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Purpose We evaluated the diagnostic performance of the texture features of dynamic contrast-enhanced (DCE) MRI for breast cancer diagnosis in which the discriminator was optimized, so that the specificity was maximized via the restriction of the negative predictive value (NPV) to greater than 98%. Methods Histologically proven benign and malignant mass lesions of DCE MRI were enrolled retrospectively. Training and testing sets consist of 166 masses (49 benign, 117 malignant) and 50 masses (15 benign, 35 malignant), respectively. Lesions were classified via MRI review by a radiologist into 4 shape types: smooth (S-type, 34 masses in training set and 8 masses in testing set), irregular without rim-enhancement (I-type, 60 in training and 14 in testing), irregular with rim-enhancement (R-type, 56 in training and 22 in testing), and spicula (16 in training and 6 in testing). Spicula were immediately classified as malignant. For the remaining masses, 298 texture features were calculated using a parametric map of DCE MRI in 3D mass regions. Masses were classified into malignant or benign using two thresholds on a feature pair. On the training set, several feature pairs and their thresholds were selected and optimized for each mass shape type to maximize specificity with the restriction of NPV > 98%. NPV and specificity were computed using the testing set by comparison with histopathologic results and averaged on the selected feature pairs. Results In the training set, 27, 12, and 15 texture feature pairs are selected for S-type, I-type, and R-type masses, respectively, and thresholds are determined. In the testing set, average NPV and specificity using the selected texture features were 99.0% and 45.2%, respectively, compared to the NPV (85.7%) and specificity (40.0%) in visually assessed MRI category-based diagnosis. Conclusion We, therefore, suggest that the NPV of our texture-based features method described performs similarly to or greater than the NPV of the MRI category-based diagnosis.

Background: Monocarboxylate transporter 8 (MCT8) deficiency is an X-chromosome-linked neurodevelopmental disorder resulting from impaired thyroid hormone transport across the cell membrane. The diagnosis of MCT8 deficiency is typically delayed owing to the late appearance of signs and symptoms as well as the inability of standard biomarkers of neonatal screening to provide early detection. In this study, we report, for the first time, the ability to detect MCT8 deficiency at birth using dried blood spot (DBS) samples. Methods: We retrospectively measured triiodothyronine (T3), thyroxine (T4), and reverse T3 (rT3) levels in DBS samples obtained at 4–5 days of life from 6 infants with genetically confirmed MCT8 deficiency and from 110 controls. The latter consisted of 58 healthy term neonates obtained at the same time, 16 were stored for more than 1 year before measurement to match samples from the MCT8-deficient infants. Ten DBS samples were collected at day 1 of life and 42 samples were from prematurely born neonates. Measurements were carried out in extract from eight millimeters diameter DBS using liquid chromatography-tandem mass spectrometry. Results: Contrary to characteristic iodothyronine abnormalities of MCT8 deficiency during later life, T3 and T4 values were not discriminatory from those of other study groups. In contrast, rT3 was significantly lower. The T3/rT3 ratio was higher in the DBS samples from the MCT8-deficient infants compared with all other groups with no overlap (p

SHORT syndrome is a rare developmental disorder frequently associated with growth failure and insulin resistant diabetes mellitus (IRDM). Since GH has a diabetogenic effect, GH therapy has been regarded as a contraindication. We observed a Brazilian girl with SHORT syndrome who received GH therapy from 4 6/12 years of age for SGA short stature. GH dosage was increased from 0.23 to 0.36 mg/kg/week, but statural response to GH therapy remained poor. Her blood HbA1c level, though it remained 5.5-6.0% in childhood, began to elevate with puberty and increased to 9.2% at 10 6/12 years of age, despite the discontinuation of GH therapy at 9 11/12 years of age. Laboratory studies indicated antibody-negative IRDM. She was treated with metformin and canagliflozin (a sodium glucose co-transporter 2 (SGLT2) inhibitor), which ameliorated overt diurnal hyperglycemia and mild nocturnal hypoglycemia and reduced her blood HbA1c around 7%. Whole exome sequencing revealed a de novo heterozygous pathogenic variant (c.1945C>T:p.(Arg649Trp)) in PIK3R1 known as the sole causative gene for SHORT syndrome. Subsequent literature review for patients with molecularly confirmed SHORT syndrome revealed the development of IRDM in 10 of 15 GH-untreated patients aged ≥12 years but in none of three GH-treated and six GH-untreated patients aged ≤10 years. These findings imply a critical role of pubertal development and/or advanced age rather than GH therapy in the development of IRDM, and a usefulness of SGLT2 inhibitor in the treatment of ‍IRDM.

We report a Japanese girl with Coffin‐Lowry syndrome phenotype such as hypertelorism, hypodontia, and tapering fingers and 46,XX,t(X;11)(p22;p15)dn. Whole genome sequencing revealed RPS6KA3 disruption by the translocation, and X‐inactivation analysis indicated preferential inactivation of the normal X chromosome. The results explain the development of an X‐linked disease in this girl.

Mutations in PAX8, the gene for a thyroid-specific transcription factor, causes congenital hypothyroidism (CH) with autosomal dominant inheritance. All previously detected PAX8 mutations except one are located in the DNA-binding paired domain. The proband, a 1-yr-old boy, was diagnosed with CH in the frame of newborn screening. He had high serum TSH level (180 mU/L) and low serum free T4 level (0.4 ng/dL). Ultrasonography revealed that the proband had thyroid hypoplasia. Importantly, he had a family history of CH, i.e., his mother also had CH and hypoplasia. Next generation sequencing-based mutation screening revealed a novel heterozygous PAX8 mutation (c.116A>C, p.His39Pro) that was transmitted to the proband from the mother. Expression experiments with HeLa cells confirmed that His39Pro-PAX8 exhibited defective transactivation of the TG promoter-luciferase reporter. In conclusion, we identified and described a novel loss-of-function PAX8 mutation in a family with thyroid hypoplasia. Patients with dominantly inherited CH and no extrathyroidal abnormalities could have PAX8 mutations.

Background The need for quantitative assessment of interstitial lung involvement on thin-section computed tomography (CT) has arisen in interstitial lung diseases including connective tissue disease (CTD). Purpose To evaluate the capability of machine learning (ML)-based CT texture analysis for disease severity and treatment response assessments in comparison with qualitatively assessed thin-section CT for patients with CTD. Material and Methods A total of 149 patients with CTD-related ILD (CTD-ILD) underwent initial and follow-up CT scans (total 364 paired serial CT examinations), pulmonary function tests, and serum KL-6 level tests. Based on all follow-up examination results, all paired serial CT examinations were assessed as “Stable” (n = 188), “Worse” (n = 98) and “Improved” (n = 78). Next, quantitative index changes were determined by software, and qualitative disease severity scores were assessed by consensus of two radiologists. To evaluate differences in each quantitative index as well as in disease severity score between paired serial CT examinations, Tukey's honestly significant difference (HSD) test was performed among the three statuses. Stepwise regression analyses were performed to determine changes in each pulmonary functional parameter and all quantitative indexes between paired serial CT scans. Results Δ% normal lung, Δ% consolidation, Δ% ground glass opacity, Δ% reticulation, and Δdisease severity score showed significant differences among the three statuses ( P 2 ≤0.42; P Conclusion ML-based CT texture analysis has better potential than qualitatively assessed thin-section CT for disease severity assessment and treatment response evaluation for CTD-ILD.

Purpose To prospectively compare the capability of dynamic first-pass contrast-enhanced (CE) perfusion MR imaging with ultra-short TE and area-detector CT (ADCT), analyzed with the same mathematical methods, and that of FDG-PET/CT for diagnosis and management of solitary pulmonary nodules (SPNs). Methods and materials Our institutional review board approved this study and written informed consent was obtained from all subjects. A total 57 consecutive patients with 71 nodules prospectively underwent dynamic CE-perfusion ADCT and MR imaging with ultra-short TE, FDG-PET/CT, as well as microbacterial and/or pathological examinations. The nodules were classified into malignant nodules (n = 45) and benign nodules (n = 26). Pulmonary arterial, systemic arterial and total perfusions were determined by means of dual-input maximum slope models on ADCT and MR imaging and maximum values of standard uptake values (SUVmax) on PET/CT. Receiver operating characteristic (ROC) analysis was performed for each index, and sensitivity, specificity and accuracy were compared by McNemar's test. Results Areas under the curve (Azs) of total perfusion on ADCT (Az = 0.89) and MR imaging (Az = 0.88) were significantly larger than those of systemic arterial perfusion and MR imaging (p Conclusion Dynamic CE-perfusion MR imaging with ultra-short TE and ADCT and have similar potential capabilities, and are superior to FDG-PET/CT in this setting.

Aims/Introduction Glucokinase–maturity‐onset diabetes of the young (GCK‐MODY; also known as MODY2) is a benign hyperglycemic condition, which generally does not require medical interventions. The only known exception is increased birthweight and related perinatal complications in unaffected offspring of affected women. As previous data were obtained mostly from white Europeans, the present study analyzed the pregnancy outcomes of Japanese women with GCK‐MODY to better formulate the management plan for this population. Materials and Methods The study participants were 34 GCK‐MODY families whose members were diagnosed at Osaka City General Hospital during 2010–2017. A total of 53 pregnancies (40 from 23 affected women, 13 from 11 unaffected women) were retrospectively analyzed by chart review. Results Birthweights of unaffected offspring born to affected women were significantly greater as compared with those of affected offspring (P = 0.003). The risk of >4,000 g birthweight (16%), however, was lower as compared with that previously reported for white Europeans, and none of the offspring had complications related to large birthweight. Insulin treatment of the affected women resulted in a significant reduction in the birthweights of unaffected offspring. Perinatal complications including small‐for‐gestational age birthweight were found only in affected offspring born to insulin‐treated women. Conclusions In Japanese GCK‐MODY families, unaffected offspring born to affected women were heavier than affected offspring. However, insulin treatment of affected women might not be advisable because of the lower risk of macrosomic birth injury, and an increased risk of perinatal complications in affected offspring.

Glaucoma leads to irreversible blindness. Numerous anti-glaucoma eye drops have been developed. Unfortunately, many patients with glaucoma still suffer from progressive visual disorders. Recently, ripasudil hydrochloride hydrate, a selective Rho-associated protein kinase inhibitor, was launched for the treatment of glaucoma. However, adverse events, such as conjunctival hyperemia, are often noted in clinical trials using healthy subjects. Therefore, we investigated the onset, offset, and kinetic changes of conjunctival hyperemia induced by ripasudil ophthalmic solution in patients with open-angle glaucoma or ocular hypertension who had already been treated with anti-glaucoma eye drops other than ripasudil. Conjunctival hyperemia was evaluated by both clinical grading by 3 ophthalmic physicians and pixel coverage of conjunctival blood vessels determined by conjunctival hyperemia-analyzing software. Conjunctival hyperemia appeared within 10 min post-instillation in most of the participants. Clinical grade and pixel coverage increased significantly 10 min post-instillation and then decreased. In most of the participants, hyperemia resolved within 2 h. Median conjunctival hyperemia offset was 90 min. A tendency of monotonic increase was observed between clinical grade and pixel coverage. Taken altogether, hyperemia induced by ripasudil was transient in glaucoma patients who had already been treated with anti-glaucoma eye drops other than ripasudil.

Background Cosmetic problems induced by conventional prostaglandin F2α (PGF2α) analogs are common. We prospectively evaluated the improvement of patients with prostaglandin-associated periorbital syndrome (PAPS) for whom the treatment regimen was switched from conventional PGF2α analogs to a new selective prostaglandin-EP2 agonist (i.e., omidenepag isopropyl). Methods We finally evaluated 12 patients with follow-up for one year who changed the therapy from conventional PGF2α drugs to omidenepag isopropyl. Digital facial images of the patients were captured prior to the initiation of therapy with omidenepag isopropyl and after approximately three, six, and 12 months. Three independent observers judged the recovery according to the five signs of PAPS - deepening of the upper eyelid sulcus (DUES), flattening of the lower eyelid bags, upper eyelid ptosis, ciliary hypertrichosis, and periorbital skin hyperpigmentation - by comparing images at baseline and each month. Results The mean age of patients (eight females; four males) was 61 years. The original PGF2α drugs were bimatoprost (N = 7), latanoprost (N = 3), travoprost (N = 1), and tafluprost (N = 1). The mean duration of treatment with PGF2α was 61 months. PAPS signs were evaluated in 11 patients after three months and in all 12 patients after six and 12 months. After three, six, and 12 months, DUES improved in five, six, and six patients, respectively; flattening of the lower eyelid bags improved in two, two, and three patients, respectively; upper eyelid ptosis improved in zero, one, and two patients, respectively; ciliary hypertrichosis improved in zero, one, and zero patients, respectively; and eyelid pigmentation improved in one, five, and three patients, respectively. Recovery of DUES was the most observed sign at ≤50%, whereas the recovery of ciliary hypertrichosis was the least sign at ≤8% at 12 months. All patients with improved DUES at one year had been receiving bimatoprost or travoprost. Conclusions Some PAPS signs improved after the administration of omidenepag isopropyl for one year. Our findings are useful for patients suffering from cosmetic problems induced by conventional PGF2α analogs.

Purpose To evaluate the capability of inspiratory/expiratory Xe-enhanced ADCT for assessment of changes in pulmonary function and regional ventilation of surgically treated NSCLC patients. Method and materials Forty consecutive surgically treated NSCLC patients underwent pre- and postoperative inspiratory/expiratory Xe-enhanced ADCT and pulmonary function tests. For each patient, pre- and post-operative data were analyzed and pre- and post-operative wash-in (WI) and wash-out (WO) indexes and ventilation ratio (VR=[WI-WO]/WI) maps generated by means of pixel-by-pixel analyses. Differences between pre- and postoperative WI (ΔWI), WO (ΔWO) and VR (ΔVR) were also determined. To determine the relationship between all ventilation index changes and pulmonary functional loss, Pearson’s correlation was used to correlate each ventilation index change with the corresponding pulmonary functional parameter change. In addition, stepwise regression analysis was performed for all ventilation index changes and each corresponding pulmonary functional parameter change. Results FEV1/FVC% change showed fair or good and significant correlations with ΔWI (r = 0.39, p = 0.01) and ΔVR (r = 0.68, p = 0.001), %FEV1 change good or moderate and significant correlations with ΔWI (r = 0.56, p = 0.0001) and ΔVR (r = 0.76, p Conclusion Inspiratory/expiratory Xe-enhanced ADCT has the potential to demonstrate that pre- and postoperative ventilation status of surgically treated NSCLC patients correlates with pulmonary function.

To evaluate the capability ML-based CT texture analysis for improving interobserver agreement and accuracy of radiological finding assessment in patients with COPD, interstitial lung diseases or infectious diseases.Training cases (n = 28), validation cases (n = 17) and test cases (n = 89) who underwent thin-section CT at a 320-detector row CT with wide volume scan and two 64-detector row CTs with helical scan were enrolled in this study. From 89 CT data, a total of 350 computationally selected ROI including normal lung, emphysema, nodular lesion, ground-glass opacity, reticulation and honeycomb were evaluated by three radiologists as well as by the software. Inter-observer agreements between consensus reading with and without using the software or software alone and standard references determined by consensus of pulmonologists and chest radiologists were determined using κ statistics. Overall distinguishing accuracies were compared among all methods by McNemar's test.Agreements for consensus readings obtained with and without the software or the software alone with standard references were determined as significant and substantial or excellent (with the software: κ = 0.91, p0.0001; without the software: κ = 0.81, p0.0001; the software alone: κ = 0.79, p0.0001). Overall differentiation accuracy of consensus reading using the software (94.9 [332/350] %) was significantly higher than that of consensus reading without using the software (84.3 [295/350] %, p0.0001) and the software alone (82.3 [288/350] %, p0.0001).ML-based CT texture analysis software has potential for improving interobserver agreement and accuracy for radiological finding assessments in patients with COPD, interstitial lung diseases or infectious diseases.

Objective We investigated the detailed time course of conjunctival hyperemia induced by omidenepag isopropyl ophthalmic solution 0.002% (omidenepag), a selective prostaglandin E2 receptor 2 agonist. Methods and analysis We recruited 34 healthy subjects and administered omidenepag in the right eye and ripasudil 0.4% in the left eye. We evaluated conjunctival hyperemia using slit-lamp photography at baseline and after 15, 30, 60, 120, 180 and 360 min. The conjunctival hyperemia score was graded by three independent observers using a scale from 0 (none) to 3 (severe). We also evaluated conjunctival hyperemia by the pixel coverage of conjunctival blood vessels (per cent coverage) determined using a conjunctival hyperemia-analysing software. Results In omidenepag, the conjunctival hyperemia score and per cent coverage peaked at both 30 min (mean score±SD: 1.57±0.67 and 11.90%±3.66%, respectively) and then gradually decreased at 60 min (10.79%±3.32%) and 120 min (1.10±0.52) when they reached a level that was not significantly different from the baseline values. For ripasudil 0.4%, the peak time of the conjunctival hyperemia score and per cent coverage were both at 15 min (score: 2.42±0.54 and 15.26%±3.38%). The degree of conjunctival hyperemia was significantly higher for ripasudil 0.4% than that for omidenepag from 15 to 30 min in both the conjunctival hyperemia score and per cent coverage (p, The article has been presented at the 30th Annual Meeting of the Japanese Glaucoma Society on 7 September 2019.

Significance This study is the first to show that the manual upper eyelid elevation (manual UEE) that is commonly used to prevent disruption of the IOP measurement due to blinking or upper eyelid contact with the tip of the tonometer does not affect the IOP values. Purpose We investigated whether manual UEE affects the IOP readings using three rebound tonometers (Icare TA01i, Icare PRO, and Icare ic100) and Goldmann applanation tonometry (GAT). Methods One eye was measured for 101 patients (56 eyes of primary open-angle glaucoma patients and 45 healthy subjects). The IOPs were measured without and with manual UEE. Each IOP was measured twice; the measurement order using the tonometers was randomly selected. In addition, palpebral fissure height (distance between the upper and lower eyelids) was measured. Results The IOPs without manual UEE were 12.1 ± 2.9, 13.3 ± 2.7, 11.7 ± 2.9, and 16.0 ± 3.2 mmHg (Icare TA01i, Icare PRO, Icare ic100, and GAT), and those with manual UEE were 12.3 ± 3.0, 13.3 ± 2.8, 11.7 ± 2.9, and 16.0 ± 3.3, respectively. No significant difference was found between the IOP without and with manual UEE (IOP difference; all, P > .50; paired t test). Multiple linear regression analyses revealed that palpebral fissure height did not affect IOP difference for any of the tonometers. Conclusions Simple manual UEE when measuring the IOP has little effect on the IOP obtained using all current rebound tonometers and GAT.

Purpose We evaluated the recovery of patients with PAPS for whom the treatment regimen switched from conventional prostaglandin F2α analogues to a new selective prostaglandin-EP2 agonist: omidenepag isopropyl. Patients and methods From November 2018 to July 2019, we prospectively evaluated 11 patients who had been using conventional PGF2α drugs. Digital photographs of the patients were taken before the start of omidenepag isopropyl therapy and ~3 and 6 months after. Three independent observers used the photographs to judged recovery according to the 5 signs of PAPS: deepening of the upper eyelid sulcus (DUES), flattening of the lower eyelid bags, upper eyelid ptosis, ciliary hypertrichosis, and periorbital skin hyperpigmentation. Results The mean age of patients was 61, and 7 patients were female. The original PGF2α drugs were bimatoprost, latanoprost, travoprost, and tafluprost. The mean duration of PGF2α treatment was 65 months. PAPS signs were evaluated in 10 patients after 3 months and in all 11 patients after 6 months: After 3 and 6 months, DUES improved in 3 and 3 patients, respectively; flattening of the lower eyelid bags improved in 1 and 2 patients, respectively; upper eyelid ptosis did not improve in any patients; ciliary hypertrichosis improved in 0 and 2 patients, respectively; and eyelid pigmentation improved in 2 and 8 patients, respectively. The 3 patients who showed improvement in DUES at 6 months had all previously used bimatoprost. Conclusions Some PAPS signs improved after patients started taking omidenepag isopropyl. Our findings will be useful for patients taking antiglaucoma eye drops.

Aims To compare the diagnostic performance of a reduced-order computed tomography-derived fractional flow reserve (CT-FFR) technique derived from luminal deformation and static CT stress myocardial perfusion (CTP). Methods and results Forty-six patients (84 vessels) with suspected coronary artery disease from a single institution planned for elective coronary angiography prospectively underwent research indicated invasive fractional flow reserve (FFR) and 320-detector CT coronary angiography (CTA) and static CTP. Analyses were performed in separate blinded core laboratories for CT-FFR and CTP. CT-FFR was derived using a reduced-order model with dedicated software on a standard desktop computer. CTP was assessed visually and quantitatively by transmural perfusion ratio (TPR). Invasive FFR was significant in 33% (28/84) of vessels. Overall per-vessel sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for CT-FFR were 81%, 84%, 71%, 90%, and 83%, respectively, those of visual CTP were 54%, 92%, 79%, 77%, and 78%, respectively, and TPR were 64%, 48%, 42%, 70%, and 54%, respectively. Per-vessel receiver operator curve analysis demonstrated a significantly larger area under the curve (AUC) for CT-FFR (0.89) with that for visual CTP (0.72; P = 0.016), TPR (0.55; P

The objective of our study was to directly compare the capability of dynamic first-pass contrast-enhanced (CE) perfusion area-detector CT (ADCT) and FDG PET/CT for differentiation of metastatic from nonmetastatic lymph nodes and assessment of N stage in patients with non-small cell lung carcinoma (NSCLC).Seventy-seven consecutive patients, 45 men (mean age ± SD, 70.4 ± 5.9 years) and 32 women (71.2 ± 7.7 years), underwent dynamic first-pass CE-perfusion ADCT at two or three different positions for covering the entire thorax, FDG PET/CT, surgical treatment, and pathologic examination. From all ADCT data for each of the subjects, a whole-chest perfusion map was computationally generated using the dual- and single-input maximum slope and Patlak plot methods. For quantitative N stage assessment, perfusion parameters and the maximum standardized uptake value (SUVThe area under the ROC curve (ADynamic first-pass CE-perfusion ADCT is as useful as FDG PET/CT for the differentiation of metastatic from nonmetastatic lymph nodes and assessment of N stage in patients with NSCLC.

Objectives This study describes the feasibility and accuracy of a novel computed tomography (CT) fractional flow reserve (FFR) technique based on alternative boundary conditions. Background Techniques used to compute FFR based on images acquired from coronary computed tomography angiography (CTA) are described. Boundary conditions were typically determined by allometric scaling laws and assumptions regarding microvascular resistance. Alternatively, boundary conditions can be derived from the structural deformation of coronary lumen and aorta, although its accuracy remains unknown. Methods Forty-two patients (78 vessels) in a single institution prospectively underwent 320-detector coronary CTA and FFR. Deformation of coronary cross-sectional lumen and aorta, computed from coronary CTA images acquired over diastole, was used to determine the boundary conditions based on hierarchical Bayes modelling. CT-FFR was derived using a reduced order model performed using a standard desktop computer and dedicated software. First, 12 patients (20 vessels) formed the derivation cohort to determine optimal CT-FFR threshold with which to detect functional stenosis, defined as FFR of ≤0.8, which was validated in the subsequent 30 patients (58 vessels). Results Derivation cohort results demonstrated optimal threshold for CT-FFR was 0.8 with 67% sensitivity and 91% specificity. In the validation cohort, CT-FFR was successfully computed in 56 of 58 vessels (97%). Compared with coronary CTA, CT-FFR at ≤0.8 demonstrated a higher specificity (87% vs. 74%, respectively) and positive predictive value (74% vs. 60%, respectively), with comparable sensitivity (78% vs. 79%, respectively), negative predictive value (89% vs. 88%, respectively), and accuracy (area under the curve: 0.88 vs. 0.77, respectively; p = 0.22). Based on Bland-Altman analysis, mean intraobserver and interobserver variability values for CT-FFR were, respectively, −0.02 ± 0.05 (95% limits of agreement: −0.12 to 0.08) and 0.03 ± 0.06 (95% limits: 0.07 to 0.19). Mean ± SD time per patient for CT-FFR analysis was 27.07 ± 7.54 min. Conclusions CT-FFR based on alternative boundary conditions and reduced-order fluid model is feasible, highly reproducible, and may be accurate in detecting FFR ≤ 0.8. It requires a short processing time and can be completed at point-of-care. Further validation is required in large prospective multicenter settings.

Although paternally expressed IGF2 is known to play a critical role in placental and body growth, only a single mutation has been found in IGF2. We identified, through whole-exome sequencing, a de novo IGF2 indel mutation leading to frameshift (NM_000612.5:c.110_117delinsAGGTAA, p.(Leu37Glnfs*31)) in a patient with Silver-Russell syndrome, ectrodactyly, undermasculinized genitalia, developmental delay, and placental hypoplasia. Furthermore, we demonstrated that the mutation resided on the paternal allele by sequencing the long PCR product harboring the mutation- and methylation-sensitive SmaI and SalI sites before and after SmaI/SalI digestion. The results, together with the previous findings in four cases from a single family with a paternally inherited IGF2 nonsense mutation and those in patients with variable H19 differentially methylated region epimutations leading to compromised IGF2 expression, suggest that the whole phenotype of this patient is explainable by the IGF2 mutation, and that phenotypic severity is primarily determined by the IGF2 expression level in target tissues.

To prospectively and directly compare the capability for assessments of regional ventilation and pulmonary functional loss in smokers of xenon-ventilation CT obtained with the dual-energy CT (DE-CT) and subtraction CT (Sub-CT) MATERIALS AND METHODS: Twenty-three consecutive smokers (15 men and 8 women, mean age: 69.7±8.7years) underwent prospective unenhanced and xenon-enhanced CTs, the latter by Sub-CT and DE-CT methods, ventilation SPECT and pulmonary function tests. Sub-CT was generated from unenhanced and xenon-enhanced CT, and all co-registered SPECT/CT data were produced from SPECT and unenhanced CT data. For each method, regional ventilation was assessed by using a 11-point scoring system on a per-lobe basis. To determine the functional lung volume by each method, it was also calculated for individual sublets with a previously reported method. To determine inter-observer agreement for each method, ventilation defect assessment was evaluated by using the χ2 test with weighted kappa statistics. For evaluation of the efficacy of each method for pulmonary functional loss assessment, functional lung volume was correlated with%FEVEach inter-observer agreement was rated as substantial (Sub-CT: κ=0.69, p0.0001; DE-CT: κ=0.64, p0.0001; SPECT/CT: κ=0.64, p0.0001). Functional lung volume for each method showed significant to good correlation with%FEVXenon-enhanced CT obtained by Sub-CT can be considered at least as efficacious as that obtained by DE-CT and SPECT/CT for assessment of ventilation abnormality and pulmonary functional loss in smokers.

Onsite workstation-based CT-derived Fractional-Flow-Reserve (CT-FFR) is accurate in assessing hemodynamic-significance of coronary stenoses. We aim to describe the influence of operator expertise and luminal-segmentation technique on the diagnostic performance, precision and reproducibility of CT-FFR in identifying hemodynamically-significant stenosis (FFR≤0.8).Forty-eight consecutive stable-patients (86 vessels) with suspected CAD underwent research indicated invasive-FFR and 320-detector CT-coronary-angiography (CTA). CT-FFR was derived using reduced-order model on standard desktop-computer. Semi-automated coronary luminal segmentation was performed using focused-technique with manual adjustments at regions of stenosis and calcification or comprehensive-technique with manual adjustments along the entire course of the vessel. CT-FFR analysis was performed using 3 blinded operators; core-laboratory engineer using focused-technique and radiographer and cardiologist using the comprehensive-technique. Diagnostic performance was assessed by area under receiver-operating-curve (AUC). Precision with invasive FFR was determined by Bland-Altman analysis, and reproducibility by intraclass-correlation-coefficient (ICC).Diagnostic performance was comparable among operators (Engineer: AUC = 0.88, Radiographer 0.84; Cardiologist 0.87; P = 0.59). Coronary luminal-segmentation time was shortest using focused technique (engineer 6:17 ± 2.43 min), compared with comprehensive technique (cardiologist 14.83 ± 7.09, radiographer 24.74 ± 12.65; P 0.001). Use of focused technique was associated with widest limits of agreement (LOA) with FFR and moderate intra-operator reproducibility (engineer LOA -0.20-0.33; ICC 0.66), when compared with the comprehensive technique which demonstrated narrower LOA and excellent reproducibility [radiographer (LOA -0.17-0.20, ICC = 0.91) and cardiologist (LOA-0.15-0.23, ICC = -0.93)] CONCLUSION: A workstation-based CT-FFR technique was reproducible with high and comparable diagnostic performance among operators with different expertise. A comprehensive luminal segmentation technique was the most time-consuming and associated with the highest reproducibility and precision with FFR.

We evaluated the agreement between the intraocular pressure (IOP) values of new rebound tonometer, Icare ic100, and Icare TA01i or Goldmann applanation tonometer (GAT).We studied one eye each of 106 subjects (57 with primary open-angle glaucoma, 49 healthy subjects). IOP was randomly measured twice with the patient in sitting position using the Icare ic100, Icare TA01i, and GAT. Tonometer measurements were evaluated using Bland-Altman analysis. The relationship between IOP difference (Icare ic100-GAT) and age, sex, disease, axial length, central corneal thickness (CCT), and corneal curvature was investigated using multivariate regression analysis.IOPs measured using Icare ic100, Icare TA01i, and GAT were 11.7±3.0 (mean±standard deviation), 12.2±2.9, and 16.0±3.2 mm Hg, respectively (P0.001, one-way analysis of variance). Icare ic100 showed significantly lower IOPs than GAT (P0.05), but not than Icare TA01 (P0.05; Tukey-Kramer test). Bland-Altman analysis revealed that the mean differences between Icare ic100 and Icare TA01i and those between Icare ic100 and GAT were -0.46 and -4.2 mm Hg, respectively (95% limits of agreement, -3.35 to 2.42 and -10.10 to 1.61 mm Hg, respectively). For IOP differences between Icare ic100 and GAT, parameters selected in the optimal model were CCT (coefficient, 20.3, P=0.029), corneal curvature (3.0, P=0.020), and glaucoma-normal (-1.0, P=0.004).The new rebound tonometer Icare ic100 almost constantly showed IOPs lower than GAT. The difference was affected by CCT, corneal curvature, and disease.

Although MAMLD1 on chromosome Xq28 is known as a causative gene for 46,XY disorders of sex development, clinical information is virtually limited in patients of infancy to early childhood. Here, we report long-term genital and hormonal findings in three previously described Japanese patients with MAMLD1 mutations, i.e., patients 1 and 2 with p.E197X and patient 3 with p.R726X. As previously reported, patients 1-3 exhibited penoscrotal hypospadias with chordee, microphallus, bifid/hypoplastic scrotum, and/or bilateral cryptorchidism/retractile testes, in the presence of sufficiently high serum basal or hCG-stimulated testosterone values in the mini-pubertal period to early childhood. Subsequently, patient 1 had low serum hCG-stimulated testosterone value (126 ng/dL) at 13 11/12 years of age, and manifested microphallus (4.5 cm), relatively small testes (left 8 mL and right 10 mL), Tanner stage 3 genitalia and pubic hair development at 18 3/12 years of age. Similarly, patients 2 and 3 showed mild hypergonadotropic hypogonadism at 7 0/12 and 9 9/12 years of age, respectively, with serum GnRH-stimulated LH values of 5.5 and 7.2 mIU/mL and FSH values of 10.3 and 19.8 mIU/mL and hCG-stimulated testosterone values of 70 and 80 ng/dL, respectively. Testis ultrasound studies delineated microlithiasis in patients 1 and 3. These results imply for the first time deterioration of testicular function with age in patients with pathologic MAMLD1 mutations.

Although partial androgen insensitivity syndrome (PAIS) is caused by attenuated responsiveness to androgens, androgen receptor gene (AR) mutations on the coding regions and their splice sites have been identified only in AR (NM_000044.4:c.2450−42 G > A). This variant created the splice acceptor motif that was accompanied by pyrimidine-rich sequence and two candidate branch sites. Consistent with this, reverse transcriptase (RT)-PCR experiments for cycloheximide-treated lymphoblastoid cell lines revealed a relatively large amount of aberrant mRNA produced by the newly created splice acceptor site and a relatively small amount of wildtype mRNA produced by the normal splice acceptor site. Furthermore, most of the aberrant mRNA was shown to undergo nonsense mediated decay (NMD) and, if a small amount of aberrant mRNA may have escaped NMD, such mRNA was predicted to generate a truncated AR protein missing some functional domains. These findings imply that the deep intronic mutation creating an alternative splice acceptor site resulted in the production of a relatively small amount of wildtype AR mRNA, leading to PAIS.

Aims To determine the diagnostic accuracy of semi-automatic quantitative metrics compared to expert reading for interpretation of computed tomography perfusion (CTP) imaging. Methods The CORE320 multicenter diagnostic accuracy clinical study enrolled patients between 45 and 85 years of age who were clinically referred for invasive coronary angiography (ICA). Computed tomography angiography (CTA), CTP, single photon emission computed tomography (SPECT), and ICA images were interpreted manually in blinded core laboratories by two experienced readers. Additionally, eight quantitative CTP metrics as continuous values were computed semi-automatically from myocardial and blood attenuation and were combined using logistic regression to derive a final quantitative CTP metric score. For the reference standard, hemodynamically significant coronary artery disease (CAD) was defined as a quantitative ICA stenosis of 50% or greater and a corresponding perfusion defect by SPECT. Diagnostic accuracy was determined by area under the receiver operating characteristic curve (AUC). Results Of the total 377 included patients, 66% were male, median age was 62 (IQR: 56, 68) years, and 27% had prior myocardial infarction. In patient based analysis, the AUC (95% CI) for combined CTA-CTP expert reading and combined CTA-CTP semi-automatic quantitative metrics was 0.87(0.84–0.91) and 0.86 (0.83–0.9), respectively. In vessel based analyses the AUC's were 0.85 (0.82–0.88) and 0.84 (0.81–0.87), respectively. No significant difference in AUC was found between combined CTA-CTP expert reading and CTA-CTP semi-automatic quantitative metrics in patient based or vessel based analyses(p > 0.05 for all). Conclusion Combined CTA-CTP semi-automatic quantitative metrics is as accurate as CTA-CTP expert reading to detect hemodynamically significant CAD.

The purpose of this study was to clarify the degree of early postnatal growth by birthweight and detect early predictive factors for pediatric obesity. Body mass index (BMI) and degree of obesity were examined in children in the fourth year of elementary school and second year of junior high school. Their BMI at birth and three years of age were also examined. Based on birthweight, participants were divided into three groups: low (< 2500 g), middle (2500–3500 g), and high (> 3500 g). Furthermore, according to the degree of obesity, they were divided into two groups: obese (20% ≤) and non-obese (20% >). The change of BMI from birth to three years of age (ΔBMI) showed a strong inverse relationship with birthweight and was significantly different among the three birthweight groups (low > middle > high). The ΔBMI and BMI at three years of age were higher in obese than in non-obese children and showed significant positive correlations with the degree of obesity. Early postnatal growth might be determined by birthweight and was higher in obese than in non-obese children. The ΔBMI from birth to three years of age and BMI at age of three years could be predictive factors for pediatric obesity.

Coronary computed tomography angiography (CCTA) plaque morphology based on conventional Hounsfield units relies on absolute CT numbers is influenced by imaging and anatomical variables. The project describes and tests a novel alternative method, termed the "labeling method", which uses relative CT numbers and 3-dimensional plaque structure. Using virtual histology intravascular ultrasound (VH-IVUS) as the reference standard, this study compares the labeling method to a conventional CT-number based method to determine coronary plaque morphology. Thirty-seven high-risk, non-calcified atherosclerotic coronary lesions were prospectively evaluated in 33 consecutive patients who underwent CCTA followed by VH-IVUS (mean interval 8.6 ± 13.3 days). CCTA-derived vessel and minimum lumen areas were compared to VH-IVUS measures. Fibrotic and necrotic core areas were calculated by both the labeling method to the CT-number based method; both were tested for agreement with reference standard VH-IVUS. Inter- and intra-observer correlations were assessed. CCTA significantly underestimated minimum lumen area when compared to VH-IVUS (mean difference -1.4 ± 0.9 mm(2), p < 0.0001). Necrotic core and fibrous areas quantified using the labeling method demonstrated superior correlation with VH-IVUS compared to those quantified using the CT-number based method, Pearson's r = 0.75 versus 0.42 and r = 0.80 and 0.59, respectively. Compared to VH-IVUS, limits of agreement for the labeling method-derived necrotic core (-2.0 to 2.5 mm(2)) and fibrous areas (0.6-8.0 mm(2)) were more narrow than those determined using the CT-number based method (-3.7 to 7.3 and -4.0 to 8.9 mm(2), respectively). Inter- and intraobserver correlations were excellent for all CCTA derived measures (r = 0.85-0.98). A novel CCTA-based labeling method offers an alternative to conventional CT-number based analyses for plaque morphology. The labeling method demonstrates superior correlation to VH-IVUS for measures of fibrotic and necrotic core areas within non-calcified coronary atherosclerotic plaques.

We investigated the detailed time course of conjunctival hyperemia induced by ripasudil 0.4%, a novel Rho-kinase inhibitor anti-glaucoma eye drop, in healthy subjects.We recruited 51 healthy subjects and administered ripasudil 0.4% in their right eye. We evaluated conjunctival hyperemia using slit lamp photography and measured the intraocular pressure (IOP) using the Icare PRO Rebound Tonometer at baseline and after 5, 15, 30, 60, 90, and 120 min. The conjunctival hyperemia score was graded by three independent observers on a scale of 0 (none) to 3 (severe). Additionally, we analyzed the "percent coverage" of conjunctival hyperemia by using an automated hyperemia analysis software program; this program provides the pixel coverage of the conjunctival vessels in the region of interest. Dunnett and Steel multiple comparison tests were used, as appropriate, for the subsequent analyses.The conjunctival hyperemia score and percent coverage increased rapidly after the instillation of ripasudil 0.4%, peaking at 15 min (score: 1.83 ± 0.29 [mean ± SD]) and 5 min (11.6% ± 4.7%), respectively, and then gradually decreasing until 120 min (0.45 ± 0.22 and 4.7% ± 1.8%, respectively), when they reached a level that was not significantly different from the baseline values. The IOP decreased significantly compared to the baseline at 30, 60, and 90 min, based on the Dunnett test.Conjunctival hyperemia induced by ripasudil 0.4% peaks rapidly to moderate severity, but subsides relatively quickly.

Heterozygous loss-of-function mutations of FGFR1 (fibroblast growth factor receptor 1) cause various disorders including hypogonadotropic hypogonadism with split-hand/foot malformation (HH-SHFM). We examined FGFR1 in four Japanese patients with HH-SHFM (cases 1-4) and the mother of case 4 with HH only. Cases 1 and 2 had heterozygous loss-of-function mutations with no dominant negative effect (c.289G>A, p.[G97S]; and c.2231G>C, p.[R744T]), and case 3 had a splice donor site mutation (c.1663+1G>T). Notably, case 4 had a maternally inherited 8,312 bp microdeletion that involved noncoding exon 1U and impaired FGFR1 expression. Furthermore, consistent with the presence of transcription-related histone marks (e.g., H3K4Me3, H3K4Me1, and H3K27Ac) and multiple transcription factor-binding sites around exon 1U, functional studies demonstrated a marked transactivation function of a 414-bp segment harboring the transcription start site. These results support the relevance of FGFR1 mutations to HH-SHFM, and argue for the presence of the FGFR1 core-promoter elements around exon 1U.

Purpose To directly compare the capability of dynamic first-pass contrast-enhanced (CE-) perfusion area-detector CT (ADCT) and PET/CT for early prediction of treatment response, disease progression and overall survival of non-small cell carcinoma (NSCLC) patients treated with chemoradiotherapy. Materials and methods Fifty-three consecutive Stage IIIB NSCLC patients who had undergone PET/CT, dynamic first-pass CE-perfusion ADCT, chemoradiotherapy, and follow-up examination were enrolled in this study. They were divided into two groups: 1) complete or partial response (CR+PR) and 2) stable or progressive disease (SD+PD). Pulmonary arterial and systemic arterial perfusions and total perfusion were assessed at targeted lesions with the dual-input maximum slope method, permeability surface and distribution volume with the Patlak plot method, tumor perfusion with the single-input maximum slope method, and SUV max , and results were averaged to determine final values for each patient. Next, step-wise regression analysis was used to determine which indices were the most useful for predicting therapeutic effect. Finally, overall survival of responders and non-responders assessed by using the indices that had a significant effect on prediction of therapeutic outcome was statistically compared. Results The step-wise regression test showed that therapeutic effect (r 2 =0.63, p=0.01) was significantly affected by the following three factors in order of magnitude of impact: systemic arterial perfusion, total perfusion, and SUV max . Mean overall survival showed a significant difference for total perfusion (p=0.003) and systemic arterial perfusion (p=0.04). Conclusion Dynamic first-pass CE-perfusion ADCT as well as PET/CT are useful for treatment response prediction in NSCLC patients treated with chemoradiotherapy.

Although childhood adrenocortical carcinomas (c-ACCs) with a TP53 mutation are known to produce androgens, detailed steroidogenic characters have not been clarified. Here, we examined steroid metabolite profiles and expression patterns of steroidogenic genes in a c-ACC removed from the left adrenal position of a 2-year-old Brazilian boy with precocious puberty, using an atrophic left adrenal gland removed at the time of tumorectomy as a control. The c-ACC produced not only abundant dehydroepiandrosterone-sulfate but also a large amount of testosterone via the Δ5 pathway with Δ5-androstenediol rather than Δ4-androstenedione as the primary intermediate metabolite. Furthermore, the c-ACC was associated with elevated expressions of CYP11A1, CYP17A1, POR, HSD17B3, and SULT2A1, a low but similar expression of CYB5A, and reduced expressions of AKR1C3 (HSD17B5) and HSD3B2. Notably, a Leydig cell marker INSL3 was expressed at a low but detectable level in the c-ACC. Furthermore, molecular studies revealed a maternally inherited heterozygous germline TP53 mutation, and several post-zygotic genetic aberrations in the c-ACC including loss of paternally derived chromosome 17 with a wildtype TP53 and loss of maternally inherited chromosome 11 and resultant marked hyperexpression of paternally expressed growth promoting gene IGF2 and drastic hypoexpression of maternally expressed growth suppressing gene CDKN1C. These results imply the presence of combined steroidogenic properties of fetal adrenal and Leydig cells in this patient's c-ACC with a germline TP53 mutation and several postzygotic carcinogenic events.

Intrauterine growth restriction (IUGR) is associated with a substantially greater incidence of metabolic syndrome in adulthood. Animal studies have shown that IUGR offspring are hyperphagic during the early postnatal period and therefore exhibit obesity. The molecular mechanisms underlying food intake regulation in the gastrointestinal tract have not been clarified in IUGR. In the present study, we utilized a rat model of IUGR by restricting the food intake of the mother (50% of the normal intake, ad libitum; FR group) from day 7 of gestation until delivery. Pups from undernourished mothers were fostered by control mothers. We examined the food intake and assessed the gene expressions of ghrelin, peptide YY (PYY), and cholecystokinin (CCK) in the alimentary tract of male newborns (postnatal day1) and adult offspring (age, 7 months). Compared to the offspring whose mothers received the standard diet ad libitum (CON offspring), FR offspring were hyperphagic from the weaning time until the end of the experiment, and resulted in a heavier final weight. Both newborn and adult FR offspring had higher ghrelin gene expression in the stomach and higher ghrelin plasma levels than did the controls. Although the gastrointestinal gene expressions and plasma levels of the anorexic peptides, PYY and CCK, were elevated in the FR newborns, they decreased in the FR adults. Our findings suggest that the altered gene expressions of orexigenic and anorexigenic gut peptides in the gastrointestinal tract in the maternal undernutrition-induced IUGR offspring provide a potential mechanism to explain hyperphagia and obesity seen in these offspring.

Population-based studies have shown that the offspring of diabetic mothers have an increased risk of developing obesity, insulin resistance, type 2 diabetes and hypertension in later life. To investigate mechanism for the high incidence of metabolic diseases in the offspring of diabetic mothers, we focused on the tissue-specific glucocorticoid regulation by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) and studied offspring born to streptozotocin-induced diabetic rats. The body weights of newborn rats from diabetic mothers were heavier than those from control mothers. Offspring born to diabetic mothers demonstrated insulin resistance and mild glucose intolerance after glucose loading at 10 weeks and showed significantly increased 11beta-HSD1 mRNA and enzyme activity in adipose tissue at 12 weeks of age without obvious obesity. Hepatic 11beta-HSD1 mRNA was also elevated. We propose that the 11beta-HSD1 in adipose tissue and liver may play a key role in the development of metabolic syndrome in the offspring of diabetic mothers. Tissue-specific glucocorticoid dysregulation provides a candidate mechanism for the high incidence of metabolic diseases in the offspring of diabetic mothers. Therefore early analyses before apparent obesity are needed to elucidate the molecular mechanisms that may be programmed during the fetal period.

Purpose To determine the capability and influence of the mathematical method on dynamic contrast-enhanced (CE-) perfusion area detector CT (ADCT) for early prediction of treatment response as well as progression free and overall survival (PFS and OS) of non-small cell lung cancer (NSCLC) patients treated with chemoradiotherapy. Materials and methods Sixty-six consecutive stage III NSCLC patients underwent dynamic CE-perfusion ADCT examinations, chemoradiotherapy and follow-up examinations. Response Evaluation Criteria in Solid Tumors (RECIST) criteria were used to divide all patients into responders and non-responders. Differences in each of the indices for all targeted lesions between measurements obtained 2 weeks prior to the first and the third course of chemotherapy were determined for all patients. ROC analyses were employed to determine the capability of perfusion indices as markers for distinguishing RECIST responders from non-responders. To evaluate their capability for early prediction of therapeutic effect, OS of perfusion index-based responders and non-responders were compared by using the Kaplan–Meier method followed by log-rank test. Results Area under the curve (Az) for total perfusion by means of the dual-input maximum slope method was significantly larger than that of pulmonary arterial perfusion using the same method (p = 0.007) and of perfusion with the single-input maximum slope method (p = 0.007). Mean OS demonstrated significantly difference between responder- and non-responder groups for total perfusion (p = 0.02). Conclusion Mathematical models have significant influence on assessment for early prediction of treatment response, disease progression and overall survival using dynamic CE-perfusion ADCT for NSCLC patients treated with chemoradiotherapy.

Non invasive fractional flow reserve derived from CT coronary angiography (CT-FFR) has to date been typically performed using the principles of fluid analysis in which a lumped parameter coronary vascular bed model is assigned to represent the impedance of the downstream coronary vascular networks absent in the computational domain for each coronary outlet. This approach may have a number of limitations. It may not account for the impact of the myocardial contraction and relaxation during the cardiac cycle, patient-specific boundary conditions for coronary artery outlets and vessel stiffness. We have developed a novel approach based on 4D-CT image tracking (registration) and structural and fluid analysis, to address these issues. In our approach, we analyzed the deformation variation of vessels and the volume variation of vessels, primarily from 70% to 100% of cardiac phase, to better define boundary conditions and stiffness of vessels. We used a statistical estimation method based on a hierarchical Bayes model to integrate 4D-CT measurements and structural and fluid analysis data. Under these analysis conditions, we performed structural and fluid analysis to determine pressure, flow rate and CT-FFR. The consistency of this method has been verified by a comparison of 4D-CTFFR analysis results derived from five clinical 4D-CT datasets with invasive measurements of FFR. Additionally, phantom experiments of flexible tubes with/without stenosis using pulsating pumps, flow sensors and pressure sensors were performed. Our results show that the proposed 4D-CT-FFR analysis method has the potential to accurately estimate the effect of coronary artery stenosis on blood flow.

BACKGROUND Urinary myo-inositol (UMI) level is elevated in adult diabetic patients, and also increases after glucose loading. However, the relationship between UMI and plasma glucose levels in children is unknown. We aimed to assess whether UMI is a practical marker for glucose intolerance in children or not. METHODS In Study 1 (328 schoolchildren), fasting and postprandial UMI were measured, with ΔUMI defined as the difference between fasting and postprandial UMI levels. In Study 2, oral glucose tolerance tests and UMI measurements were conducted in 18 children with suspected having diabetes. RESULTS For Study 1, ΔUMI was observed [-0.65 (-3.9, 1.35) mg/g creatinine]. For Study 2, children with diabetes or impaired glucose tolerance had a significantly higher ΔUMI than children with normal glucose tolerance. CONCLUSIONS These studies demonstrated the normal range of UMI in children and possibility of a novel biomarker for early detection of glucose intolerance in children.

Although AP2S1 has recently been shown to be a causative gene for familial hypocalciuric hypercalcemia type 3 (FHH3), knowledge about FHH3 remains poor.Our objective was to report AP2S1 mutation and effects of low calcium formula in a patient with hypercalcemia and hypercalciuria.This Japanese female infant was found to have hypercalcemia by a routine laboratory test for poor weight gain on breast feeding. At 49 days of age, serum calcium (adjusted by Payne's formula) was 13.1 mg/dL, intact PTH 27 pg/mL, and urinary calcium-to-creatinine ratio 1.29 mg/mg. There was no evidence for hyperparathyroidism, PTHrP-producing neoplasm, and vitamin D excess. These data, except for hypercalciuria, appeared to be consistent with defective calcium-sensing receptor-mediated signaling. With use of low calcium formula containing 2.6 mg/dL of calcium, she showed catch-up growth, and serum calcium was decreased, as was urinary calcium-to-creatinine ratio. Furthermore, feeding with a mixture of low calcium formula and standard formula with a 2:1 ratio maintained serum calcium ∼12 mg/dL without markedly increasing serum PTH.Although no pathologic mutation was detected in CASR or GNA11, a presumably de novo heterozygous mutation (p.Arg15Leu), a previously reported causative mutation for FHH3, was identified in AP2S1 of this patient.The results imply that lack of hypocalciuria does not necessarily argue against the presence of AP2S1 mutations. The early infantile age of this patient would have played a certain role in the occurrence of hypercalciuria, and low calcium formula is worth attempting in infants with FHH.

Introduction Polychlorinated biphenyls (PCBs) are a class of biologically active, highly stable compounds. Exposure risks include consumption of fatty fish, meat, dairy products and human breast milk, as well as environmental and occupational settings. Numerous reports have described PCB-dependent adverse effects on human fetal growth, including increased risk for IUGR, changes in endocrine function and hormone metabolism, and immunosuppressive and neurological deficits. Here we test the prediction that in utero PCB exposure adversely effects placental morphology, potentially leading to placental insufficiency en route to fetal growth restriction. Methods PCB homologs (10) were measured in the maternal and fetal blood of a small cohort of normotensive pregnancies (22) by gas chromatography–mass spectrometry. PCB levels were compared with angiogenesis associated proteins Placental Growth Factor (PlGF) and sFlt-1, determined by ELISA, and the total estimated syncytiotrophoblast (ST) volume. Results Significant associations between PCB exposure and both PlGF and ST volume were identified. Discussion PCB effects on placenta morphology and predicted function are discussed. Conclusion These results demonstrate that the human placenta, including ST, is a target of PCB toxicity, and that current environmental PCB exposure levels are a risk to reproductive health.

To prospectively compare the capability of quantitative first-pass perfusion 320-detector row computed tomography (CT) (ie, area-detector CT) with that of combined positron emission tomography and CT (PET/CT) for differentiation between malignant and benign pulmonary nodules.This prospective study was approved by the institutional review board, and written informed consent was obtained from 50 consecutive patients with 76 pulmonary nodules. All patients underwent dynamic area-detector CT, PET/CT, and microbacterial and/or histopathologic examinations. All pulmonary nodules were divided into three groups: malignant nodules (n = 43), benign nodules with low biologic activity (n = 6), and benign nodules with high biologic activity (n = 27). For each dynamic area-detector CT data set, the perfusion derived by using the maximum slope model (PF(MS)), extraction fraction derived by using the Patlak plot model (EF(PP)), and blood volume derived by using the Patlak plot model (BV(PP)) were calculated. These parameters were statistically compared among the three nodule groups. Receiver operating characteristic (ROC) analyses were used to compare the diagnostic capability of the CT and PET/CT indexes. Finally, the sensitivity, specificity, and accuracy of each index were compared by using the McNemar test.All indexes in the malignant nodule group were significantly different from those in the low-biologic-activity benign nodule group (P.05). Areas under the ROC curve for PF(MS) and EF(PP) were significantly larger than those for BV(PP) (P.05) and maximal standard uptake value (SUV(max)) (P.05). The specificity and accuracy of PF(MS) and EF(PP) were significantly higher than those of BV(PP) and SUV(max) (P.05).Dynamic first-pass area-detector perfusion CT has the potential to be more specific and accurate than PET/CT for differentiating malignant from benign pulmonary nodules.http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100245/-/DC1.

Antithyroid drugs are widely used in the therapy of Graves’ disease (GD), and methimazole (MMI) is preferred for treatment of pediatric GD. The recommended initial dosage of MMI is 0.5–1.0 mg/kg/d for pediatric GD, although there are few studies on the optimal MMI dosage for initial treatment in children. We retrospectively compared the efficacy of different doses of MMI in 35 children with GD. Eight children were excluded due to lack of follow-up, etc. The remaining 27 children were divided into a high-dose group (HD; MMI≥0.7 (0.85 ± 0.13) mg/kg/d, n=8) and a low-dose group (LD; MMI

Tissue-specific dysregulation of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity in obese humans and animals may be associated with obesity and the metabolic syndrome. We investigated the effect of inhibition of 11beta-HSD with glycyrrhetinic acid (GE), an effective 11beta-HSD inhibitor, on body weight regulation in obese Zucker rats, which have a defect in the leptin receptor gene. GE (280 mg/kg/d) was administered in drinking water to 8-week-old male Zucker rats for 14 weeks. GE had no effect on food intake or weight gain, and did not affect hepatic 11beta-HSD1 and renal 11beta-HSD2 mRNA levels in obese rats. In contrast, average daily food intake and body weight on week 14 were significantly reduced by GE in lean rats (both P.0001). Hepatic 11beta-HSD1 and renal 11beta-HSD2 mRNA levels were also significantly decreased by GE in lean rats (both P.05). GE had no significant effect on plasma corticosterone levels in obese rats but lowered them in lean rats (P.05). Plasma leptin levels declined in both GE-treated obese and lean rats (both P.01). In conclusion, long-term GE treatment decreased weight gain in lean Zucker rats but not in obese Zucker rats. These findings suggest that the differing responses of 11beta-HSD1 to GE in obese and lean Zucker rats are closely associated with the different weight-gain responses. Furthermore, the weight-lowering effect of GE may require intact leptin receptors.

Several epidemiological and animal studies have shown that the offsprings of diabetic mothers have higher incidences of glucose intolerance, obesity, insulin resistance, and hypertension in later life. It is well known that glucocorticoid metabolism plays a crucial role on several adult disease originated from fetal environment. The aim of this study was to investigate the relation between diabetic pregnancy and glucocorticoid metabolism of both mother and fetus, focusing on the 11 beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2. A model of diabetic pregnancy was made by intravenous injection of streptozotocin (35 mg/kg body weight) to Sprague-Dawley rats, and blood and tissue samples were collected on day 20 of pregnancy. In the diabetic group, expression of 11 beta-hydroxysteroid dehydrogenase type 2 in placentas and fetal kidneys was decreased remarkably. Corticosterone levels of diabetic mothers were lower than those of control rats. Despite the differences in maternal corticosterone levels, fetal levels of corticosterone did not differ between the groups. Our results lend support to the concept that diabetic pregnancy imprints glucocorticoid regulation in these fetuses, which may contribute to their increased incidence of higher blood pressure as adults.

We describe for the first time an infant with Down syndrome and congenital nephrogenic diabetes insipidus (NDI). The 11-day-old Japanese boy was admitted with failure to thrive and fever. Polyuria (3,000-3,500 ml/m(2) per day), low urine specific gravity (1.001-1.002), and high plasma arginine vasopressin (AVP) (18.2 pg/ml) suggested NDI. Gene analysis confirmed the diagnosis of congenital NDI due to a novel mutation of the V2 receptor gene (L309P). He also had symptoms of Down syndrome and karyotype analysis of the peripheral lymphocytes revealed trisomy 21. The relationship between pyelectasis and a risk of Down syndrome is discussed.