Comparative evaluation of 11C-methionine and 18F-fluorodeoxyglucose positron emission tomography for distinguishing between primary central nervous system lymphoma and isocitrate dehydrogenase-wildtype glioblastoma.

PURPOSE: Distinguishing between primary central nervous system lymphoma (PCNSL) and isocitrate dehydrogenase (IDH)-wildtype glioblastoma is important for therapeutic decision-making. This study aimed to compare the performance of 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for distinguishing between these two major malignant brain tumors. METHODS: We retrospectively conducted qualitative and semiquantitative analyses of pre-treatment MET and FDG PET/computed tomography (CT) images of 22 patients with PCNSL and 64 patients with IDH-wildtype glioblastoma. For semiquantitative analysis, we calculated the tumor-to-normal tissue (T/N) ratio by dividing the maximum standardized uptake value (SUV) for the tumor (T) by the average SUV for the normal tissue (N). For performance evaluation, we employed receiver operating characteristic curve analysis and calculated the areas under the curve (AUC) values. RESULTS: In the qualitative analysis, all PCNSLs and IDH-wildtype glioblastomas were MET-positive, while 95% and 84% of PCNSLs and IDH-wildtype glioblastomas, respectively, were FDG-positive. Eleven patients were excluded from the FDG PET/CT semiquantitative analysis because of hyperglycemia. There was no difference in MET T/N ratio between PCNSL and IDH-wildtype glioblastoma (p = 0.37). FDG T/N ratio was significantly higher in PCNSL than in IDH-wildtype glioblastoma (p < 0.001). The AUC value for distinguishing PCNSL from IDH-wildtype glioblastoma was significantly higher for the FDG T/N ratio (0.871) than for the MET T/N ratio (0.565) (p = 0.0027). CONCLUSION: MET PET could detect both PCNSL and IDH-wildtype glioblastoma, but unlike FDG PET, it could not distinguish between these two major malignant brain tumors.

Feasibility of PiB positron emission tomography/computed tomography for treatment monitoring with Tafamidis in a patient with transthyretin cardiac amyloidosis.

We present a 77-year-old woman with wild-type ATTR cardiac amyloidosis (ATTR-CA) who presented with dyspnea, arrhythmia, and elevated NT-pro BNP. Initial imaging including cardiac MRI, PYP scintigraphy, PiB PET/CT and NaF PET/CT revealed cardiac abnormalities. Tafamidis treatment was initiated. After 14 months, symptomatic improvement and reduced NT-pro BNP were observed. Cardiac MRI and PYP scintigraphy showed no significant change and increased NaF accumulation, while PiB PET/CT showed decreased amyloid deposition, suggesting that it may be superior to NaF PET/CT in assessing the therapeutic effect of tafamidis in ATTR-CA.

Feasibility of 11C-Pittsburgh compound B positron emission tomography/computed tomography for treatment monitoring with Tafamidis in a patient with transthyretin cardiac amyloidosis.

We present a 77-year-old woman with wild-type ATTR cardiac amyloidosis (ATTR-CA) who presented with dyspnea, arrhythmia, and elevated NT-pro BNP. Initial imaging including cardiac MRI, PYP scintigraphy, PiB PET/CT and NaF PET/CT revealed cardiac abnormalities. Tafamidis treatment was initiated. After 14 months, symptomatic improvement and reduced NT-pro BNP were observed. Cardiac MRI and PYP scintigraphy showed no significant change and increased NaF accumulation, while PiB PET/CT showed decreased amyloid deposition, suggesting that it may be superior to NaF PET/CT in assessing the therapeutic effect of tafamidis in ATTR-CA.

S-Palmitoylation of the serotonin transporter promotes its cell surface expression and serotonin uptake.

The neurotransmitter serotonin (5-HT) is transported back into serotonergic neurons by the serotonin transporter (SERT). SERT is a main target of antidepressants, and much effort has therefore focused on finding relationships between SERT and depression. However, it is not fully understood how SERT is regulated at the cellular level. Here, we report post-translational regulation of SERT by S-palmitoylation, in which palmitate is covalently attached to cysteine residues of proteins. Using AD293 cells (a human embryonic kidney 293-derived cell line with improved cell adherence) transiently transfected with FLAG-tagged human SERT, we observed S-palmitoylation of immature SERT containing high-mannose type N-glycans or no N-glycan, which is presumed to be localized in the early secretory pathway, such as the endoplasmic reticulum. Mutational analysis by alanine substitutions shows that S-palmitoylation of immature SERT occurs at least at Cys-147 and Cys-155, juxtamembrane cysteine residues within the first intracellular loop. Furthermore, mutation of Cys-147 reduced cellular uptake of a fluorescent SERT substrate that mimics 5-HT without decreasing SERT on the cell surface. On the other hand, combined mutation of Cys-147 and Cys-155 inhibited SERT surface expression and reduced the uptake of the 5-HT mimic. Thus, S-palmitoylation of Cys-147 and Cys-155 is important for both the cell surface expression and 5-HT uptake capacity of SERT. Given the importance of S-palmitoylation in brain homeostasis, further investigation of SERT S-palmitoylation could provide new insights into the treatment of depression.

Normative change with gestation in fetal intraventricular pressure difference with color M-mode Doppler echocardiography.

AIM: The intraventricular pressure difference (IVPD) is the pressure difference in early diastole from the base to the apex of the ventricle. It is a useful marker for evaluating diastolic function because of its role as a suction force. This study investigated the changes in total and segmental IVPDs in normal fetuses throughout gestation to obtain normative data equations. METHODS: One hundred thirty-seven healthy pregnant women at 12-40 weeks of gestation were prospectively enrolled to evaluate IVPD. The color M mode was performed, and the image was evaluated using our own code to calculate the IVPD. Segmental IVPD was divided into mid to apex and base. Pearson's correlation coefficient was used to evaluate this relationship. RESULTS: There was a significant, positive relationship between IVPD and gestational age in both ventricles (right ventricle [RV]: r = 0.800, left ventricle [LV]: r = 0.818). As for segmental IVPD, basal and mid-apical IVPD also increased with gestation in both ventricles (RV: basal, r = 0.627; mid-apical, r = 0.705; LV: basal r = 0.758; mid-apical, r = 0.756). IVPG, which was calculated as IVPD/ventricular length, also showed a weak, positive relationship with gestation in both ventricles (RV r = 0.351, p < 0.001; LV r = 0.373, p < 0.001). CONCLUSION: The total and segmental IVPDs significantly increased linearly through time.

Relationship between [18F]FDG PET/CT and metabolomics in patients with colorectal cancer.

INTRODUCTION: Advances in metabolomics have significantly improved cancer detection, diagnosis, treatment, and prognosis. OBJECTIVES: To investigate the relationship between metabolic tumor volume (MTV) using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET)/ computed tomography (CT) and metabolomics data in patients with colorectal cancer (CRC). METHODS: The metabolome in tumor tissues was analyzed using capillary electrophoresis time-of-flight mass spectrometry in 33 patients with newly diagnosed CRC who underwent FDG PET/CT before treatment and had tumor tissue post-surgery. Based on the FDG PET data, MTV was calculated and was dichotomized according to the median value, and tumors were divided into low-MTV and high-MTV tumors. Metabolomics data were compared between the low-MTV and high-MTV tumors. RESULTS: The levels of most glycolysis-related metabolites were not different between low-MTV and high-MTV tumors. The level of component of the initial part of the tricarboxylic acid (TCA) cycle, citrate, was significantly lower in the high-MTV tumor than in the low-MTV tumor. The TCA intermediate succinate level was significantly higher in the high-MTV tumor than in the low-MTV tumor. In contrast, the TCA intermediate fumarate level was significantly lower in the high-MTV tumor than in the low-MTV tumor. The levels of many amino acids were significantly higher in the high-MTV tumor than in the low-MTV tumor. CONCLUSIONS: Although preliminary, these results suggest that tumors with high FDG metabolism in CRC may obtain more energy by using a reverse reaction of the TCA cycle and amino-acid metabolism. However, further research is required to clarify this relationship.

Discovery of EP300/CBP histone acetyltransferase inhibitors through scaffold hopping of 1,4-oxazepane ring.

EP300 and its paralog CBP play an important role in post-translational modification as histone acetyltransferases (HATs). EP300/CBP inhibition has been gaining attention as an anticancer treatment target in recent years. Herein, we describe the identification of a novel, highly selective EP300/CBP inhibitor, compound 11 (DS17701585), by scaffold hopping and structure-based optimization of a high-throughput screening hit 1. Compound 11 (DS17701585) shows dose-dependent inhibition of SRY-box transcription factor 2 (SOX2) mRNA expression in a human lung squamous cell carcinoma cell line LK2-xenografted mouse model.

A preliminary study of relationship among the degree of internal carotid artery stenosis, wall shear stress on MR angiography and 18F-FDG uptake on PET/CT.

BACKGROUND: This preliminary study was undertaken to evaluate relationship among the degree of internal carotid artery (ICA) stenosis, wall shear stress (WSS) by computational fluid dynamics (CFD) on magnetic resonance angiography (MRA) and 18F-FDG uptake of ICA on PET/CT. METHODS: A total of 40 carotid arteries in 20 patients with carotid atherosclerotic disease were examined with MRA and 18F-FDG PET/CT. Atherosclerotic risk factors were assessed in all patients. Degree of ICA stenosis was calculated according to NASCET method. CFD analysis was performed and maximum WSS (WSSmax) was measured. 18F-FDG uptake in ICA was quantified using maximum target-to-blood pool ratio (TBRmax). RESULTS: Atherosclerotic risk factors did not affect imaging findings. There were significant correlations between WSSmax and degree of ICA stenosis (ρ = .81, P < .001), WSSmax and TBRmax (ρ = .64, P < .001), and TBRmax and degree of ICA stenosis (ρ = .50, P = .001). CONCLUSIONS: These preliminary results indicate that there may be significant correlations among the degree of ICA stenosis, WSSmax and TBRmax in patients with carotid artery stenosis.

Whole exome sequencing of fetal structural anomalies detected by ultrasonography.

The objective of this study was to evaluate the efficacy of whole exome sequencing (WES) for the genetic diagnosis of cases presenting with fetal structural anomalies detected by ultrasonography. WES was performed on 19 cases with prenatal structural anomalies. Genomic DNA was extracted from umbilical cords or umbilical blood obtained shortly after birth. WES data were analyzed on prenatal phenotypes alone, and the data were re-analyzed after information regarding the postnatal phenotype was obtained. Based solely on the fetal phenotype, pathogenic, or likely pathogenic, single nucleotide variants were identified in 5 of 19 (26.3%) cases. Moreover, we detected trisomy 21 in two cases by WES-based copy number variation analysis. The overall diagnostic rate was 36.8% (7/19). They were all compatible with respective fetal structural anomalies. By referring to postnatal phenotype information, another candidate variant was identified by a postnatal clinical feature that was not detected in prenatal screening. As detailed phenotyping is desirable for better diagnostic rates in WES analysis, we should be aware that fetal phenotype is a useful, but sometimes limited source of information for comprehensive genetic analysis. It is important to amass more data of genotype-phenotype correlations, especially to appropriately assess the validity of WES in prenatal settings.

Texture Indices of 18F-FDG PET/CT for Differentiating Squamous Cell Carcinoma and Non-Hodgkin's Lymphoma of the Oropharynx.

We assessed the role of 18F-FDG PET/CT texture indices for the differentiation of squamous cell carcinoma (SCC) and non-Hodgkin's lymphoma (NHL) in the oropharynx. 18F-FDG PET/CT data for 27 patients with SCC and 25 patients with NHL in the oropharynx were investigated. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and six texture indices (homogeneity, entropy, short-run emphasis, long-run emphasis, low gray-level zone emphasis [LGZE], and high graylevel zone emphasis [HGZE]) were derived from PET images. PET/CT parameters of the SCC patients were compared with those of the NHL patients. The diagnostic accuracy of the indices for differentiating SCC from NHL was calculated by a receiver operating characteristic curve analysis. 18F-FDG uptake in the oropharynx was observed in all of the patients. The SUVmax, MTV, and TLG did not differ significantly between the SCC and NHL groups, but two of the six texture indices (LGZE [p=0.004] and HGZE [p=0.03]) showed significant differences between the groups. LGZE was the best discriminative index for the differentiation of SCC and NHL (55.6% sensitivity, 88.0% specificity). The LGZE and HGZE texture indices derived from 18F-FDG PET/CT images may be useful in differentiating SCC and NHL in the oropharynx.

Serial Radiological Findings in Meningovascular Neurosyphilis Presenting as Acute Ischemic Stroke: A Case Report.

BACKGROUND: Meningovascular neurosyphilis, a form of early neurosyphilis, can cause infectious arteritis, which can be complicated by cerebral infarction. High-resolution vessel wall imaging (HR-VWI) is one of the techniques used to directly visualize the vessel wall. Herein, we present a rare case of meningovascular neurosyphilis, in which intracranial arterial vasculitis was evaluated using HR-VWI. CASE PRESENTATION: A 22-year-old man with no medical history of any condition was brought to the emergency room with one day history of right upper and lower extremity weakness. Diffusion-weighted magnetic resonance (MR) imaging showed a high signal from the left putamen to the corona radiata, and MR angiography showed stenosis of the right internal carotid artery (ICA) and the bilateral middle cerebral arteries (MCAs). HR-VWI showed thickening, along with smooth, intense, and concentric enhancement of the right ICA and the bilateral MCAs. The patient was diagnosed with neurosyphilis based on the findings of the blood tests and cerebrospinal fluid examination. The patient's symptoms gradually improved after treatment with intravenous penicillin G and oral antiplatelet agents. HR-VWI, performed approximately 6 months after the treatment, revealed improvement in the contrast enhancement of the vessel wall and the vascular stenosis. CONCLUSION: To the best of our knowledge, this is the first report of meningovascular neurosyphilis that evaluated the course of treatment using HR-VWI. Our report highlights the effectiveness of HR-VWI to determine the effects of treatment on meningovascular neurosyphilis.

High Salt Intake Impairs Erectile Function in Salt-Sensitive Rats Through Mineralocorticoid Receptor Pathway Beyond Its Effect on Blood Pressure.

BACKGROUND: High salt intake is a risk factor for hypertension, which can potentially lead to erectile dysfunction (ED); however, the underlying pathological mechanisms remain unclear. AIM: To investigate whether erectile function is directly impaired by high salt intake and whether selective inhibition of mineralocorticoid receptor (MR) could provide protection from ED. METHODS: 6-week-old male Dahl salt-sensitive rats were randomly divided into 3 groups: normal diet (0.3% NaCl; control, n = 8), high-salt diet (8% NaCl; HS, n = 8), and high-salt diet plus eplerenone (HS + EPL, n = 11). HS + EPL rats were orally administered daily doses of EPL (75 mg/kg) for 6 weeks; control and HS rats received purified water on the same schedule. OUTCOMES: At the end of the study period, erectile function was evaluated by measuring intracavernosal pressure and mean arterial pressure after cavernous nerve stimulation. Serum levels of asymmetric dimethylarginine and L-arginine were determined using ultraperformance liquid chromatography-tandem mass spectrometry. Quantitative PCR was used to assess the expression of MR, inflammation, and oxidative stress markers (nicotinamide adenine dinucleotide phosphate oxidase-1/4, p22phox, interleukin-6, and superoxide dismutase-1), and protein arginine N-methyltransferase-1. RESULTS: The intracavernosal pressure/mean arterial pressure ratio was significantly lower, whereas systolic blood pressure, MR expression, serum asymmetric dimethylarginine levels, oxidative stress, and levels of inflammatory biomarkers were significantly higher in HS rats than in control rats (P < .05). EPL administration significantly improved each of these parameters except systolic blood pressure and MR expression. No significant intergroup differences were observed for L-arginine and superoxide dismutase-1 levels. CLINICAL TRANSLATION: Our results provide a rationale for the need of salt restriction and the use of selective MR inhibitors in prophylaxis or treatment of ED in men consuming a high-salt diet. STRENGTHS & LIMITATIONS: We are the first to report that the adverse impact of high salt intake on erectile function is mediated via MR activation, independent of its effect on blood pressure. A major limitation of this study is that responses of salt-resistant rats were not studied. CONCLUSIONS: High salt intake directly impaired erectile function in Dahl salt-sensitive rats, whereas selective MR inhibition ameliorated this effect. Kishimoto T, Kataoka T, Yamamoto Y, et al. High Salt Intake Impairs Erectile Function in Salt-Sensitive Rats Through Mineralocorticoid Receptor Pathway Beyond Its Effect on Blood Pressure. J Sex Med 2020;17:1280-1287.

Structure and diversity of 13S globulin zero-repeat subunit, the trypsin-resistant storage protein of common buckwheat (Fagopyrum esculentum M.) seeds.

The zero-repeat subunit of 13S globulin, which lacks tandem repeat inserts, is trypsin-resistant and suggested to show higher allergenicity than the other subunits in common buckwheat (Fagopyrum esculentum Moench). To evaluate allelic variations and find novel alleles, the diversity of the zero-repeat genes was examined for two Japanese elite cultivars and 15 Pakistani landraces. The results demonstrated that two new alleles GlbNA1 and GlbNC1, plus three additional new alleles GlbNA2, GlbNA3, and GlbND, were identified besides the already-known GlbNA, GlbNB, and GlbNC alleles. In the Pakistani landraces, GlbNA was the most dominant allele (0.60-0.88 of allele frequency) in all except one landrace, where GlbNB was the most dominant allele (0.50 of allele frequency). Similar to GlbNC, the alleles GlbNA2 and GlbNA3 had extra ~200 bp MITE-like sequences around the stop codon. Secondary structure predictions of a sense strand demonstrated that the extra ~200 bp sequences of GlbNC, GlbNA2, and GlbNA3 can form rigid hairpin structures with free energies of -78.95, -67.06, and -29.90 kcal/mol, respectively. These structures may affect proper transcription and/or translation. In the GlbNC homozygous line, no transcript of a zero-repeat gene was detected, suggesting the material would be useful for developing hypoallergenic buckwheat.

Fetal umbilical cord cyst may evolve to omphalocele during pregnancy.

Omphalocele is rarely complicated by umbilical cord cysts. In our case, an umbilical cord cyst and fetal ascites were detected at 26 weeks' gestation in a fetus with trisomy 13. This changed to omphalocele with subsequently absorbed fetal ascites at 35 weeks' gestation. We propose two hypotheses. The abdominal wall may have been physically pierced or an omphalocele might have preexisted, and the intestinal tract in the hernia sac was pushed by fetal ascites.

Functional and Morphological Characteristics of Pancreatic Islet Lesions Induced by Quinolone Antimicrobial Agent Gatifloxacin in Rats.

We characterized pancreatic islet lesions induced by several quinolones using functional and morphological examinations of the pancreatic islets in male rats orally administered gatifloxacin, lomefloxacin, or levofloxacin at 300 mg/kg for 14 consecutive days. Consequently, in contrast to lomefloxacin or levofloxacin, gatifloxacin increased serum glucose and glycosylated albumin on day 14 and elevated serum glucose tended to decrease insulin in the intravenous glucose tolerance test. Microscopically, only gatifloxacin induced cytoplasmic vacuoles containing eosinophilic homogenous contents in islet cells. Immunohistochemical examination revealed that vacuolated islet cells were positively stained for insulin, demonstrating they were pancreatic ß cells. Electron microscopy showed that the cytoplasmic vacuoles represented dilated cisterna of the rough endoplasmic reticulum filled with electron-lucent materials in pancreatic ß cells. Moreover, insulin secretory granules were drastically decreased in vacuolated islet cells, suggesting impaired insulin synthesis and/or transport. This gatifloxacin-induced pancreatic toxicity in rats was considered to be associated with high pancreatic drug distribution. These results demonstrated that gatifloxacin provoked functional and morphological pancreatic ß cell alteration associated with impaired insulin synthesis and/or transport, leading to hyperglycemia.

Legumain Promotes Atherosclerotic Vascular Remodeling.

Legumain, a recently discovered cysteine protease, is increased in both carotid plaques and plasma of patients with carotid atherosclerosis. Legumain increases the migration of human monocytes and human umbilical vein endothelial cells (HUVECs). However, the causal relationship between legumain and atherosclerosis formation is not clear. We assessed the expression of legumain in aortic atheromatous plaques and after wire-injury-induced femoral artery neointimal thickening and investigated the effect of chronic legumain infusion on atherogenesis in Apoe-/- mice. We also investigated the associated cellular and molecular mechanisms in vitro, by assessing the effects of legumain on inflammatory responses in HUVECs and THP-1 monocyte-derived macrophages; macrophage foam cell formation; and migration, proliferation, and extracellular matrix protein expression in human aortic smooth muscle cells (HASMCs). Legumain was expressed at high levels in atheromatous plaques and wire injury-induced neointimal lesions in Apoe-/- mice. Legumain was also expressed abundantly in THP-1 monocytes, THP-1 monocyte-derived macrophages, HASMCs, and HUVECs. Legumain suppressed lipopolysaccharide-induced mRNA expression of vascular cell adhesion molecule-1 (VCAM1), but potentiated the expression of interleukin-6 (IL6) and E-selectin (SELE) in HUVECs. Legumain enhanced the inflammatory M1 phenotype and oxidized low-density lipoprotein-induced foam cell formation in macrophages. Legumain did not alter the proliferation or apoptosis of HASMCs, but it increased their migration. Moreover, legumain increased the expression of collagen-3, fibronectin, and elastin, but not collagen-1, in HASMCs. Chronic infusion of legumain into Apoe-/- mice potentiated the development of atherosclerotic lesions, accompanied by vascular remodeling, an increase in the number of macrophages and ASMCs, and increased collagen-3 expression in plaques. Our study provides the first evidence that legumain contributes to the induction of atherosclerotic vascular remodeling.

Peripheral neuropathy induced by drinking water contaminated with low-dose arsenic in Myanmar.

BACKGROUND: More than 140 million people drink arsenic-contaminated groundwater. It is unknown how much arsenic exposure is necessary to cause neurological impairment. Here, we evaluate the relationship between neurological impairments and the arsenic concentration in drinking water (ACDW). PARTICIPANTS AND METHODS: A cross-sectional study design was employed. We performed medical examinations of 1867 residents in seven villages in the Thabaung township in Myanmar. Medical examinations consisted of interviews regarding subjective neurological symptoms and objective neurological examinations of sensory disturbances. For subjective neurological symptoms, we ascertained the presence or absence of defects in smell, vision, taste, and hearing; the feeling of weakness; and chronic numbness or pain. For objective sensory disturbances, we examined defects in pain sensation, vibration sensation, and two-point discrimination. We analyzed the relationship between the subjective symptoms, objective sensory disturbances, and ACDW. RESULTS: Residents with ACDW ≥ 10 parts per billion (ppb) had experienced a "feeling of weakness" and "chronic numbness or pain" significantly more often than those with ACDW < 10 ppb. Residents with ACDW ≥ 50 ppb had three types of sensory disturbances significantly more often than those with ACDW < 50 ppb. In children, there was no significant association between symptoms or signs and ACDW. CONCLUSION: Subjective symptoms, probably due to peripheral neuropathy, occurred at very low ACDW (around 10 ppb). Objective peripheral nerve disturbances of both small and large fibers occurred at low ACDW (> 50 ppb). These data suggest a threshold for the occurrence of peripheral neuropathy due to arsenic exposure, and indicate that the arsenic concentration in drinking water should be less than 10 ppb to ensure human health.

Myocarditis with high 18F-FDG uptake and no 18F-FLT uptake.

We present a case of myocarditis with increased 18F-FDG uptake and no 18F-fluorothymidine (FLT) uptake.