Prognostic Implications of Sarcoidosis Granulomas　- Insights From the Multicenter Registry, the Japanese Cardiac Sarcoidosis Prognostic Study.

Background: Definitions of cardiac sarcoidosis (CS) differ among guidelines. Any systemic histological finding of CS is essential for the diagnosis of CS in the 2014 Heart Rhythm Society statement, but not necessary in the Japanese Circulation Society 2016 guidelines. This study aimed to reveal the differences in outcomes by comparing 2 groups, namely CS patients with or without systemic histologically proven granuloma. Methods and Results: This study retrospectively included 231 consecutive patients with CS. CS with granulomas in ≥1 organs was diagnosed in 131 patients (Group G), whereas CS without any granulomas was diagnosed in the remaining 100 patients (Group NG). Left ventricular ejection fraction (LVEF) was significantly reduced in Group NG compared with Group G (44±13% vs. 50±16%, respectively; P=0.001). However, Kaplan-Meier curves showed that major adverse cardiovascular events (MACE)-free survival outcomes were comparable between the 2 groups (log-rank P=0.167). Univariable analyses showed that significant predictors of MACE were Groups G/NG, histological CS, LVEF, and high B-type natriuretic peptide (BNP) or N-terminal pro BNP concentrations, but none of these was significant in multivariable analyses. Conclusions: Overall risks of MACE were similar between the 2 groups despite different manifestations in cardiac dysfunction. The data not only validate the prognostic value of non-invasive diagnosis of CS, but also show the need for careful observation and therapeutic strategy in patients with CS without any granuloma.

Clinical utility of 67 Gallium-SPECT/CT for determining osteotomy indication in patients with lower-limb osteomyelitis.

Standard non-invasive methods for diagnosing and selecting the best treatment for osteomyelitis in patients with multiple chronic conditions remain to be established. We aimed to evaluate the ability of quantitative 67 Ga-citrate single-photon emission computed tomography (67 Ga-SPECT/CT) to determine the indication for either non-surgical treatment or osteotomy in patients with lower-limb osteomyelitis (LLOM) associated with diabetes mellitus and lower-extremity ischemia, based on monitoring of inflammatory activity in bone tissue. This single-centre prospective study conducted from January 2012 to July 2017 included 90 consecutive patients with suspected LLOM. Regions of interest were drawn on SPECT images during quantification of Ga accumulation. Subsequently, the inflammation-to-background ratio (IBR) was calculated by dividing the maximal accumulated lesion number by the mean number for the distal femur bone marrow of the unaffected side. Osteotomy was performed in 28 of 90 patients (31%). The osteotomy rate was higher for patients with IBR >8.4 (71.4%) than for those with IBR ≤8.4 (5.5%) (p < 0.001, sensitivity: 0.89, specificity: 0.84). In the multivariate Cox regression analysis, IBR >8.4 was an independent risk factor for osteotomy (hazard ratio [HR]: 19.0, 95% confident interval [CI]: 5.6-63.9, p < 0.001). Transcutaneous oxygen tension (TcPO2 ) was identified as an independent risk factor for lower-limb amputation (HR: 0.96, 95% CI: 0.92-0.99, p = 0.01). The current results indicate that quantitative 67 Ga-SPECT/CT is useful for distinguishing patients with LLOM likely to require osteotomy.

Multicenter Registry in the Japanese Cardiac Sarcoidosis Prognostic (J-CASP) Study: Baseline Characteristics and Validation of the Non-invasive Approach Using 18F-FDG PET.

Background: Recent advances in cardiac modalities contribute to the guidelines on the diagnosis of cardiac sarcoidosis (CS) updated by the Japanese Circulation Society. The multicenter registry, Japanese Cardiac Sarcoidosis Prognostic (J-CASP) study tried to reveal recent trends of diagnosis and outcomes in CS patients and to validate the non-invasive diagnostic approach, including cardiac 18F-fluorodeoxyglucose (FDG) study. Methods/results: Databases from 12 hospitals consisting of 231 CS patients (mean age, 64 years; female, 65%; LV ejection fraction, 47%) diagnosed by the guidelines with FDG positron emission tomography (PET) study were integrated to compile clinical information on the diagnostic criteria and outcomes. Cardiac 18F-FDG uptake and magnetic resonance imaging (CMR) was positive identically in the histology-proven and clinically-diagnosed groups. The histology-proven group more frequently had reduce LV ejection fraction, myocardial perfusion abnormality and low-grade electrocardiogram (ECG) abnormality (P=0.003 to 0.016) than did the clinical group. During a 45-month period, the histology-proven group more frequently underwent appropriate implantable cardioverter-defibrillator (ICD) treatment (14% versus 4%, P=0.013) and new electronic device implantation (30% versus 12%, P=0.007) than did clinical group, respectively. There, however, was no difference in all-cause or cardiac mortality or in new hospitalization due to heart failure progression between them. Conclusion: The J-CASP registry demonstrated the rationale and clinical efficacies of non-invasive approach using advanced cardiac imaging modalities in the diagnosis of CS even when histological data were available.

Diagnostic performance of quantitative Ga-SPECT/CT for patients with lower-limb osteomyelitis.

BACKGROUND: Patients with lower-limb osteomyelitis (LLOM) may experience major adverse events, such as lower-leg amputations or death; therefore, early diagnosis and risk stratification are essential to improve outcomes. Ga-scintigraphy is commonly used for diagnosing inflammatory diseases. Although the diagnostic performance of planar and SPECT imaging for localized lesions is limited, SPECT/CT, which simultaneously acquires functional and anatomical definition, has resulted in significant improvements to diagnostic confidence. While quantitative Ga-SPECT/CT is an emerging approach to improve diagnoses, its diagnostic performance has not been sufficiently evaluated to date. Therefore, this study aimed to evaluate the diagnostic performance of Ga-SPECT/CT with quantitative analyses for patients with LLOM. METHODS: A total of 103 consecutive patients suspected of LLOM between April 2012 and October 2016 were analyzed. All patients underwent Ga-scintigraphy with SPECT/CT imaging. Findings were assessed visually, with higher than background accumulation considered positive, and quantitatively, using Ga-SPECT/CT images to calculate the lesion-to-background ratio (LBR), the maximum standardized uptake value (SUVmax), and total lesion uptake (TLU). Diagnoses were confirmed using pathological examinations and patient outcomes, and diagnostic performances of planar, SPECT, and SPECT/CT images were compared. To evaluate prognostic performance, all patients were observed for 5 years for occurrences of major adverse events (MAE), defined as recurrence of osteomyelitis, major leg amputation, or fatal event. Multivariate Cox regression was performed to evaluate outcome factors. RESULTS: The overall diagnoses indicated that 54 out of 103 patients had LLOM. LBR, SUVmax, and TLU were significantly higher in patients with LLOM (12.23 vs. 1.00, 4.85 vs. 1.34, and 68.77 vs. 8.63, respectively; p < 0.001). Sensitivity and specificity were 91% and 96% for SPECT/CT with LBR, 89% and 94% for SPECT/CT with SUVmax, and 91% and 92% for SPECT/CT with TLU, respectively. MAE occurred in 23 of 54 LLOM patients (43%). TLU was found to be an independent prognostic factor (p = 0.047). CONCLUSIONS: Ga-SPECT/CT using quantitative parameters, namely LBR and TLU, had better diagnostic and prognostic performances for patients with LLOM compared to conventional imaging. The results suggest that Ga-SPECT/CT is a good alternative for diagnosing LLOM in countries where FDG-PET/CT is not commonly available.

Localization of Late Gadolinium Enhancement and Its Association with Ventricular Tachycardia in Patients with Cardiac Sarcoidosis.

Sustained ventricular tachycardia (sVT), leading to sudden cardiac death, is one of the common manifestations in cardiac sarcoidosis (CS). Although late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) has been reported to be associated with sVT, the relationships of its localization to sVT have not been fully evaluated.To evaluate the localization of LGE and its relationships to sVT in patients with CS, we reviewed medical record of consecutive 31 patients with CS who underwent CMR. The localization of LGE was divided into four categories: Left ventricular (LV) septum, LV free wall, right ventricular (RV) septum, and RV free wall. We investigated the association of sVT with localization of LGE and other parameters including serum biomarkers LV ejection fraction on echocardiography and Fluorine-18-fluorodeoxyglucose (FDG) accumulation on positron emission tomography (PET) -CT.Of the studied population, 8 patients (25.8%) were known to present with sVT among 31 CS patients. LGE was observed in the RV free wall in 6 patients with sVT, whereas it was in 5 patients without sVT (75.0% versus 21.7%, P = 0.022). Univariate analysis showed that only LGE in the RV free wall was associated with sVT (odds ratio [OR]: 10.80; 95% confidence interval [CI]: 1.64-70.93, P = 0.013).LGE in the RV free wall was associated with sVT in patients with CS.

Serial change in perfusion-metabolism mismatch after coronary artery bypass grafting.

OBJECTIVE: Myocardial ischemia is known to suppress fatty acid metabolism and favor glucose metabolism. However, changes in myocardial metabolism after coronary revascularization are not fully elucidated. METHODS: Thirty-eight patients with coronary artery disease were retrospectively enrolled. These patients had undergone stress perfusion single photon emission computed tomography (SPECT) and 123I-BMIPP SPECT in both the short-term (6.4 ± 4.7 months) and mid-term (29.9 ± 7.2 months) after isolated coronary artery bypass grafting. Tracer uptake was graded using a 17-segment, 5-point scoring model. Serial changes in SRS (summed rest score), SDS (summed difference score), the BMIPP score (total defect score of BMIPP), and the mismatch score (BMIPP score-SRS) were evaluated. In addition, persistent perfusion-metabolism mismatch (PM) was defined as mismatch score minus SDS of 3 or more during the mid-term postoperative period. The clinical parameters associated with PM were examined. RESULTS: From short- to mid-term postoperative period, the extent of infarcted myocardium (SRS) did not change significantly (7.8 ± 8.0 to 7.1 ± 7.0, P = 0.117). The extent of ischemic myocardium (SDS), the BMIPP score and the mismatch score, which reflects perfusion-metabolism mismatch, were significantly improved (2.0 ± 2.8 to 0.7 ± 1.0, P = 0.010; 12.2 ± 9.0 to 9.5 ± 7.9, P < 0.001; 4.4 ± 3.7 to 2.5 ± 2.6, P < 0.001; respectively). Remarkably, perfusion-metabolism mismatch persisted in 13 patients (34%) even in the mid-term postoperative period. eGFR and SYNTAX score were independent predictors of persistent perfusion-metabolic mismatch in multivariable analysis (OR = 0.951, 95% CI 0.898-0.985, P = 0.010 and OR = 1.126, 95% CI 1.011-1.254, P = 0.031, respectively). The mismatch score both in the short- and mid-term significantly correlated with SYNTAX score (r = 0.400 and r = 0.472, respectively). CONCLUSIONS: Fatty acid metabolism disturbance improved from short- to mid-term postoperative period in patients with successful reperfusion by coronary artery bypass grafting. However, in patients with severe atherosclerosis, impaired fatty acid metabolism was sustained until the mid-term postoperative period, even though ischemia had resolved.

Neuropsychological and neurophysiological features of WAGR syndrome: Detailed comprehensive evaluation of a patient with severe intellectual disability and autism spectrum disorder.

BACKGROUND: Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome is a contiguous gene deletion syndrome caused by a de novo deletion including the 11p13 region. Although autism spectrum disorder (ASD) is frequently observed in patients with WAGR syndrome, few reports have comprehensively described its characteristics. We herein present the detailed neuropsychological and neurophysiological findings of a patient with WAGR syndrome complicated with severe psychomotor developmental delay and ASD. CASE PRESENTATION: The patient is presently a 6-year-old boy. Microarray analysis revealed a 7.1 Mb loss at 11p14.3-p13 and a 9.3 Mb loss at 11p13-p12, which encompassed the PAX6, WT1, and PRRG4 genes. His behavioral features were characteristic even among the ASD population: severe hypoesthesia to touch, pain, and temperature in addition to remarkable sensory seeking posing a high risk of serious accident. Sensory Profile analysis objectively identified a strong preference for sensory stimulation. Furthermore, his somatosensory evoked potential (SSEP) showed a mild delay in central conduction time, suggesting partial brain stem dysfunction-induced hypoalgesia. DISCUSSION: This first attempt to characterize sensory dysfunction using Sensory Profile and SSEP in WAGR syndrome may contribute to understanding its neuropsychological features and improve the quality of rehabilitation and socioeducational support in affected children.

Heterozygous missense variant in TRPC6 in a boy with rapidly progressive infantile nephrotic syndrome associated with diffuse mesangial sclerosis.

Transient receptor potential channel C6 encoded by TRPC6 is involved in slit diaphragm formation in podocytes, and abnormalities of the TRPC6 protein cause various glomerular diseases. The first identified pathogenic variant of TRPC6 was found to cause steroid-resistant nephrotic syndrome that typically developed in adulthood and then slowly led to end-stage renal disease, along with a renal pathology of focal segmental glomerulosclerosis. Here, we report a patient with rapidly progressing infantile nephrotic syndrome and a heterozygous missense TRPC6 variant. The patient, a 2-year-old Japanese boy, developed steroid-resistant nephrotic syndrome at age 11 months. His renal function deteriorated rapidly, and peritoneal dialysis was introduced at age 1 year and 6 months. His renal pathology, obtained at age 1 year and 1 month, was consistent with diffuse mesangial sclerosis (DMS). Clinical exome analysis and custom panel analysis for hereditary renal diseases revealed a reported heterozygous missense variant in TRPC6 (NM_004621.5:c.523C > T:p.Arg175Trp). This is the first report of a patient with a TRPC6-related renal disorder associated with DMS.

Clinical Genetics in Japan: Efforts of Human Genetics Societies and Related Organizations.

The Japanese government finally started measures to promote the realization of genomic medicine that can promote the accumulation of individual genomic information for improving medical care in 2015. However, readiness in terms of social infrastructure (including legal, administrative, ethical, and educational aspects in Japan) remains inadequate. Associations related to medical genetics have been making consistent efforts to realize genomic medicine by establishing guidelines, nurturing genetic professionals, providing support for constructing cross-disciplinary medical systems, enriching genetic education, etc., and it is important that the Japanese government supports these initiatives.

Prevalence of atrial FDG uptake and association with atrial arrhythmias in patients with cardiac sarcoidosis.

BACKGROUND: There is increasing evidence that a proportion of patients with cardiac sarcoidosis (CS) have atrial arrhythmias (AA). Although 18F-fluorodeoxy-glucose (FDG) uptake in the ventricle on positron emission tomography/computed tomography (PET/CT) is well studied, FDG uptake in the atrium has not been elucidated in detail. OBJECTIVES: To evaluate FDG uptake in the atrium and its relationship with AA in patients with CS. METHODS: We retrospectively investigated 62 CS patients. All patients underwent echocardiography and PET/CT. Serum angiotensin converting enzyme (ACE) and soluble IL-2 receptor (sIL-2R) levels, plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations were also evaluated. ECG, Holter monitoring and device interrogations were used to detect AA. RESULTS: Of the studied population, 25 patients (40.3%) had AA, of which 2 patients had atrial tachycardia (AT) and 23 patients had atrial fibrillation (AF). Eighteen patients with AA had atrial FDG uptake on PET/CT, whereas 14 patients without AA had atrial FDG uptake (72.0% vs 37.8%, P = 0.017). Multivariate analysis revealed a significant association between AA and age (odds ratio [OR]: 1.15; 95% confidence interval [CI]: 1.01-1.31, P = 0.040), atrial FDG uptake (odds ratio [OR]: 7.23; 95% confidence interval [CI]: 1.91-27.36, P = 0.004), and left atrial diameter (OR: 1.08; 95% CI: 1.01-1.16, P = 0.027). Meanwhile, gender, serum ACE and BNP levels, and left ventricular ejection fraction were not associated with AA. CONCLUSIONS: Atrial FDG uptake was common in patients with CS and strongly associated with AA.

PIEZO2 deficiency is a recognizable arthrogryposis syndrome: A new case and literature review.

PIEZO2 encodes a mechanically activated cation channel, which is abundantly expressed in dorsal root ganglion neuron and sensory endings of proprioceptors required for light touch sensation and proprioception in mice. Biallelic loss-of-function mutations in PIEZO2 (i.e., PIEZO2 deficiency) were recently found to cause an arthrogryposis syndrome. Sixteen patients from eight families have been reported to date. Herein we report a new case, including detailed clinical characteristics and courses as well as comprehensive neurological features. The patient was a 12-year-old girl presenting with congenital multiple contractures, progressive severe scoliosis, prenatal-onset growth impairment, motor developmental delay with hypotonia and myopathy-like muscle pathology, mild facial features, and normal intelligence. Her neurological features included areflexia, impaired proprioception, and decreased senses. Neurophysiological examination revealed decreased amplitude of sensory nerve action potentials, absent H reflex, and prolongation of central conduction times. Clinical exome sequencing revealed a novel homozygous frameshift mutation in PIEZO2 (NM_022068: c.4171_4174delGTCA: p.Val1391Lysfs*39) with no detectable mRNA expression of the gene. PIEZO2 deficiency represents a clinical entity involving characteristic neuromuscular abnormalities and physical features. Next generation sequencing-based comprehensive molecular screening and extensive neurophysiological examination could be valuable for diagnosis of the disorder.

Frequency and clinical features of hearing loss caused by STRC deletions.

Sensorineural hearing loss is a common deficit and mainly occurs due to genetic factors. Recently, copy number variants (CNVs) in the STRC gene have also been recognized as a major cause of genetic hearing loss. We investigated the frequency of STRC deletions in the Japanese population and the characteristics of associated hearing loss. For CNV analysis, we employed a specialized method of Ion AmpliSeqTM sequencing, and confirmed the CNV results via custom array comparative genomic hybridization. We identified 17 probands with STRC homozygous deletions. The prevalence of STRC homozygous deletions was 1.7% in the hearing loss population overall, and 4.3% among mild-to-moderate hearing loss patients. A 2.63% carrier deletion rate was identified in both the hearing loss and the control population with normal hearing. In conclusion, our results show that STRC deletions are the second most common cause of mild-to-moderate hearing loss after the GJB2 gene, which accounts for the majority of genetic hearing loss. The phenotype of hearing loss is congenital and appears to be moderate, and is most likely to be stable without deterioration even after the age of 50. The present study highlights the importance of the STRC gene as a major cause of mild-to-moderate hearing loss.

Maternal Uniparental Disomy for Chromosome 20: Physical and Endocrinological Characteristics of Five Patients.

Context: Maternal uniparental disomy for chromosome 20 [UPD(20)mat], resulting in aberrant expression of imprinted transcripts at the GNAS locus, is a poorly characterized condition. These patients manifested a phenotype similar to that of Silver-Russell syndrome (SRS) and small for gestational age-short stature (SGA-SS); however, the etiological relationship between UPD(20)mat and SRS/SGA-SS remains unclear. Moreover, no report has described endocrinological assessment of UPD(20)mat patients, although paternal UPD(20), the mirror image entity of UPD(20)mat, is known to cause multiple hormone resistance reflecting reduced α-subunit of the stimulatory G protein expression. Participants: Patients 1 to 5 showed nonmosaic heterodisomy and/or isodisomy for the entire chromosome 20. Patients 1 to 3 and 4 were identified through UPD(20)mat screening for 55 patients with etiology-unknown SRS and 96 patients with SGA-SS, respectively. Patient 5 was identified through molecular analysis for patients with developmental defects. Patients 1 to 5 manifested postnatal growth failure and feeding problems, with or without developmental delay, and other clinical features. Patients 1 to 4 were born SGA. Patients 4 and 5 exhibited hypercalcemia and low or low-normal parathyroid hormone levels. Patient 1 showed constantly decreased thyroid-stimulating hormone (TSH) levels after 12 years of age, although she had a normal TSH level at 5.2 years of age. Conclusion: The results suggest that UPD(20)mat underlies growth failure and feeding problems with additional features and could account for >5% of etiology-unknown SRS and small percentages of SGA-SS. Most important, this study provides an indication that UPD(20)mat can be associated with hypersensitivity of hormone receptors, which may gradually develop with age.

Myelodysplastic syndrome in an infant with constitutional pure duplication 1q41-qter.

We report on a Japanese female infant as the fourth patient with the constitutional pure duplication 1q41-qter confirmed by chromosomal microarray and as the first who developed myelodysplastic syndrome (MDS) among those with the constitutional 1q duplication. Common clinical features of the constitutional pure duplication 1q41-qter include developmental delay, craniofacial characteristics, foot malformation, hypertrichosis, and respiratory insufficiency. The association between MDS and the duplication of the genes in the 1q41-qter region remains unknown.

Diagnostic performance of hybrid cardiac SPECT/CT imaging for patients with takotsubo cardiomyopathy.

BACKGROUND: The diagnostic performance of SPECT-only imaging for takotsubo cardiomyopathy (TC) is limited due to the lack of coronary artery distribution information. The aim of this study was to evaluate the diagnostic performance of hybrid cardiac SPECT/CT for patients with TC or acute coronary syndrome (ACS). METHODS: Twenty-two patients with apical ballooning left ventricular (LV) dysfunction who underwent cardiac perfusion SPECT using 99mTc-methoxy-isobutyl-isonitrile (MIBI), cardiac fatty-acid metabolism SPECT using 123I-beta-methyl-P-iodophenyl-pentadecanoic acid (BMIPP), cardiac CT, and hybrid cardiac SPECT/CT imaging were analyzed. On the SPECT images, MIBI and BMIPP defects were quantified using a 17-segment model with a 5-point grading system and a summed MIBI defect score (SMDS), summed BMIPP defect score (SBDS), and summed mismatch score (SMS) were calculated. Furthermore, apical and non-apical MDS, BDS, and mismatch scores (A- and NA-MDS, A- and NA-BDS, and A- and NA-MS) were calculated. These quantitative scores were compared between the TC (n = 11) and ACS (n = 11) groups, and the diagnostic performances of SPECT-only imaging and hybrid SPECT/CT imaging were compared. For all patients, the diagnoses of both SPECT-only and SPECT/CT imaging were categorized as TC: SPECT accumulation defects around apical LV wall deviated from the actual coronary artery territories, equivocal: unclear relationship of accumulation defects and the coronary artery territories, or non-TC: accumulation defects coincided with the coronary artery territories. RESULTS: SMDS and SBDS did not significantly differ between TC and ACS patients [SMDS: 5 (3-7) vs. 8 (4-16), p = 0.216; SBDS: 10 (8-12) vs. 18 (9-24), p = 0.354]. While A-MDS and A-BDS did not significantly differ between patients with TC and ACS (p = 0.567 and p = 0.386, respectively), NA-MDS and NA-BDS were significantly lower for patients with TC (p = 0.022 and p = 0.022, respectively). Compared with SPECT-only imaging (sensitivity: 30% and specificity: 81%), hybrid SPECT/CT imaging showed a higher accuracy (sensitivity: 90% and specificity: 100%) for the diagnosis of TC. CONCLUSIONS: Hybrid cardiac SPECT/CT imaging may have superior diagnostic performance compared with SPECT-only imaging for patients with TC.

Feasibility of myocardial flow reserve prediction without the use of dynamic data from myocardial perfusion positron emission tomography.

Quantification of myocardial flow reserve (MFR) provides diagnostic value for detection of cardiovascular artery disease. However, the common calculation method for MFR requires dynamic acquisition and specific software. The study aimed to predict coronary artery disease by simpler calculation of myocardial count without the use of dynamic data from 13N-ammonia myocardial perfusion positron emission tomography (MP-PET). This study included 40 consecutive patients suspected of ischemic heart disease and 7 healthy controls (34 men and 13 women, 66 ± 12 years). All participants underwent adenosine stress and rest 13N-ammonia MP-PET. From the dynamic images, the MFR in the entire left ventricular myocardium (ELV) and the three-vessel area was calculated by dividing stress myocardial blood flow (MBF) by rest MBF. From the static images, the myocardium-to-background ratio (MBR) was calculated by dividing each area's counts/pixel by background counts in the upper thoracic aorta/pixel in both stress and rest images. The MBR-increasing rate (MBR-IR) was calculated by dividing stress MBR by rest MBR. The relationship between MFR and MBR-IR in each area was examined. The cutoff diagnostic value of MBR-IR corresponding to that of MFR for detection of cardiovascular artery disease was calculated. Each MBR-IR was closely correlated with each MFR (r = 0.830 in ELV, r = 0.864 in LAD, r = 0.829 in LCX, r = 0.757 in RCA). The cutoff values of MBR-IR were 1.45 in ELV, 1.46 in LAD, 1.41 in LCX, and 1.45 in RCA, respectively. This study demonstrated that quantification of MBR-IR may provide diagnostic value for detection of coronary artery disease as well as MFR.

4D Flow MR Imaging of Ophthalmic Artery Flow in Patients with Internal Carotid Artery Stenosis.

BACKGROUND AND PURPOSE: To assess the clinical feasibility of time-resolved 3D phase contrast (4D Flow) MRI assessment of the ophthalmic artery (OphA) flow in patients with internal carotid artery stenosis (ICS). MATERIALS AND METHODS: Twenty-one consecutive patients with unilateral ICS were recruited. 4D Flow MRI and acetazolamide-stress brain perfusion single photon emission computed tomography (SPECT) were performed. The flow direction on the affected-side OphA was categorized into native flow (anterograde or unclear) and non-native flow (retrograde flow) based on 4D Flow MRI. In the affected-side middle cerebral artery (MCA) territory, the ratio of rest cerebral blood flow to normal control (RCBFMCA) and cerebral vascular reserve (CVRMCA) were calculated from SPECT dataset. High-risk patients were defined based on the previous large cohort study (RCBFMCA < 80% and CVRMCA < 10%). RESULTS: Eleven patients had native OphA flow (4 anterograde, 7 unclear) and the remaining 10 had non-native OphA flow. RCBFMCA and CVRMCA each were significantly lower in non-native flow group (84.9 ± 18.9% vs. 69.8 ± 7.3%, P < 0.05; 36.4 ± 20.6% vs. 17.0 ± 15.0%, P < 0.05). Four patients in the non-native flow group and none in the native flow group were confirmed as high-risk (Sensitivity/Specificity, 1.00/0.65). CONCLUSION: The 6 min standard 4D Flow MRI assessment of OphA in patients with ICS can predict intracranial hemodynamic impairment.

Feasibility of combined risk stratification with coronary CT angiography and stress myocardial SPECT in patients with chronic coronary artery disease.

OBJECTIVE: To examine the additional prognostic value of coronary CT angiography (CTA) over myocardial perfusion imaging (MPI) in patients with suspected or known coronary artery disease. METHODS: A series of 157 patients (mean age 69 ± 9 years; 76% male; median follow-up 49 months; range 12-82 months) underwent stress MPI with SPECT and coronary CTA within a 6-month interval. Summed stress score (SSS) and summed difference score (SDS) of stress MPI, number of vessels with stenosis, and presence of left main trunk stenosis and high-risk plaques on coronary CTA were examined. Primary endpoints were cardiac death, acute myocardial infarction, or unstable angina requiring revascularization. Secondary endpoints were revascularization > 60 days after the latter imaging test. All patients were followed up for at least 1 year (mean 45 ± 19 months; range 12-82 months). RESULTS: Nine (6%) patients reached primary endpoints. Cardiac death occurred in 1 (0.6%) patient, myocardial infarction in 5 (3%), and unstable angina requiring hospitalization in 3 (2%). Elective revascularization within 60 days was performed in 31 (20%) patients. Sixteen (10%) patients required revascularization after > 60 days. Primary endpoint event-free survival rates were significantly lower in patients with myocardial ischemia (SDS ≥ 2) and high-risk plaques (HRP), and secondary endpoint event-free survival rates in patients with SSS ≥ 4 and 3VD. In multivariate analysis, Cox proportional hazards regression analysis revealed HRP (HR = 8.02; P = 0.006) and myocardial ischemia (HR = 11.487; P = 0.025) were significant predictors of primary endpoints, and 3VD of secondary endpoints (HR = 4.981; P = 0.008). Combined ischemia and HRP resulted in the significant increase of the model Chi square in prediction of primary end points from ischemia or HRP alone (17.4 vs. 9.41; P = 0.005, 17.4 vs. 9.39; P = 0.005, respectively). CONCLUSION: Coronary CT angiography may provide additional prognostic information over MPI.

A novel frameshift mutation of SYNE1 in a Japanese family with autosomal recessive cerebellar ataxia type 8.

A Japanese family with autosomal recessive cerebellar ataxia type 8 (SCAR8, MIM 610743) is described. We identified a novel SYNE1 frameshift deletion (c.6843del, p.Q2282Sfs*3). This family shared similar clinical manifestations characterized by adult-onset, relatively pure cerebellar ataxia with mild eye movement abnormality. Intelligence and bulbar and respiratory functions were unaffected. This study suggests the clinical utility of using panel-based exome sequencing for genetic diagnosis in hereditary ataxias in a cost-efficient manner.