Development of bifunctional radiopharmaceuticals for targeted imaging and therapy

In vivo radiopharmaceuticals have two different uses - for nuclear diagnostic imaging and for internal radiation therapy. For nuclear diagnostic imaging, it is necessary to make the difference of radioactivity levels between in the target regions and in the other regions at an early time after administration. For internal radiation therapy, a more selective accumulation of the radioactivity to the target regions is required to minimize an adverse effect. In order to achieve the highly selective accumulation of in vivo radiopharmaceuticals, it is necessary to find an appropriate target molecule in the first place and design a compound which can recognize the target molecule and stably label it with radionuclide. There are several proposed approaches to chemical design for this purpose. However, even with the specific recognition and stable radiolabel, targeted imaging and therapy are not necessarily achieved. We have been developing in vivo radiopharmaceuticals based on a chemical design called "bifunctional radiopharmaceutical." Bifunctional radiopharmaceuticals have the recognition site of the target molecule and binding site for the radionuclide independently in one molecule. This review summarizes our examples of chemical design of in vivo radiopharmaceuticals to achieve the targeted imaging and therapy.     

Social participation and incident disability and mortality among frail older adults: A JAGES longitudinal study

Background

Frailty is the highest risk factor for incident disability and mortality. Social participation is a modifiable factor for reducing adverse outcomes among independent older adults. However, the association between social participation and incident disability and mortality among frail older adults remains unclear. Therefore, we examined the association between various social activities and incident disability and mortality.

Methods

This nationwide prospective cohort study (The Japan Gerontological Evaluation Study) recruited older adults with frailty, aged 65 years and older (N = 9090) who were followed up for 6 years (2010–2016). We examined incident disability and all-cause mortality at the end of the follow-up period. Frailty was assessed using the Kihon Checklist. The independent variable was social participation in 2010, grouped into the following seven categories: hobby groups, sports groups or clubs, volunteer groups, senior citizens' clubs, industries, neighborhood communities, and paid work.

Results

The incidence of disability among participants was 19.5% (1770) and that of mortality was 19.2% (1753). Belonging to sports groups or clubs (Hazard Ratios [HR] = 0.74; 95% Confidence Interval [CI] = 0.57, 0.98) or hobby groups (HR = 0.77; 95% CI = 0.60, 0.98) was significantly associated with a lower risk of incident disability. Meanwhile, hobby groups (HR = 0.68; 95% CI = 0.56, 0.83), sports groups or clubs (HR = 0.71; 95% CI = 0.57, 0.88), volunteer groups (HR = 0.69; 95% CI = 0.54, 0.88), and senior citizens' club (HR = 0.75; 95% CI = 0.61, 0.90) were associated with lower risk of incident mortality.

Conclusions

Social participation was associated with a lower risk of incident disability and mortality, not only in healthy older adults but also in frail older adults who are at higher risk of incident disability and mortality. This suggests that frail older adults should be encouraged to participate in all the seven types of social participation examined in this study, as this may lower the risk of subsequent disability and mortality.     

Force exerted on maxillary anterior teeth in mandibular unilateral and bilateral distal extension partial edentulous situation

Odontology - The purpose of this study was to determine the influence of mandibular unilateral and bilateral distal extension partial edentulous situation and the use of removable partial dental...     

Pleomorphic type of malignant fibrous histiocytoma with myxoid stroma of the vulva in a young woman

Malignant fibrous histiocytoma (MFH) of the vulva is extremely rare; to date, there have been nine case reports. Almost all of these cases involved middle-aged women. We encountered a 21-year-old woman with a 4.5 × 2.6 cm superficial, localized, exophytic tumor of the right vulva. Microscopic findings on punch biopsy of the tumor initially suggested a vulvar sarcoma. The patient underwent wide local excision of the vulva. The extirpated specimen demonstrated the pleomorphic type of MFH with myxoid stroma of the vulva. The clinical stage was found to be IIB, based on the American Joint Committee on Cancer staging system. Chromosomal analysis of the tumor using the conventional G-band method was normal (46XX). This seems to be a very rare case of MFH of the vulva in a young woman. Physicians should therefore include MFH in the differential diagnosis of vulvar tumors, even though it is a rare disease.     

Prenatal diagnosis of short-rib polydactyly syndrome type 3 (Verma-Naumoff type) by three-dimensional helical computed tomography

We present a case of short-rib polydactyly syndrome (SRPs) type 3 in which accurate prenatal diagnosis was feasible using both ultrasonography and 3D-CT. SRP encompass a heterogeneous group of lethal skeletal dysplasias. However, the phenotypes overlap with those of nonlethal skeletal dysplasias (i.e. Ellis-van Creveld syndrome and Jeune syndrome). As accurate prenatal diagnosis of SRP is helpful for parents, we used 3D-CT in the early third trimester to examine a fetus suggested to have phenotypes of 'short-rib dysplasia group' on ultrasonography. 3D-CT showed mild modification of the vertebral bodies, small ilia with horizontal acetabula and triangular partial ossification defects, and subtle metaphyseal irregularities of the femora. These CT findings and an extensive literature search regarding the phenotypes of various diseases categorized as short-rib dysplasia group led to a correct prenatal diagnosis of SRP type 3. This case exemplified the usefulness of 3D-CT for the precise prenatal diagnosis of skeletal dysplasias.     

A case report of fatal tumor lysis syndrome after chemotherapy in a pregnant patient with Burkitt's lymphoma

A 35-year-old Japanese woman in the 24th week of gestation with bilateral breast enlargement was referred to hospital. She was diagnosed with Burkitt's lymphoma and admitted for detailed evaluation and treatment. Early delivery and subsequent chemotherapy was chosen after considering the gestational week, her general condition and the wishes of the patient and her husband. She gave birth to a male infant by cesarean section in the 25(th) week of gestation. It had been planned to begin high-dose chemotherapy, such as CODOX-M/IVAC, on day 7 of the puerperium; however, her general condition worsened and chemotherapy was therefore begun on day 2 after the birth. Eight hours after chemotherapy (cyclophosphamide, vincristine and doxorubicin), she developed cardiac arrest due to tumor lysis syndrome. Despite medical treatment, her bleeding tendency did not improve and she died of respiratory failure with alveolar bleeding five days after chemotherapy.     

Contribution of sarcoplasmic reticulum Ca²+ release and Ca²+ transporters on sarcolemmal channels to Ca²+ transient in fetal mouse heart

Sarcoplasmic reticulum (SR) Ca release has been shown not to be the predominant mechanism responsible for excitation-contraction (E-C) coupling in fetal myocytes. However, most of the studies have been conducted either on primary cultures or acutely isolated cells, in which an apparent reduction of ryanodine receptor density have been reported. We aimed to elucidate the contribution of SR Ca release and Ca transporters on sarcolemmal channels to Ca transients in fetal mouse whole hearts. On embryonic day 13.5, ryanodine significantly reduced the amplitude of the Ca transient to 27.2 ± 4.4% of the control, and both nickel and SEA0400 significantly prolonged the time to peak from 84 ± 2 ms to 140 ± 5 ms and 129 ± 6 ms, respectively, whereas nifedipine did not alter it. Therefore, at early fetal stages, SR Ca release should be an important component of E-C coupling, and T-type Ca channel and reverse mode sodium-calcium exchanger (NCX)-mediated SR Ca release could be the predominant contributors. Using embryonic mouse cultured cardiomyocytes, we showed that both nifedipine and nickel inhibited the ability of NCX to extrude Ca from the cytosol. From these results, we propose a novel idea concerning E-C coupling in immature heart.