Noninvasive quantitative evaluation of viable islet grafts using ¹¹¹In-exendin-4 SPECT/CT

Islet transplantation (IT) is an effective β-cell replacement therapy for patients with type 1 diabetes; however, the lack of methods to detect islet grafts and evaluate their β-cell mass (BCM) has limited the further optimization of IT protocols. Therefore, the development of noninvasive β-cell imaging is required. In this study, we investigated the utility of the ¹¹¹Indium-labeled exendin-4 probe {[Lys12(111In-BnDTPA-Ahx)] exendin-4} (¹¹¹In exendin-4) to evaluate islet graft BCM after intraportal IT. The probe was cultured with various numbers of isolated islets. Streptozotocin-induced diabetic mice were intraportally transplanted with 150 or 400 syngeneic islets. After a 6-week observation following IT, the ex-vivo liver graft uptake of ¹¹¹In-exendin-4 was compared with the liver insulin content. In addition, the in-vivo liver graft uptake of ¹¹¹In exendin-4 using SPECT/CT was compared with that of liver graft BCM measured by a histological method. As a result, probe accumulation was significantly correlated with islet numbers. The ex-vivo liver graft uptake in the 400-islet-transplanted group was significantly higher than that in the control and the 150-islet-transplanted groups, consistent with glycemic control and liver insulin content. In conclusion, in-vivo SPECT/CT displayed liver islet grafts, and uptakes were corroborated by histological liver BCM. ¹¹¹In-exendin-4 SPECT/CT can be used to visualize and evaluate liver islet grafts noninvasively after intraportal IT

Voxel‐based specific regional analysis system for Alzheimer’s disease utility as a screening tool for unrecognized cognitive dysfunction of elderly patients in diabetes outpatient clinics: Multicenter retrospective exploratory study

AIMS/INTRODUCTION: An efficient screening strategy for identification of cognitive dysfunction remains a clinical issue in the management of elderly adults with diabetes. A magnetic resonance imaging voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) has been developed as an automated brain morphometry system that includes the hippocampus. We carried out a multicenter retrospective study to evaluate the utility of VSRAD for screening cognitive dysfunction in diabetes outpatient clinics. MATERIALS AND METHODS: We enrolled patients with diabetes aged >65 years who underwent brain magnetic resonance imaging scans for the purpose of a medical checkup between November 2018 and May 2019. Patients who were already suspected or diagnosed with mild cognitive impairment and/or dementia as well as those with a history of cerebrovascular disease were excluded. RESULTS: A total of 67 patients were enrolled. Five patients were diagnosed with mild cognitive impairment or dementia (clinical cognitive dysfunction). Patients with clinical cognitive dysfunction showed a significantly higher z-score in VSRAD analysis (2.57 ± 0.47 vs 1.15 ± 0.55, P < 0.01). The sensitivities and specificities for diagnosis of clinical cognitive dysfunction were 80 and 48% for the Mini-Mental State Examination, 100 and 89% for the z-score, and 100 and 90% for the combination of the Mini-Mental State Examination score and z-score, respectively. CONCLUSIONS: VSRAD analysis can distinguish patients with clinical cognitive dysfunction in the elderly with diabetes, and also shows reasonable sensitivity and specificity compared with the Mini-Mental State Examination alone. Thus, VSRAD analysis can be useful for early identification of clinical cognitive dysfunction in the elderly with diabetes

Development of a 1,3a,6a-triazapentalene derivative as a compact and thiol-specific fluorescent labeling reagent

For the fluorescence imaging of biologically active small compounds, the development of compact fluorophores that do not perturb bioactivity is required. Here we report a compact derivative of fluorescent 1,3a,6a-triazapentalenes, 2-isobutenylcarbonyl-1,3a,6a-triazapentalene (TAP-VK1), as a fluorescent labeling reagent. The reaction of TAP-VK1 with various aliphatic thiols proceeds smoothly to afford the corresponding 1,4-adducts in high yields, and nucleophiles other than thiols do not react. After the addition of thiol groups in dichloromethane, the emission maximum of TAP-VK1 shifts to a shorter wavelength and the fluorescence intensity is substantially increased. The utility of TAP-VK1 as a compact fluorescent labeling reagent is clearly demonstrated by the labeling of Captopril, which is a small molecular drug for hypertension. The successful imaging of Captopril, one of the most compact drugs, in this study demonstrates the usefulness of compact fluorophores for mechanistic studies

CAUSES OF FUNCTIONAL DECLINE IN ELDERLY HOSPITALIZED PATIENTS RECEIVING EITHER INDIVIDUAL OR EXCLUSIVE REHABILITATION THERAPY: A COHORT STUDY

Background: Recently, exclusive rehabilitation therapy was introduced to prevent functional decline due to hospital-associated deconditioning by managing older inpatients’ activities of daily living in Japan. However, this type of therapy does not provide one-on-one exercises similar to individual rehabilitation therapy. This study aimed to report the present ward conditions and the causes of the functional decline in elderly patients receiving individual or exclusive rehabilitation therapy. Methods: A total of 1,636 inpatients, aged 65 years or older, were included in the study. Barthel Index at admission and discharge was assessed prospectively to analyze functional decline. We further analyzed the causes of functional decline by investigating the inpatient’s medical records. Results: Forty-three inpatients (2.6%) had functional decline during hospitalization. There were no significant differences in age, Barthel Index at the time of admission, and the type of clinical department between inpatients with and without functional decline. The functional decline rate in individual rehabilitation therapy was 8.2%, which was significantly higher compared to exclusive rehabilitation therapy (0.8%). The most common causes of functional decline were a pain, low postoperative physical fitness, malignant neoplasm, and new-onset cerebral stroke. Conclusion: We report the present ward conditions in elderly patients receiving either individual or exclusive rehabilitation therapies. Functional decline was correlated to the inpatients’ disease and conditions. The causes of the functional decline can be classified based on whether rehabilitation was effective or ineffective. If the functional decline was caused by hospital-associated deconditioning, we should address the functional decline by providing appropriate rehabilitation methods

Genomic Profiling of a Case of Glioneuronal Tumor with Neuropil-like Islands

Glioneuronal tumor with neuropil-like islands (GNTNI) is a very rare subtype of glioneuronal tumor. We present a case of a 62-year-old man with GNTNI. Two adjacent lesions in the left parietal lobe were removed by left parietal craniotomy. The histological findings were glial cell proliferation and scattered rosettes consisting of synaptophysin-positive and NeuN-positive cells, leading to the diagnosis of GNTNI. Target sequencing revealed a genetic alteration similar to glioblastoma, IDH-wild type, which suggested adjuvant therapies. There are few previous reports on the treatment of this disease, and the patient should be followed carefully

Utility of Comprehensive Genomic Profiling for Precise Diagnosis of Pediatric-Type Diffuse High-Grade Glioma

In the current World Health Organization classification of central nervous system tumors, comprehensive genetic and epigenetic analyses are considered essential for precise diagnosis. A 14-year-old male patient who presented with a cerebellar tumor was initially diagnosed with glioblastoma and treated with radiation and concomitant temozolomide chemotherapy after resection. During maintenance temozolomide therapy, a new contrast-enhanced lesion developed in the bottom of the cavity formed by the resection. A second surgery was performed, but the histological findings in specimens from the second surgery were different from those of the first surgery. Although genome-wide DNA methylation profiling was conducted using frozen tissue for a precise diagnosis, the proportion of tumor cells was insufficient and only normal cerebellum was observed. We then performed comprehensive genetic analysis using formalin-fixed paraffin-embedded sections, which revealed MYCN amplification without alteration of IDH1, IDH2, or Histone H3. Finally, the patient was diagnosed with pediatric-type diffuse high-grade glioma, H3-wildtype and IDH-wildtype. In conclusion, comprehensive genetic and epigenetic analysis should be considered in pediatric brain tumor cases

Association between Serum Soluble Klotho Levels and Mortality in Chronic Hemodialysis Patients

Klotho is a single-pass transmembrane protein predominantly expressed in the kidney. The extracellular domain of Klotho is subject to ectodomain shedding and is released into the circulation as a soluble form. Soluble Klotho is also generated from alternative splicing of the Klotho gene. In mice, defects in Klotho expression lead to complex phenotypes resembling those observed in dialysis patients. However, the relationship between the level of serum soluble Klotho and overall survival in hemodialysis patients, who exhibit a state of Klotho deficiency, remains to be delineated. Here we prospectively followed a cohort of 63 patients with a mean duration of chronic hemodialysis of 6.7±5.4 years for a median of 65 months. Serum soluble Klotho was detectable in all patients (median 371 pg/mL, interquartile range 309–449). Patients with serum soluble Klotho levels below the lower quartile (<309 pg/mL) had significantly higher cardiovascular and all-cause mortality rates. Furthermore, the higher all-cause mortality persisted even after adjustment for confounders (hazard ratio 4.14, confidence interval 1.29–13.48). We conclude that there may be a threshold for the serum soluble Klotho level associated with a higher risk of mortality