Tailored notification encouraging examinees with abnormal glucose levels in health checkups to seek medical care.

The aims of this study were to generate a written notification message using social marketing methods to encourage examinees with abnormal glucose levels to seek medical care and to evaluate the optimized message. A semi-structured interview was conducted among examinees with abnormal glucose levels who had never visited a medical clinic for diagnosis of hyperglycemia. Patients were divided into two segments. A tailored notification letter was developed according to these segments using a social marketing approach. Other examinees were prospectively enrolled as the control group. The tailored notification for Segment 1 included a web code to access a health care provider. Future loss of time and money was emphasized in the message for Segment 2. According to responses in a telephone interview, 654 examinees with abnormal fasting glucose levels in a health checkup were divided into Group 1 (n = 178), Group 2 (n = 24), and a control group (n = 452) and given a tailored or conventional notification letter. The proportion of examinees who actually visited a health care provider in Group 1 (20.8%) was significantly higher than that in the control group (11.1%); no examinees in Group 2 visited a health care provider. Receipt of a tailored notification was a significant factor associated with visiting a health care provider, independent of age, sex, or severity of glucose abnormality (odds ratio 1.77; p = 0.02). Our results showed that tailored notification developed using a social marketing approach prompted health checkup examinees with abnormal glucose levels to seek medical care. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00534-1.

Extraordinarily high aldosterone, 901.0 ng/dL, in a patient with primary aldosteronism: an insight into the underlying mechanism.

A 43-yr-old hypertensive male was admitted due to hypokalemia (1.8 mEq/L) and renal dysfunction (eGFR, 20.0 mL/min/1.73 m2). His plasma aldosterone was 901.0 ng/dL, plasma renin activity 5.7 ng/mL/hr, and aldosterone/renin activity ratio 158. Angiotensin II (AII) was 0.7 pg/mL, ACTH <1.0 pg/mL, and cortisol 21.6 µg/dL. Liquid chromatography-tandem mass spectrometry analysis showed that aldosterone (104 times the control) as well as its precursors were significantly elevated in the patient's plasma. A left adrenal (4-cm-diameter) tumor with 131I-Adosterol uptake was found and removed. Four days later, plasma aldosterone and renin activity had dropped to 7.73 ng/dL and 1.6 ng/mL/hr, respectively. However, they rose to 24.0 ng/dL and 10.9 ng/mL/hr, respectively, by Day 102. Nevertheless, magnetic resonance angiography found no evidence of a renovascular lesion. The tumor was a benign adrenocortical adenoma composed predominantly of clear cells positive for 17α-hydroxylase, [hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerases], and aldosterone synthase. A quantitative real-time polymerase chain reaction analysis of the tumor cells revealed that expression of the gene encoding aldosterone synthase was 85 times the control level. In addition, the tumor cells harbored G151R mutation of the inward rectifying potassium channel subfamily j, member 5 gene. The striking overexpression of aldosterone synthase by the tumor cells was considered the primary mechanism for the extravagant overproduction of aldosterone in this case. This overexpression may have resulted from integration of signals from AII and forced membrane depolarization due to the potassium channel mutation.

Liver dysfunction and thrombocytopenia diagnosed as intravascular large B-cell lymphoma using a timely and accurate transjugular liver biopsy.

A 72-year-old man suffered from paraparesis with a sensory impairment and bladder and rectal disturbances. Magnetic resonance imaging T2-weighted images depicted a high-intensity lesion in the spinal cord that was consistent with myelitis. A blood examination revealed severe thrombocytopenia and liver dysfunction. No malignant cells were detected by peripheral smears or bone marrow biopsy. Systemic computed tomography detected hepatosplenomegaly and ascites but no lymphadenopathies. Transjugular liver biopsy (TJLB) safely confirmed a diagnosis of intravascular large B-cell lymphoma (IVLBCL), and the patient achieved a complete response following treatment with an appropriate chemotherapy. TJLB is therefore a timely and accurate diagnostic approach for IVLBCL, especially when a bleeding tendency and ascites are noted.

A novel prodrug strategy for extremely hydrophobic agents: conjugation to symmetrically branched glycerol trimer improves pharmacological and pharmacokinetic properties of fenofibrate.

Management of a lipophilic-hydrophilic balance is a key element in drug design to achieve desirable pharmacokinetic characters. Therefore we have created unique modular molecules, symmetrically branched oligoglycerols (BGL), as an alternative way to endow hydrophobic molecules with sufficient hydrophilicity. We have successfully demonstrated amelioration of the water solubility and thermal stability of several hydrophobic agents by covalent conjugation to BGL so far. However, it has not been clarified whether the molecular modification by BGL also improves the pharmacological and/or pharmacokinetic properties indeed. Recently, we synthesized a novel BGL-prodrug derivative of fenofibrate, which is an antihyperlipidemic agent and one of the most hydrophobic medicinal compounds currently used clinically, by conjugating fenofibric acid to symmetrically branched glycerol trimer (BGL003), the simplest BGL. We have previously demonstrated that the hydrophilicity and water solubility of fenofibrate are improved more than 2000 times just by conjugation to the BGL003. To verify our hypothesis that the prodrug strategy with BGL should improve pharmacological efficacy and pharmacokinetic properties of extremely hydrophobic agents such as fenofibrate by the rise in hydrophilicity, we evaluated the BGL003-prodrug derivative of fenofibrate (FF-BGL) using rodent models. Here we demonstrate that the lipid-lowering effects of fenofibrate are much potentiated by chemical conjugation to BGL003 without exhibiting significant toxicity. Plasma concentration of fenofibric acid, an active metabolite of fenofibrate, after single oral administration of FF-BGL was more than 3 times higher than that of fenofibrate, in accordance. In fasting rats, plasma concentration of fenofibric acid after fenofibrate administration was curtailed into less than half of that in ad libitum-fed rats, while FF-BGL showed about the same plasma level even in the starving rats. This is the first report showing that BGL-prodrug improves pharmacological and pharmacokinetic properties as well as hydrophilicity of highly hydrophobic compounds. Furthermore, prodrug strategy using BGL suggests the possibility of diminishing the food-drug interaction effects, which should be advantageous for promoting drug compliance. BGL will be a suitable prodrug strategy to ameliorate physical, pharmacological, and pharmacokinetic characteristics of extremely hydrophobic compounds.

Electron-rich carbon nanorings as macrocyclic hosts for fullerenes.

Electron-rich cycloparaphenyleneacetylenes as well as their twin "glasses-like" conjugates form stable complexes with fullerenes.

MR features of primary and secondary malignant lymphoma of the pancreas: a pictorial review.

OBJECTIVE: To describe the imaging findings of primary and secondary pancreatic malignant lymphoma on magnetic resonance imaging (MRI), to help differentiate lymphoma of the pancreas from primary adenocarcinoma and autoimmune pancreatitis among others, and to discuss a few atypical presentations of pancreatitis mimicking lymphoma. CONCLUSION: Knowledge of these imaging manifestations of lymphoma may be helpful to arrive at an accurate diagnosis and avoid unnecessary morbidity and mortality from inadvertent surgery. MAIN MESSAGES: • Pancreatic malignant lymphoma is shown as a nodular low-density area with mild enhancement on CT. • It sometimes shows variable manifestations mimicking other tumours and inflammatory conditions. • MRI provides useful information for differentiating malignant lymphoma from other mimickers.

Acute oral toxicity evaluation of symmetrically branched glycerol trimer in ddY mice.

Lipophilic-hydrophilic balance is a quite important determinant of pharmacokinetic properties of pharmaceuticals. Thus it is a key step to successfully manage lipophilic-hydrophilic balance in drug design. We have designed unique modular molecules, symmetrically branched oligoglycerols (BGL) as an alternative means to endow hydrophobic molecules with much hydrophilicity. We have succeeded in improving the water-solubility of several hydrophobic medicinal small molecules and thermal stability of artificial protein by covalent conjugation to BGL. We have also demonstrated that a representative BGL, symmetrically branched glycerol trimer (BGL003) does not exhibit significant cytotoxicity against human hepatocarcinoma HepG2 cells. However, there have been no reports suggesting whether BGL could be used in safety in vivo. Therefore, evaluation of acute oral toxicity of BGL003 in healthy mice was conducted. Here we demonstrate that an oral administration of BGL003 did not exhibit acute lethal toxicity up to 3,000 mg/kg. Body weight, food intake, blood glucose levels and weights of tissues were not affected by a short-term repetitive administration of increasing doses of BGL003. Biochemical indications related to hepatic disorders and tissue damage were unchanged, either. A single administration study revealed that 50% lethal dose of BGL003 should be more than 2,000 mg/kg. BGL003 will be safe and suitable approach to improve hydrophilicity of hydrophobic compounds.

Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells.

An appropriate balance between lipophilicity and hydrophilicity is necessary for pharmaceuticals to achieve fine Absorption, Distribution, Metabolism and Excretion (ADME) properties including absorption and distribution, in particular. We have designed and proposed symmetrically branched oligoglycerols (BGL) as an alternative approach to improve the lipophilic-hydrophilic balance. We have previously shown that stability in circulation and water-solubility of such molecules as proteins, liposomes and hydrophobic compounds are much improved by conjugation to BGL. Albeit these successful applications of BGL, little was known whether BGL could be used in safety. Thus we conducted evaluation of the cytotoxicity of a representative BGL, symmetrically branched glycerol trimer (BGL003) in the cultured cells to clarify its biological safeness. Here we demonstrate that water-solubility of an extremely hydrophobic agent, fenofibrate was more than 2,000-fold improved just by conjugated with BGL003. BGL003 did not exhibit any significant cytotoxicity in human hepatocarcinoma HepG2 cells. Thus BGL003 should be safe and suitable strategy to endow hydrophobic molecules with much hydrophilicity.

Synthesis of highly water-soluble fibrate derivatives via BGLation.

Three water-soluble fibrates (fenofibrate, bezafibrate and chlofibrate) conjugated with a symmetrically branched glyceryl trimer (BGL003) were synthesized, and an evaluation of the fenofibrate-BGL003 conjugate as a candidate for anti-hyperlipemia drug was carried out using rats. The water-solubility of the fenofibrate-BGL003 conjugate was several thousand times greater than that of the original fenofibrate. The lipid-lowering effects of the fenofibrate-BGL003 conjugate were as strong as those of the same grams of fenofibrate. The actual active species of fenofibrate, fenofibric acid, was detected in rats' blood, but neither the fenofibrate-BGL003 conjugate nor fenofibrate was detected, probably due to enzymatic hydrolysis of the ester bond. The plasma concentration of fenofibric acid derived from the fenofibrate-BGL003 conjugate was five times higher than that derived from fenofibrate 4h after administration.

Changes in CT density of solitary capillary hemangioma of the lung upon varying patient position.

Solitary capillary hemangioma of the lung (SCHL) is a rare benign tumor that is difficult to differentiate from other nodular lesions, including lung cancer, on CT. We report a case of 58-year-old man with an SCHL of the left lower lung. A nodular lesion 7 mm in size varied in CT appearance when the position of the patient was changed: it was part solid and part ground-glass opacity (mixed GGO) in the supine position, but pure GGO (nonsolid) in the prone position. However, the possibility of a malignancy could not be completely excluded because the density of the lesion had increased slightly over the past five years, so the patient underwent surgical resection. The histological diagnosis was SCHL. Therefore, changes in the CT density of a nodule upon changing patient position may indicate an SCHL.

Synthesis of paclitaxel-BGL conjugates.

Four kinds of symmetrically branched oligoglyceryl trimeric (BGL003)-paclitaxel conjugates and a corresponding heptameric (BGL007) conjugate were synthesized. Molecular weights of all the compounds were less than two times that of paclitaxel. The anti-tumor activity of the most water-soluble BGL003 conjugate was examined and found to be preserved in spite of the chemical modification that is displacement of the N3'-debenzoyl residue with the BGL003 succinyl residue.

Synthesis and evaluation of water-soluble resveratrol and piceatannol via BGLation.

Synthesis of four water-soluble resveratrol and piceatannol derivatives bearing symmetrically branched glyceryl trimer (BGL003) with a non-biocleavable linkage, and their biological evaluation as a mitochondrial fusion-inducing agent with cellular fat-reducing effect from cells, is described. The effect of Piceatannol-BGL003 conjugate was as high as that of original stilbenoids.

Effect of hepatobiliary uptake of Gd-EOB-DTPA on the hepatic venous phase of dynamic magnetic resonance imaging on a 3.0-T apparatus: comparison between Gd-EOB-DTPA and Gd-DTPA.

PURPOSE: We aimed to reveal the difference in contrast enhancement of the abdominal organs and major vessels on dynamic contrast-enhanced magnetic resonance imaging (DCM-MRI) using gadoxetic sodium (Gd-EOB-DTPA) and gadopentetate dimeglumine (Gd-DTPA) in the same patients. MATERIALS AND METHODS: DCM-MRI using Gd-EOBDTPA and Gd-DTPA were performed in the same 17 patients. Precontrast and DCM-MRI images [arterial phase (AP), portal venous phase (PP), hepatic venous phase (HP)] were acquired before and after bolus injection of each contrast agent. The organ-to-muscle ratio [liver (L/M), spleen (S/M), aorta (A/M), portal vein (P/M), hepatic vein (V/M)] were calculated at each phase and analyzed statistically. RESULTS: There was no significant difference between Gd-EOB-DTPA and Gd-DTPA images regarding the L/M or V/M mean on precontrast images or the mean of L/M at AP and L/M at the PP. At the AP, PP, and HP, the means of S/M, A/M, P/M, and V/M with Gd-EOBDTPA were lower than those with Gd-DTPA. On HP, The mean L/M with Gd-EOB-DTPA was higher than that with Gd-DTPA. CONCLUSION: On 3-T DCM-MRI using Gd-EOB-DTPA, contrast enhancement of the organs, except for the liver, was lower than that on DCM-MRI using Gd-DTPA. The HP was already affected by hepatobiliary uptake in Gd-EOB-DTPA.

Improved performance by replacing iminodiacetic residues with glyceryl residues in symmetrically branched oligoglycerols.

Synthesis of a symmetrically branched diglycerol (BGL002, involving one iminodiacetic residue) as a G2 dendron, and the tetradecaglycerol (BGL014, involving one iminodiacetic residue) as a G4 dendron, is described. Several members of the BGL family of G2-G4 dendrons were assembled, with G2 bearing four hydroxyl groups at the terminus region, G3 bearing eight, and G4 bearing sixteen. It is noteworthy that triglycerol (BGL003, including no iminodiacetic residue), has a water-solubility ten times higher than BGL002, and the liposome surrounded by BGL014 has a duration period in blood vessel roughly two times longer than the liposome surrounded by dodecaglycerol (BGL012, including three iminodiacetic residues).

Usefulness of the automatic quantitative estimation tool for cerebral blood flow: clinical assessment of the application software tool AQCEL.

OBJECTIVE: AQCEL enables automatic reconstruction of single-photon emission computed tomogram (SPECT) without image degradation and quantitative analysis of cerebral blood flow (CBF) after the input of simple parameters. We ascertained the usefulness and quality of images obtained by the application software AQCEL in clinical practice. METHODS: Twelve patients underwent brain perfusion SPECT using technetium-99m ethyl cysteinate dimer at rest and after acetazolamide (ACZ) loading. Images reconstructed using AQCEL were compared with those reconstructed using conventional filtered back projection (FBP) method for qualitative estimation. Two experienced nuclear medicine physicians interpreted the image quality using the following visual scores: 0, same; 1, slightly superior; 2, superior. For quantitative estimation, the mean CBF values of the normal hemisphere of the 12 patients using ACZ calculated by the AQCEL method were compared with those calculated by the conventional method. The CBF values of the 24 regions of the 3-dimensional stereotaxic region of interest template (3DSRT) calculated by the AQCEL method at rest and after ACZ loading were compared to those calculated by the conventional method. RESULTS: No significant qualitative difference was observed between the AQCEL and conventional FBP methods in the rest study. The average score by the AQCEL method was 0.25 ± 0.45 and that by the conventional method was 0.17 ± 0.39 (P = 0.34). There was a significant qualitative difference between the AQCEL and conventional methods in the ACZ loading study. The average score for AQCEL was 0.83 ± 0.58 and that for the conventional method was 0.08 ± 0.29 (P = 0.003). During quantitative estimation using ACZ, the mean CBF values of 12 patients calculated by the AQCEL method were 3-8% higher than those calculated by the conventional method. The square of the correlation coefficient between these methods was 0.995. While comparing the 24 3DSRT regions of 12 patients, the squares of the correlation coefficient between AQCEL and conventional methods were 0.973 and 0.986 for the normal and affected sides at rest, respectively, and 0.977 and 0.984 for the normal and affected sides after ACZ loading, respectively. CONCLUSIONS: The quality of images reconstructed using the application software AQCEL were superior to that obtained using conventional method after ACZ loading, and high correlations were shown in quantity at rest and after ACZ loading. This software can be applied to clinical practice and is a useful tool for improvement of reproducibility and throughput.

Semiquantitative measurement of pulmonary hilar gallium-67 uptake using single photon emission computed tomography/computed tomography for the diagnosis of autoimmune pancreatitis.

PURPOSE: We ascertained the difference in the level of pulmonary hilar (PH) gallium-67 (Ga-67) uptake in autoimmune pancreatitis (AIP) patients between the active (before corticosteroid therapy) and remittent (after 4 weeks of corticosteroid therapy) phases using a semiquantitative measurement method based on single photon emission computed tomography (SPECT) with integrated low-dose computed tomography (CT). MATERIALS AND METHODS: Ga-67 planar scans and SPECT were performed in 11 AIP patients before and after 4 weeks of corticosteroid therapy. A region of interest (ROI) was drawn over the bilateral pulmonary hilum and the liver, and average counts of the pulmonary hilum and liver were calculated. The average counts of the pulmonary hilum divided by those of the liver gave the pulmonary hilum/liver ratio (H/L). RESULTS: A significant difference was observed in the H/L between active and remittent phases. H/L in the active phase was 1.03±0.32 and that in the remittent phase was 0.58±0.25 (t-test, P=0.0016). CONCLUSIONS: PH Ga-67 uptake in patients with active AIP was semiquantitatively higher than that in those with remittent AIP. Hence, this may be a useful finding for an early diagnosis, estimating the effectiveness of corticosteroid therapy, and following up patients with this disease.

Usefulness of 67Ga SPECT and integrated low-dose CT scanning (SPECT/CT) in the diagnosis of cardiac sarcoidosis.

OBJECTIVE: We performed 67Gallium (Ga) single-photon emission computed tomography (SPECT) with integrated low-dose computed tomography (CT) for the interpretation of myocardial outline to investigate the value of co-registered fusion imaging using a hybrid system (SPECT/CT) in patients with cardiac sarcoidosis. METHODS: SPECT/CT of the region in question was performed with VG Hawkeye. The subjects in this study were 37 patients [mean (+/-SD) age 61.0+/-13.0 years; 12 men and 25 women], 13 of whom had a clinical diagnosis of cardiac sarcoidosis and 24 a negative diagnosis. An intravenous injection of Ga (dosage 111 MBq) was performed on patients 48 h or 72 h before obtaining static planar images of the whole-body and the SPECT/CT scan. RESULTS: Abnormal Ga uptake in the myocardium was observed in 10 of the 13 subjects with true sarcoidosis, and in 11 of 24 with negative sarcoidosis without CT fusion. The sensitivity without CT fusion was 77%, the specificity 54%, and the accuracy 62%. Use of SPECT/CT changed the diagnosis only in a patient with true sarcoidosis, and changed the diagnosis in eight patients with negative sarcoidosis. The sensitivity with CT fusion was 69%, the specificity 79%, and the accuracy 76%. The difference in diagnostic accuracy was statistically significant (McNemar's test, P=0.039). CONCLUSIONS: SPECT scanning using Ga and integrated low-dose CT is a very useful diagnostic imaging technique because it improves the diagnostic specificity of Ga SPECT to allow the highly specific diagnosis of cardiac sarcoidosis.

Serial assessment of left ventricular function in various patient groups with Tl-201 gated myocardial perfusion SPECT.

PURPOSE: The present study was performed to assess stress-related left ventricular (LV) function variations in various patient groups and to determine if they were affected by sex or the type of stress experienced. We used thallium (Tl)-201 gated myocardial perfusion single-photon emission computed tomography (SPECT) for the analysis. MATERIALS AND METHODS: A total of 270 patients were examined by electrocardiography-gated myocardial perfusion SPECT imaging to assess LV function. After injection of Tl-201 at a dose of 111 MBq at peak stress, SPECT scans were acquired at 10 min (after stress) and 3 h (rest) after injection on a three-headed camera. RESULTS: In the normal perfusion group, the mean LV ejection fraction (LVEF) was significantly higher, and both the end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) were significantly lower in women than in men (P < 0.05). Poststress stunning occurred in 29 of 98 patients (30.0%) in the ischemia group and in 42 of 90 patients (46.7%) in the fixed group. There was a significant difference in poststress stunning between bicycle ergometer stress and dipyridamole stress (P < 0.05). CONCLUSION: In patients with normal perfusion, LVEF, EDVI, and ESVI determined by gated Tl-201 SPECT should be corrected for sex. In addition, the influence of the type of stress should be considered when assessing stress-related LV function variations.

Dynamic MR imaging for diagnosis of lesions adjacent to pituitary gland.

In this study, we evaluated the usefulness of dynamic studies for the preoperative diagnosis of tumor lesions adjacent to the pituitary gland. We examined 13 tumors. We obtained pre- and post-contrast thin slice T1-weighted images of the sellar regions. FSE sequences were used for dynamic study. The capability to distinguish the tumor from the pituitary gland and additional information obtained from the dynamic study were evaluated. Two meningiomas were identified more clearly on the dynamic than on the delayed study. In two cavernous hemangiomas, the peripheral nodular stains gradually increased during the dynamic study. For the preoperative evaluation of lesions adjacent to the pituitary gland, the dynamic study can often identify the lesions more clearly and may provide additional information.

Small solitary pulmonary nodules (< or =1 cm) detected at population-based CT screening for lung cancer: Reliable high-resolution CT features of benign lesions.

OBJECTIVE: We assessed thin-section CT features specific to benignity in solitary pulmonary nodules of 1 cm or smaller that were detected at population-based CT screening for lung cancer. MATERIALS AND METHODS: Two reviewers independently made qualitative (presence or absence of lobulation, spiculation, air bronchogram, cavity, satellite lesions, pleural tag, concave margins, polygonal shape, and peripheral subpleural lesion) and quantitative (lesion size, percentage of ground-glass opacity areas, and two- and three-dimensional ratios of lesion) assessments in CT images of 72 nodules (25 lung cancers, seven atypical adenomatous hyperplasias, and 40 benign lesions). Optimal criteria specific to benignity were studied. RESULTS: The prevalence of polygonal shape (p = 0.005 and p = 0.019, reviewer 1 and reviewer 2), peripheral subpleural lesion (p = 0.011 and p = 0.033), a predominantly solid lesion (p < 0.001 and p < 0.001), and three-dimensional ratios (p < 0.001 and p < 0.001) were greater in benign lesions than in malignancies. The prevalence of a predominantly solid lesion (p < 0.001 and p < 0.001) was greater in benign lesions than in atypical adenomatous hyperplasias, and the prevalence of a peripheral subpleural lesion (p = 0.004 and p = 0.012) was greater in atypical adenomatous hyperplasias than in malignancies. Using a single CT feature, polygonal shape and a three-dimensional ratio of greater than 1.78 showed 100% specificity for both reviewers. Among all combinations of CT findings specific to benignity, a combined criterion of a predominantly solid lesion and peripheral subpleural lesion or polygonal shape or the three-dimensional ratio attained the highest sensitivity (63% and 60%) for both reviewers. CONCLUSION: A combined criterion of CT features was optimal for predicting benign pulmonary lesions.