with loss of K(ATP) channel activity.

Transactivation of the mouse sulfonylurea receptor I gene by BETA2/NeuroD.

The sulfonylurea receptor 1 (SUR1) plays a key role in regulation of insulin secretion in pancreatic beta-cells. In this study we investigated the mechanism for tissue-specific expression of the SUR1 gene. A -138/-20 fragment exhibited basal promoter activity while the -660/-20 fragment contained a regulatory element for tissue-specific expression of the mouse SUR1 gene. A pancreatic beta-cell-specific transcription factor, BETA2 (beta-cell E box transcription factor)/NeuroD, enhanced the promoter activity of the -660/-20 fragment in cooperation with E47. Coexpression of a dominant negative mutant of BETA2/NeuroD, BETA2(1-233), repressed the promoter activity of the -660/-20 fragment. BETA2/NeuroD bound specifically to the E3 element located at -141. The E3 sequence in a heterologous context conferred transactivation by BETA2/NeuroD in HeLa and HIT cells. Mutation of E3 eliminated the stimulatory effect of BETA2/NeuroD. Unlike BETA2/NeuroD, neurogenin 3 (ngn3) could not activate the E3 element in HeLa cells. Overexpression of ngn3 concomitantly increased expression of BETA2/NeuroD and SUR1 in HIT cells but not in HeLa cells. These results indicate that BETA2/NeuroD induces tissue-specific expression of the SUR1 gene through the E3 element. These results also suggest that E3 is specific for BETA2/NeuroD, and the stimulatory effect of ngn3 in HIT cells may require factors specifically expressed in HIT cells.

Sulfonylurea receptor knockout causes glucose intolerance in mice that is not alleviated by concomitant somatostatin subtype receptor 5 knockout.

OBJECTIVE: To examine the long-term effects of Sur KO, SSTR5 KO, and double Sur/SSTR5 KO on insulin secretion and glucose regulation. SUMMARY BACKGROUND DATA: The sulfonylurea receptor (Sur) and somatostatin receptor type 5 (SSTR5) play an integral role in the regulatory pathways of the endocrine pancreas. Sur knockout (KO) and SSTR5 KO mice were generated in the authors' laboratories and crossbred to generate Sur/SSTR5 KO mice. All mice were genotyped by Southern blotting and polymerase chain reaction analysis. METHODS: One-year-old Sur KO, Sur/SSTR5 KO, SSTR5 KO, and age-matched wild-type control mice underwent single-pass perfusion of isolated pancreata with low and high glucose concentration (n = 4-6/group). Another group of mice also underwent intraperitoneal glucose tolerance tests with 1.2 g glucose/kg body weight (n = 4/group per time point). RESULTS: Sur1 KO and Sur/SSTR5 KO mice had profoundly decreased insulin secretion in vitro, whereas SSTR5 KO had increased insulin secretion compared with wild-type mice. Sur1 KO and Sur/SSTR5 mice had increased glucose response in vivo compared with wild-type mice. Sur1 KO and Sur/SSTR5 KO mice exhibit glucose intolerance and SSTR5 KO mice show increased insulin response in vitro. CONCLUSIONS: Sur1 KO causes glucose intolerance and SSTR5 KO causes increased insulin secretion. However, Sur/SSTR5 double ablation does not alleviate the diabetic state of the Sur1 KO.