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Urban agriculture is the key to creating healthy cities and developing resilient urban food systems in uncertain times. However, relevant empirical evidence is limited. This study quantitatively verified the association of access to local food through urban agriculture with subjective well-being, physical activity, and food security concerns of neighborhood communities in the context of the COVID-19 pandemic. The target was Tokyo, Japan, where small-scale local food systems are widespread in walkable neighborhoods. We found that diversity in local food access, ranging from self-cultivation to direct-to-consumer sales, was significantly associated with health and food security variables. In particular, the use of allotment farms was more strongly associated with subjective well-being than the use of urban parks, and it was more strongly associated with the mitigation of food security concerns than the use of food retailers. These findings provide robust evidence for the effectiveness of integrating urban agriculture into walkable neighborhoods.

We used publicly available land-cover datasets (1921, 1947, 1976, 1992, 2001, 2006, 2014) to assess land-cover change on Babeldaob Island, Republic of Palau. Land-cover data were organized, classified, and summarized by area and percentage of island cover for forest, mangrove, non-forest vegetation, and non-vegetation. Japanese colonial administration of the island between 1921 and 1947 included industrial mining and agriculture, which reduced total non-mangrove forest cover by 16%. Temporal vegetation cover dynamics from 1947 through 2014 indicate unassisted forest regeneration of 12% with a concomitant decrease in non-forest vegetation including abandoned agriculture, the majority of which happened by 1976. Mangrove cover appears to have remained stable throughout the 93 year study period. Ground-truth observations showed the highest rates of vegetation cover change since 1976 for non-vegetated areas, followed by marsh and swamp forest. The proportion of non-vegetated cover increased at least twofold after WWII, with at least half comprising roads. Contrary to other tropical geographies, we saw forest expansion following completion of a major perimeter road. However, the larger landscape is permeated by dynamic forest edges subject to wildfire and other land-use disturbances.

The coronavirus disease 2019 (COVID-19) pandemic of 2020 drastically changed urban lifestyles. Workers were forced to minimize commuting to their workplaces, older adults were banned from using meeting facilities, and children were prohibited from going to school. The consequent lack of exercise, accumulated stress, and reduced well-being are likely to have become problems, which may be improved by using urban green spaces (UGS). This study clarified the characteristics of users of UGS in Tokyo during the COVID-19 pandemic, focusing on telecommuters, older adults, and families with children. An online questionnaire survey was conducted among Tokyo residents, and 3085 responses were obtained. A binomial logistic regression analysis was conducted with the use and evaluation of UGS as the objective variables. The results showed that older adults and families with children who had been using UGS before the pandemic and telecommuters who newly started using UGS during the pandemic used UGS differently. Older adults and families with children tended to use small parks and appreciated human connections. Telecommuters often used greenways, temples, and shrines, valuing stress-reducing functions. Given that a changing lifestyle brings new UGS users new preferences, urban planners should consider that UGS require change with the time.

In Japan, the world&rsquo, s most rapidly aging country, urban farming is attracting attention as an infrastructure for health activities. In Tokyo, urban residents generally participate in two types of farming programs: allotments and experience farms. The availability of regular interaction among participants distinguishes these two programs. We quantitatively examined the difference in changes in self-reported health status between participants in these two types of urban farming. We obtained retrospective cross-sectional data from questionnaire surveys of 783 urban farming participants and 1254 nonparticipants and analyzed the data using ordinal logistic regressions. As a result, compared with nonparticipants, participants in both types of urban farming reported significantly improved self-rated health (SRH) and mental health (MH). After controlling for changes in their physical activity (PA), although participants in allotments did not report significant improvement in SRH and MH, those in experience farms did, suggesting that their health improvement was not only caused by an increase in PA but also by social interaction among participants. From the perspective of health promotion, public support is needed not only for the municipality&rsquo, s allotments but also for the experience farms operated by the farmers themselves.

Responding to the international trend of urban population decline, a sustainable urban form has been pursued around the world, with the compact city movement a typical example. However, compact city debate has often been criticized for its inclination to bio-physical environmental and economic goals and a lack of treatment of empirical social aspects like residential behavior. The present study was thus aimed at examining the gap between Japanese compact city policy and actual spatial patterns of population turnover, inheritance and migration. The case study was of residential areas of a Japanese regional city, Utsunomiya. The study used a four-step procedure: a) identifying the distributions of inheritors and migrators; b) constructing a detailed database of five characteristics of the residential areas, i.e., age of development, orderliness, road width, transport access, and social cohesion; c) identifying relationships between the number of inheritors and migrators and residential characteristics using a Poisson regression model; d) comparing the compact city plan underway with established patterns of population turnover. The results show that the number of inheritors has positive relationships with age of the residential area and access to rail transport and downtown. The migrators tend to have a random distribution in comparison with inheritors. These empirical residential patterns appear irrelevant to the government's bus-oriented compact city policy, so the government should reconsider approaches to realize an acceptable sustainable urban form.

Modern dietary habits in communities are linked and are part of the global food supply chain. To achieve sustainable food production and consumption, communicating the impact associated with food production and dietary choices at community level to consumers is important. However, previous footprint studies have primarily focussed on food consumption at the national level and neglected community–level consumption activities. This study surveyed the diets of a small island community and linked the results with multi-region land footprint analysis in Ollei Village, Republic of Palau. The analysis was used to determine the extent to which the dietary lifestyles of communities depend on external land use through the global supply chain. We showed that the global food supply chain has reached this corner of the world, and the dietary habits of the community are already heavily dependent on processed and imported foods. The community and country are highly dependent on large land use in some major producer/exporting countries through the global food supply chain. In addition, the amount of external land used for food production exceeds the biocapacity of the agricultural land in the community and country. This study bridges the gap between community–level consumption activities and national-scale footprint analysis, and quantitatively assesses the impact of consumption activities at the community level on the global environment. The results and approach of this study could contribute to the development and implementation of vertically integrated food policies between the national and community level in Palau.

Experimental autoimmune myasthenia gravis (EAMG), an animal model of myasthenia gravis (MG), can be induced in C57BL/6 (B6, H-2 b) mice by 2-3 injections with Torpedo californica AChR (tAChR) in complete Freund's adjuvant. Some EAMG mice exhibit weight loss with muscle weakness. The loss in body weight, which is closely associated with bone structure, is particularly evident in EAMG mice with severe muscle weakness. However, the relationship between muscle weakness and bone loss in EAMG has not been studied before. Recent investigations on bone have shed light on association of bone health and immunological states. It is possible that muscle weakness in EAMG developed by anti-tAChR immune responses might accompany bone loss. We determined whether reduced muscle strength associates with decreased bone mineral density (BMD) in EAMG mice. EAMG was induced by two injections at 4-week interval of tAChR and adjuvants in two different age groups. The first tAChR injection was either at age 8 weeks or at 15 weeks. We measured BMD at three skeletal sites, including femur, tibia, and lumbar vertebrae, using dual energy X-ray absorptiometry. Among these bone areas, femur of EAMG mice in both age groups showed a significant decrease in BMD compared to control adjuvant-injected and to non-immunized mice. Reduction in BMD in induced EAMG at a later-age appears to parallel the severity of the disease. The results indicate that anti-tAChR autoimmune response alone can reduce bone density in EAMG mice. BMD reduction was also observed in adjuvant-injected mice in comparison to normal un-injected mice, suggesting that BMD decrease can occur even when muscle activity is normal. Decreased BMD observed in both tAChR-injected and adjuvant-injected mice groups were discussed in relation to innate immunity and bone-related immunology involving activated T cells and tumour necrosis factor-related cytokines that trigger osteoclastogenesis and bone loss.

The shared economy features a wide gap between the new digital sharing phenomenon and traditional communal sharing practices. This study examines the value of traditional sharing practices and discusses how new digital technologies can harness it. The study examines the use of marine and terrestrial natural resources through subsistence activities over 10 years in the Republic of Palau, Micronesia, and compares their frequency with the use of digital devices. The results show that the frequency of subsistence fishing, farming, and collecting has not substantially changed over 10 years in either urban or rural areas and that there is no relationship between the frequency of subsistence activities and digital technology use, despite the rapid spread of mobile devices. These findings indicate that nonmarket-based subsidence economies that rely heavily on local natural resources have not been completely replaced by a globalized monetary economy. Traditional practices in Palau use common natural resources and hand down the practical and empirical knowledge required to manage them in sustainable ways. Despite the many changes brought by external influences, these traditional communal sharing practices are still rooted in Palauan culture. This culture of sharing is the medium that sustains the healthy relationships between humans and ecosystems and can play a key role in building climate change resilience. It is thus desirable to employ the new digital technologies to pass traditional communal sharing practices down to future generations rather than just use them to do what they are used for in industrialized countries.

The increasing risk of coastal flooding and water shortage in Pacific Island Countries is usually attributed to climate change hazards. This ignores other risk components, exposure and vulnerability, of which a major contributor is urbanization. We develop simplified analyses that can be applied to other PICs. By dividing climate risks into hazard and exposure components we determine how urbanization contributed to present-day risks and then predict how growing climate change hazards may increase future risk, using the Republic of Palau as a case study. Results show that urbanization was responsible for 94% of the buildings exposed to coastal flooding today. Projected sea level rise, 30.2 cm by 2050, only increased exposure of today’s buildings by 0.5%. In both present and future scenarios exposure resultant from urbanization was more significant than sea level rise. Our water scarcity index showed urbanization caused 3 of the 7 recorded water shortages from 1980–2018. From 2041–2079, analysis of projected rainfall showed mean reductions between 1.6–16.6% and increased variance between 0.3–3.4%. This led to three times as many water shortages under present population levels. In historical and future scenarios exposure from increased population was just as significant in causing water shortages as rainfall variation. These findings suggest that urban management is an important tool to lower exposure to coastal flooding and water shortage and we recommend that decision makers prioritize urbanization within climate risk policy in Pacific Island Countries.

The differences in land resource use methods depend largely on climate change, the natural situation of the area and society. Until now, there has been much research on climate change and the impact of economic globalization on land use in the region, but land use hasn’t been discussed as a regional strategy. In this research, the land use map was reconstructed while paying attention to the historical changes of Ishigaki Island in Japan. Tourism is the main industry in the island. However, coral reefs, which are important as tourism resources, have been threatened by red soil runoff from farmland and development sites. Red soil runoff became worse in the pineapple boom that has occurred since the 1950s. After that, the “Red soil prevention law of Okinawa Prefecture” was enacted in 1994, and the red soil runoff was suppressed. Based on these social changes, we reconstructed the land use maps in 1921 (before pineapple boom), 1966 (the pineapple boom) and 2004 (after Red Earth Ordinance). As a result, it was found that the cultivated area of pineapple is expanding and reducing with the pineapple boom.

The 2020 Olympic Games marathon will be run through the streets of Tokyo on the mornings of August 2nd and 9th, a time of year that is typically hot, sunny, and humid. Few studies have assessed the potential impact of extreme heat along the marathon course to understand the multiple factors (e.g., radiation, wind flow) affecting human thermal comfort (TC) as influenced by urban design and vegetation. The current research establishes a baseline of microclimate conditions and scenarios to estimate the projected TC along the marathon route for spectators. Mobile microclimate data (air and surface temperatures, solar radiation, humidity, wind speed) were collected along the marathon course over 15 periods in the summer of 2016 and aligned with sky view factors (SVF). Human energy budget modeling was applied to provide spatially-explicit heat budget and TC information along the route. Conditions are expected to create the most discomfort along open, sun-exposed locations, with ~50% of the area along the second half of the course resulting in ‘Hot’ (budget > 200 W m−2) or ‘Very hot’ (budget > 295 W m−2) conditions. The heat strain index frequently rises above 80% in these locations, with high humidity and low wind flow exacerbating discomfort. Buildings and trees producing a low SVF over roads and sidewalks protect spectators from the morning radiant heat, but such locations should be balanced with wind flow to optimize comfort. The modeling and spatial information can aid in preparing for and mitigating heat stress during the Olympics. Potential solutions can be implemented in collaboration with local organizers and government. This ‘research through design’ strategy can aid in preparing for and mitigating heat illness during the Olympics. Knowledge gained can be extended to other areas of Tokyo to reduce urban heat, and further provide targeted guidance for effective environmental cooling techniques for human health.

The Tokyo 2020 Olympic Games will be held in July and August. As these are the hottest months in Tokyo, the risk of heat stress to athletes and spectators in outdoor sporting events is a serious concern. This study focuses on the marathon races, which are held outside for a prolonged time, and evaluates the potential heat stress of marathon runners using the COMFA (COMfort FormulA) Human Heat Balance (HBB) Model. The study applies a four-step procedure: (a) measure the thermal environment along the marathon course; (b) estimate heat stress on runners by applying COMFA; (c) identify locations where runners may be exposed to extreme heat stress; and (d) discuss measures to mitigate the heat stress on runners. On clear sunny days, the entire course is rated as ‘dangerous’ or ‘extremely dangerous’, and within the latter half of the course, there is a 10-km portion where values continuously exceed the extremely dangerous level. Findings illustrate which stretches have the highest need for mitigation measures, such as starting the race one hour earlier, allowing runners to run in the shade of buildings or making use of urban greenery including expanding the tree canopy.

Land resources are essential for humans to survive, and different methods of land- resource use depend largely on the local natural context and society. Here we propose a method to assess land-resource use in terms of efficiency and sustainability for three historical types of land-resource use in the Babeldaob Island, Republic of Palau: self-supply, resource development and nature conservation. Our proposed index of land-use efficiency makes comparisons possible among the types of land-resource use, considering both the natural and social conditions; land-use efficiency increased in the order of self-supply, nature conservation and resource development. At the same time, sustainability of land-resource use corresponded to population growth; when the population density was less or more than 15 capita km−2, self-supply and nature conservation were the most sustainable, respectively.

Due to the global climate change, sea level rise and storm surges are worried to accelerate salt damage to coastal agricultural fields. The Republic of Palau, a small island nation in the Pacific Ocean is suffering from increasing taro patch abandonment. The purpose of this paper is to clarify the characteristics of taro patches which are damaged by seawater based on the GIS analysis and clusterings, such as elevation, distance from the sea, slope, catchment area, and area of a taro patch. The target area was the Babeldaob Island, which is the largest island in Palau. The results showed that the taro patches were mostly distributed in less than 10 m in elevation, within 1 km in distance from seawater and on slopes below 3%. We divided taro patches into two clusters by k-means clustering; cluster 1 which the elevation was low with catchment area and area of taro patch were small; cluster 2 which the elevation was high with catchment area and area of taro patch were large. These results imply that the large catchment area might lead to suppression of salt damage.

Recent evidence suggests that decreased chondrocyte function in osteoarthritis and other articular disorders may be due to chondrocyte dedifferentiation produced by altered regulatory signals from the cartilage extracellular matrix (ECM). However, there are currently no mammalian chondrocytic cell line systems adapted to the study of this process. We therefore examined the effects of ECM growth conditions on markers of differentiated chondrocytic phenotype expression in the nontransformed rat RCJ 3.1C5.18 (RCJ) chondrocyte cell line, including type II collagen expression, aggrecan production, link protein gene expression, and parathyroid hormone (PTH) receptor number. RCJ cells grown in monolayer on plastic exhibited a dedifferentiated phenotype characterized by flattened cell morphology, with > 80% type I collagen and < 5% type II collagen production, as determined by two-dimensional gel mapping electrophoresis of collagen cyanogen bromide peptides. In addition, aggrecan production was low, and link protein mRNA was not expressed at detectable levels. After transfer to growth under minimal attachment conditions on the surface of a composite type I collagen/agarose (0.15%-0.8%) gel (CAG) for 7 days, RCJ cells developed a rounded, chondrocytic morphology and a pattern of differentiated, chondrocytic gene expression, with 79% type II and 8% type I collagen production. Steady-state type I and type II procollagen mRNA levels were altered in parallel with collagen protein expression. In cells grown on CAG, aggrecan production increased 6-fold, and there was a marked increase in both aggrecan core protein and link protein mRNA levels. In addition, maximal PTH-stimulated cAMP generation increased 15-fold in association with an increased PTH receptor number. Therefore, the RCJ chondrocyte cell line is highly sensitive to ECM regulation of chondrocyte-specific gene expression.

UMR-106–01 osteoblast-like cells respond to high concentrations of parathyroid hormone (PTH) in vitro by decreasing thymidine incorporation, a marker of DNA synthesis and cell proliferation. This response is different from in vivo conditions, such as primary and secondary hyperparathyroidism, in which high PTH levels are associated with an increased number of osteoblasts. When the response of UMR-106–01 cells to PTH is evaluated in vitro, however, these cells are exposed to only a single hormone. The present study was designed to evaluate the combined effects of two hormones, PTH and insulin, on the DNA synthesis of UMR-106–01 cells. PTH is known to decrease and insulin to increase thymidine incorporation by UMR-106–01 cells. To examine the interaction of these hormones, acute studies, defined as a 24 h exposure to hormone, and chronic studies, defined as a 7 day exposure to hormone, were performed. Both acute and chronic exposure to 10−9 M PTH decreased thymidine incorporation by UMR-106–01 cells, with suppression ranging from 27 to 81% (P < 0.05). Both acute and chronic exposure to 10−8 M insulin (INS) increased thymidine incorporation by UMR-106–01 cells; this ranged from 26 to 58% (P < 0.05). However, chronic exposure to 10−9 M PTH followed by an acute exposure to 10−8 M INS resulted in a 710% increase in thymidine incorporation (P < 0.01). Reversing the sequence by chronically exposing UMR-106–01 cells to 10−8 M INS followed by acute exposure to 10−9 M PTH resulted in a 53% decrease in thymidine incorporation (P < 0.01). When 10−9 M PTH and 10−8 M INS were administered simultaneously, the increase in thymidine incorporation produced by acute and chronic administration ranged from 35 to 56% of nontreated control values (P < 0.05). In conclusion, the timing of PTH and insulin administration may produce different responses in thymidine incorporation by UMR-106–01 cells. Whether during hyperparathyroidism in vivo, pulsatile increases in insulin secretion are important for osteoblast proliferation remains to be determined.

The correlation of insulin receptor occupancy with classic insulin effects, such as stimulation of glucose uptake, have not been examined in osteoblastlike cells. Accordingly, we characterized insulin binding and examined its relationship to stimulation of glucose analog transport in the UMR-106 rat osteoblastic osteosarcoma cell line. Insulin binding in UMR-106 cells was found to be pH sensitive, temperature dependent, saturable, and specific. Proinsulin was 100-fold less effective than insulin in displacing specific [125I]insulin binding in these cells, whereas IGF-I at concentrations between 0.1 and 10 nM produced no displacement of [125I]insulin but did produce significant displacement of insulin binding at 100 and 1000 nM. Insulin receptor downregulation was observed after exposure to 100 nM insulin for 6 h at 37°C and was temperature dependent. Insulin binding was reversible after 24 h at 4°C. Insulin binding correlated directly with stimulation of 2-deoxyglucose uptake at insulin concentrations between 0.1 and 100 nM, with a half-maximal concentration (ED50) of 0.9 nM for both [125I]insulin binding displacement and stimulation of 2-deoxyglucose uptake. Hence, there was no evidence for spare insulin receptors with regard to stimulation of glucose analog transport. Scatchard analysis of insulin binding kinetics yielded a curvilinear plot, suggesting negative cooperativity. Analysis of insulin binding kinetics using a two-site model yielded a KD of 0.9 nM for the apparent high-affinity binding site and an estimated 80,000 high-affinity binding sites per cell. These findings demonstrate that osteoblastlike cells exhibit a relationship between insulin binding and glucose transport stimulation that is similar to that in liver cells and other insulin-sensitive tissues. The UMR-106 cell line therefore appears to represent a useful system for studies of the regulation of insulin binding and action in an osteoblastic cell.

Seven novel cell lines from canine histiocytic sarcoma (HS), three of which were disseminated cutaneous HS and four of which were synovial HS, were established. All of the established cell lines had the same morphological (by light and electron microscopic findings), cytochemical (alpha-naphthyl butyrate esterase-positive), and immunohistochemical (vimentin- and lysozyme-positive, and cyto-keratin-negative) characteristics as the original HS tumor cells. All of the established cell lines injected into nude mice subcutaneously produced solid tumors. Because the established cell lines also showed phagocytic and processing activities, the HS tumor cells appear to originate from the mononuclear phagocytic system cells, despite their differences in locations or organs.

Parathyroid hormone (PTH) stimulates bone resorption as well as bone formation in vivo and in organ culture. The catabolic actions of PTH have been recognized in patients with hyperparathyroidism, or with acute infusion of the N-terminal 1–34 fragment of human PTH (hPTH1–34). Whereas the anabolic actions of daily injection with PTH have been well studied in both humans and mice, the catabolic actions of PTH on murine bone remain to be defined. To do this we sought to create a model with short-term, sustained hyperparathyroidism using osmotic infusion pumps. We treated 10-week-old female C57BL/J6 mice with continuous infusion of hPTH1–34 (8.1 pmol/0.25 μl per h, equivalent to 40 μg/kg per day) or vehicle for 2 weeks, using Alzet osmotic pumps. Bone mineral density (BMD), serum total calcium, hPTH1–34, mouse intact PTH (mPTH1–84), osteocalcin and mouse tartrate-resistant acid phosphatase (mTRAP) activity, and microarchitectural variables of the distal femur were measured. Separately, we compared the effects of intermittent daily injection of hPTH1–34 (40 μg/kg per day) with continuous infusion of hPTH1–34 on BMD and bone markers. Exogenous hPTH1–34 was detected only in the PTH-infused mice. Both intermittent and continuous treatment with hPTH1–34 markedly suppressed endogenous mPTH1–84, but only the latter induced hypercalcemia. Daily PTH injection significantly increased both serum osteocalcin and mTRAP, while continuous PTH infusion showed a strong trend to stimulate mTRAP, with a slight but non-significant increase in osteocalcin. There were significant differences in BMD at all sites between animals treated with the same daily dose of intermittent and continuous hPTH1–34. Microcomputed tomography (μCT) analysis of the distal femurs revealed that hPTH1–34 infusion significantly decreased trabecular connectivity density (P

The prevailing view for many years has been that osteoclasts do not express parathyroid hormone (PTH) receptors and that PTH's effects on osteoclasts are mediated indirectly via osteoblasts. However, several recent reports suggest that osteoclasts express PTH receptors. In this study, we tested the hypothesis that human osteoclasts formed in vitro express functional PTH type 1 receptors (PTH1R). Peripheral blood monocytes (PBMC) were cultured on bone slices or plastic culture dishes with human recombinant RANK ligand (RANKL) and recombinant human macrophage colony-stimulating factor (M-CSF) for 16-21 days. This resulted in a mixed population of mono- and multi-nucleated cells, all of which stained positively for the human calcitonin receptor. The cells actively resorbed bone, as assessed by release of C-terminal telopeptide of type I collagen and the formation of abundant resorption pits. We obtained evidence for the presence of PTH1R in these cells by four independent techniques. First, using immunocytochemistry, positive staining for PTH1R was observed in both mono- and multi-nucleated cells intimately associated with resorption cavities. Second, PTH1R protein expression was demonstrated by Western blot analysis. Third, the cells expressed PTH1R mRNA at 21 days and treatment with 10 � 7 M hPTH (1-34) reduced PTH1R mRNA expression by 35%. Finally, bone resorption was reproducibly increased by two to threefold when PTH (1-34) was added to the cultures. These findings provide strong support for a direct stimulatory action of PTH on human osteoclasts mediated by PTH1R. This suggests a dual regulatory mechanism, whereby PTH acts both directly on osteoclasts and also, indirectly, via osteoblasts. J. Cell. Biochem. 95: 139- 148, 2005. 2005 Wiley-Liss, Inc.

The mouse is being increasingly used to study the anabolic action of parathyroid hormone (PTH) on the skeleton. The efficacy of intermittent PTH treatment on bone varies widely among tested strains of mice with differences in peak bone mass and structure. We have therefore examined the responses of skeletal sites with high or low cancellous bone mass to PTH treatment in a single strain with genetically low bone mass. Mature C57BL/6 mice were ovariectomized (ovx) or sham operated and, after 4 weeks, treated with PTH(1-34) (40 microg/kg/day, 5 days/week sc) or vehicle for 3 or 7 weeks. Two doses of fluorescent labels were given to the animals 9 and 3 days before euthanasia. Histomorphometry was performed on sections of the proximal tibia, tibial diaphysis, and vertebral body. The results indicate that 4 to 11 weeks of ovx induced a approximately 44% loss of cancellous bone in the proximal tibia and a approximately 25% loss of cancellous bone in the vertebra with impaired trabecular architecture and high bone turnover. In the intact animals, PTH increased cancellous bone volume to a greater extent in the vertebral body than in the proximal tibia, a site with lower cancellous bone volume at the outset. In the ovx mice, PTH increased cancellous bone volume to a greater extent in the vertebral body, a site displaying moderate cancellous bone loss, than in the proximal tibia, a site with severe cancellous bone loss. Conversely, the treatment added a little cortical bone to the tibia, a highly loaded site, but did not significantly increase cortical width of the vertebral body, a less loaded site. We conclude that, for intermittent PTH treatment to be maximally effective, there must be an adequate number of trabeculae present at the beginning of treatment, regardless of estrogen status. Our results also support an interaction between PTH anabolic action and mechanical loading.

The cellular and molecular events triggering the anabolic response of the skeleton to exogenous parathyroid hormone (PTH) are not well understood. Despite the numerous bone mass studies in rats, few data are available for mice. Therefore, we treated 10-week-old female intact C57BL/6J mice with human PTH(1-34) delivered subcutaneously at a dose of 40 microg/kg per day 5 days a week for 3 weeks and 7 weeks. Bone mineral density (BMD) of total bone, femur, tibia, and lumbar vertebrae was measured weekly by PIXImus. Bone turnover was examined by histomorphometry, and gene expression of bone formation and resorption markers and osteoclastogenesis regulators in the excised femur and tibia was assessed by reverse-transcription polymerase chain reaction (RT-PCR) at 3 weeks and 7 weeks. The PTH-stimulated increase in BMD was more prominent in the tibia and femur than in the lumbar vertebrae, with an anabolic effect detected within 1-2 weeks and BMD continuing to increase. The appearance of a detectable PTH-stimulated increase in BMD was slower in the lumbar vertebrae where the increase was only significant after 7 weeks of treatment. Histomorphometric analysis of the proximal tibia at both 3 weeks and 7 weeks indicated significant time-dependent increases in trabecular area, trabecular number, trabecular and cortical widths, and osteoblast and osteoid perimeters. In the lumbar vertebrae, these stimulatory effects of PTH on trabecular area, trabecular number, and cortical width were smaller and not detected until 7 weeks. PTH-stimulated increases in bone turnover were evident by increased gene expression of osteocalcin (OC), tartrate-resistant acid phosphatase (TRAP), and receptor of activator nuclear factor kappaB (NF-kappaB) ligand (RANKL) in the tibia and femur. No significant difference in gene expression was observed between the two long bone sites. In conclusion, PTH exerts an anabolic action at the tissue and cellular levels in intact mice and the magnitude and temporal pattern of this anabolic action, as assessed by densitometry and histomorphometry, are skeletal site specific.

Taste disorders are a common complaint among cancer patients undergoing chemotherapy on an ambulatory basis. We conducted a survey on the incidence of such disorders among 74 patients, and 45.95% (34 of 74 patients) developed taste disorders. When stratified by medication into a regimen including 5-FU and one including taxanes, taste disorders were found in 59.0% (23 of 39 patients) of the former and 60.0% (9 of 15) of the latter. The survey also included the effects of taste disorders on patients appetites. Both regimens led to reduced appetite in a number of these patients (39.1% and 44.4%, respectively). Among patients on the 5-FU-containing regimen, the FOLFOX/FOLFIRI therapy was found to be responsible for loss of appetite. Regarding change in tastes, many patients stated that the medication dulled their taste sensation except for bitterness; their capacity to sense intensity of taste remained unchanged. It was found that acute taste disorders develop frequently among patients on a high dosage of 5-FU or a taxane-containing regimen.

Taste disorders are frequent occurrences among those patients under the FOLFOX-FOLFIRI regimen for colorectal cancer. We conducted a study on the development of taste disorders among colorectal cancer patients under this regimen and the effect of such disorders on their QOL. Taste disorders occurred in 58.1%(18/31 cases)of these patients and the disorders affected appetites in 50%(9 cases). The changes in taste sensations were subtle in most but some described certain tastes as exaggerated. Others reported changes in all taste sensations, including sweet, salty, bitter and sour, as well as deliciousness. When tested via the QOL Survey Sheet(Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs: QOL-ACD), the QOL was found to have deteriorated significantly in those who stated that taste disorders affected their appetite, in comparison with those who were unaffected. In patients with colorectal cancers and treated with the FOLFOX-FOLFIRI regimen, taste disorders are frequent occurrences. The poor nutritional state due to a loss of appetite may constitute a factor responsible for a lowering QOL.

Self complementary diribonucleoside monophosphates containing 2-aminoadenosine (n2A) and uridine (U) residues, (2′-5′) n2ApU (1), (3′-5′) n2ApU (2), (2′-5′) Upn2A (3) and (3′-5′) Upn2A (4), were synthesized by condensation of suitably protected nucleoside and nucleotide units using dicyclohexylcarbodiimide (DCC). The dimers, (3) and (41, were also obtained from uridine 2′,3′-cyclic phosphate and unprotected 2-aminoadenosine using 2,4,6-triisopropylbenzenesulfonyl chloride (TPS-Cl) as the condensing agent. The conformational properties of these dimers were examined by UV, CD and NMR spectroscopy. The results reveal that the 2′-5′ isomers take a stacked conformation, which contains a larger base-base overlap and is more stable against thermal perturbation with respect to the 3′-5′ isomers. The n2ApU isomers have more stacked structure than the Upn2A isomers.

Insulin modifies the effects of PTH on osteoblast-like cells. However, the basis for this effect is unknown. In bone and kidney cells, the effects of PTH on cellular function are mediated by second messengers generated through both the phospholipase C and adenylate cyclase systems. Therefore, we examined the effects of insulin on PTH second messenger generation in UMR-106-01 rat osteoblastic osteosarcoma cells. PTH produced a rapid, transient increase in intracellular free calcium concentration ([Ca2+]i) which was maximal at 30 sec and was only minimally reduced in the absence of extracellular calcium. Inositol-triphosphate (IP3) production was increased in parallel. PTH stimulation of [Ca2+]i was concentration-dependent from 0.5-1,000 nM, with half-maximal stimulation at approximately 50 nM PTH. A 30-sec exposure to 50 nM PTH produced 32% and 23% increases in IP1 and IP3 production, respectively (both P less than 0.05). Although insulin alone did not significantly alter basal [Ca2+]i, a 1-min exposure to 1-100 nM insulin produced a concentration-dependent suppression of the PTH-stimulated transient increase in [Ca2+]i and IP3 generation. 100 nM insulin decreased 50 nM PTH stimulation of [Ca2+]i and IP3 levels by 84% (P less than 0.02) and 80% (P less than 0.001), respectively. Preexposure to insulin also decreased PTH stimulation of intracellular cAMP levels, but to a lesser degree. A 1-min exposure to 100 nM insulin produced a 32% (P less than 0.01) decrease in PTH-stimulated cAMP generation, but lower insulin concentrations were without significant effects. These results demonstrate that in UMR-106-01 cells, insulin suppresses PTH stimulation of second messengers generated through both the phospholipase C and adenylate cyclase systems, but has a more marked effect on the former.

We have used glutathione for prevention of oxaliplatin-related neurotoxicity with reference to the article of Cascinu et al. We investigated oxaliplatin-related neurotoxicity in Kariya Toyota General Hospital(KTGH)and compared with the data described in the article of Gamelin about the severity of its neurotoxicity. Grade 3 neurotoxicity was observed in only 5 of 44 patients(11.4%). The median number of cycles and cumulative dose of oxaliplatin were 12 cycles(5-27 / cycles)and 802.2(273.2-1,952.4)mg/m(2), respectively, at Grade 3 neuropathy. We evaluated retrospectively neuro-toxicity grade at cumulative oxaliplatin doses of approximately 500-520 mg/m(2). The severity of neurotoxicity observed in KTGH was significantly lower than in the group without Ca/Mg. We found no difference between the group with glutathione and / with Ca/Mg. Glutathione infusions seemed to prevent oxaliplatin-related neurotoxicity.

We describe a method of culturing intact porcine thyroid follicles for physiological de novo thyroid hormone formation; the roles of cAMP and protein kinase-C in thyroid hormone formation were also studied. Thyroid follicles were obtained by digesting minced porcine thyroid tissue with 0.04% collagenase and cultured in Coon's Modified Ham's F-12 medium supplemented with 0.5% calf serum, 0.5 mU/ml TSH, other standard hormones, and 3 antibiotics (6H medium). On the fourth day of culture, 6000-8000 follicles/well were plated in 12-well culture dishes. On the sixth day, thyroid hormone formation was carried out by incubating thyroid follicles with 0.5 microM KI in the presence of 6H medium for 2 days in a 5% CO2-95% air incubator at 37 C. To examine the effects of cAMP and protein kinase-C on de novo thyroid hormone formation, follicles were incubated with KI in the presence of 1-2.5 mM (Bu)2cAMP, 10 microM forskolin, 2 microM prostaglandin E2 (PGE2), or 0.5-1 microM 12-O-tetradecanoylphorbol-13-acetate in TSH-free medium for 2 days. The amount of newly formed thyroid hormone was measured by RIA of T3 content in the Pronase digest of thyroid follicular cells. Thyroid follicles cultured in 6H medium had normal polarity of the membrane, determined by electron microscope, and thyroid cAMP was responsive to the alteration of TSH. In this culture system cAMP alone was sufficient to form thyroid hormone. 12-O-Tetradecanoylphorbol-13-acetate, a protein kinase-C stimulator, disrupted thyroid follicles and inhibited cAMP-mediated thyroid hormone formation. The integrity of follicular structure was also required for thyroid hormone formation in this culture system. This study introduces perhaps the most physiological culture system for de novo thyroid hormone formation. Our data provide direct evidence that thyroid hormone formation is linked to cAMP and that the protein kinase-C system acts as an inhibitor of thyroid hormone formation.

A cyclic PTH regimen is as effective as a daily regimen on bone density gain in humans and in improving bone quality in mice. Our previous murine study evaluated the effects of a cyclic PTH regimen in the absence of a bisphosphonate, whereas our human study addressed the effects of a cyclic PTH regimen in the presence of ongoing alendronate (ALN) treatment. Accordingly, the current study examined the effects of cyclic or daily PTH regimens in combination with ALN on bone quality and bone density in mice. Twenty-week-old, female C57BL/6J mice were treated with the following sc injections (n = 10): 1) vehicle for 5 d/wk (control); 2) ALN (20 μg/kg·d) 3 d/wk (ALN); 3) human PTH(1–34) (40 μg/kg·d) 5 d/wk (daily PTH); 4) daily PTH in addition to ALN (daily PTH plus ALN); 5) PTH 5 d/wk and vehicle 5 d/wk alternating weekly (cyclic PTH); 6) cyclic PTH in addition to ALN (cyclic PTH plus ALN); and 7) PTH and ALN alternating weekly (alt PTH and ALN). Bone mineral density was measured weekly by dual-energy x-ray absorptiometry, and at 7 wk, bone markers, bone structure, and bone strength were evaluated by biochemical assays, peripheral quantitative computed tomography and mechanical testing, respectively. At 7 wk, all treatments significantly increased femoral and vertebral bone mineral density. ALN slightly decreased endosteal circumference, whereas PTH increased periosteal circumference, resulting in significant increases in femoral cortical thickness in all groups. PTH and ALN enhanced bone strength synergistically in the lumbar vertebrae and additively in the femur. Combined therapy, however, had no effects on bone markers. The results show that combinations of ALN and PTH, in both daily and cyclic regimens, produce more beneficial effects than treatment with either agent alone, suggesting that the mechanisms of actions of ALN and PTH on bone quality may be complementary.

Previously, we demonstrated that the human parathyroid hormone (1-34) fragment (hPTH(1-34)) increased bone strength in proportion to its effects on BMD and cortical bone structure in the murine femur by comparing cyclic vs. daily administration of hPTH(1-34). Both cyclic and daily regimens increased vertebral BMD similarly at 7 weeks. Here, we have examined the effects of daily and cyclic PTH regimens on bone structure and cellular activity by static and dynamic histomorphometry. Twenty-week-old, intact female C57BL/J6 mice were treated with the following regimens (n=7 for each group): daily injection with vehicle for 7 weeks [control]; daily injection with hPTH(1-34) (40 microg/kg/day) for 7 weeks [daily PTH]; and daily injection with hPTH(1-34) (40 microg/kg/day) and vehicle alternating weekly for 7 weeks [cyclic PTH]. At days 9 and 10, and 2 and 3 prior to euthanasia, calcein (10 mg/kg) was injected subcutaneously. At the end of study, the lumbar vertebrae 1-3 and the left femora were excised, cleaned, and processed for histomorphometry. In the lumbar vertebrae, daily and cyclic PTH regimens significantly increased cancellous bone volume (BV/TV), trabecular number, trabecular osteoclast and osteoblast perimeters, trabecular mineral apposition rate (MAR) and bone formation rate (BFR), and periosteal MAR and BFR compared to control, with no significant difference between the two PTH-treated groups. Increased trabecular tunneling was observed in both PTH-treated groups. Both regimens tended to increase vertebral cortical bone formation parameters with the effects at the periosteum site being more marked than those at the endosteum site, resulting in a significant increase in cortical width. In the femur, the effects of cyclic PTH on BV/TV, trabecular width and number, trabecular and endocortical osteoblast and osteoclast perimeters, cortical width, and trabecular and periosteal BFR were less marked than those of daily PTH. A cyclic PTH regimen was as effective as a daily regimen in improving cancellous and cortical bone microarchitecture and cellular activity in the murine vertebra.

We developed a cyclic PTH regimen with repeated cycles of 1-week on and off daily PTH injection and explored its effects on bone strength, BMD, bone markers, and bone structure in mice. Cyclic protocols produced 60–85% of the effects achieved by daily protocols with 57% of the total PTH given, indicating more economic use of PTH. The study supports further exploration of cyclic PTH regimens for the treatment of osteoporosis. Introduction: To minimize the cost and the catabolic action of hPTH(1-34), a cyclic PTH regimen with repeated 3-month cycles of on-and-off daily injection of hPTH(1-34) was developed in humans and shown to be as effective as a daily regimen in increasing vertebral BMD. However, changes in BMD may not adequately predict changes in bone strength. A murine model was developed to explore the efficacy of a cyclic PTH regimen on bone strength in association with other bone variables. Materials and Methods: Twenty-week-old, intact, female C57BL/J6 mice (n = 7/group) were treated with (1) daily injection with vehicle for 7 weeks (control); (2) daily injection with hPTH(1-34) (40 μg/kg/day) for 7 weeks (daily PTH); and (3) daily injection with hPTH(1-34) and vehicle alternating weekly for 7 weeks (cyclic PTH). BMD was measured weekly by DXA, and serum bone markers, bone structure, and strength were measured at 7 weeks. Results: Daily and cyclic PTH regimens increased BMD at all sites by 16–17% and 9–12%, respectively (all p < 0.01). The most dramatic effect of cyclic PTH occurred during the second week of treatment when PTH was off, with femoral and tibial BMD continuing to increase to the same extent as that produced by daily PTH. Both daily and cyclic PTH regimens significantly increased osteocalcin (daily, 330%; cyclic, 260%), mTRACP (daily, 145%; cyclic, 70%), femoral cortical width (daily, 23%; cyclic, 13%), periosteal circumference (daily, 5%; cyclic, 3.5%), and bone strength (max load: daily, 48%; cyclic, 28%; energy absorbed: daily, 103%; cyclic, 61%), respectively. Femoral bone strength was positively correlated with BMD, bone markers, and cortical structure. Neither regimen had an effect on vertebral bone strength. Although actual effects of cyclic PTH were 60–85% of those produced by daily PTH, the effects of cyclic PTH per unit amount administered were slightly greater than those of daily PTH for most measures. Conclusions: PTH-enhanced femoral bone strength is positively correlated with its effects on femoral BMD, bone markers, and bone structure. Cyclic PTH regimens represent a potential economic use of PTH and warrant further study.

Dual X-ray absorptiometry (DXA) has currently become a clinical standard for the assessment of bone mass and bone mineral density (BMD) at multiple sites for the diagnosis and follow-up assessment of osteoporosis in humans. The precision of DXA measurement in human studies has been well documented during the last two decades. However, there have been no systematic reports on the precision and accuracy of BMD measurements in mice using DXA, although mice have proven to be useful models for the study of osteoporosis. Accordingly, BMD of total body as well as regions of interest (ROIs) was measured twice in mice in vivo after a short (10-min) and long (16-hr) interval between scans by DXA, and scanning variations were calculated. Inter- and intra-analyzer variations from the same scans were also determined. The percent coefficients (%CVs) of short-interval scanning variation and inter- and intra-analyzer variations for total body and regional BMDs were less than 2% at sites, demonstrating high precision of in vivo BMD measurements in mice. Moreover, the BMD values comparing in vivo and ex vivo samples from the same animals were of %CV less than 10% at all sites. The correlation of bone mineral content (BMC) to bone ash was further examined, and the correlation between ROI BMC and bone ash was relatively high at all sites both in vivo and ex vivo, with the latter higher. We conclude that in vivo DXA BMD measurements in mice are very reliable with high precision and acceptable accuracy, and therefore useful for longitudinal studies of the mouse skeleton.

The UMR 106-06 rat osteosarcoma osteoblast-like cell line possesses calcitonin (CT) receptors in addition to expressing PTH receptors and a highly osteoblast-like phenotype, and may represent an intermediate developmental stage between early osteoblast precursors and mature osteoblasts. Therefore, we examined the effects of CT and PTH on second messenger generation and osteoblastic function in these cells. In UMR-106-06 cells, 10-1000 nM CT produced a dose-dependent stimulation of intracellular free calcium concentration ([Ca2+]i), which reached a plateau between 2-3 min. This stimulatory effect was abolished in the absence of extracellular Ca2+ ([Ca2+]o) and was mimicked by forskolin and (Bu)2cAMP. One hundred nanomolar CT also produced a slight but significant increase in inositol triphosphate production (13%, P less than 0.05) but did not produce a rapid, transient increase in [Ca2+]i. In contrast, PTH produced a rapid, transient increase in [Ca2+]i, which reached a maximum within 30 sec. This stimulatory effect of PTH on [Ca2+]i signal was dose-dependent and accompanied by a parallel stimulation of inositol triphosphate production. PTH, forskolin, and (Bu)2cAMP all produced a marked dose-related suppression of both DNA and collagen synthesis, which paralleled their stimulatory effects on intracellular cAMP levels. In marked contrast, CT only minimally reduced DNA and collagen synthesis despite producing comparable increases in intracellular cAMP. One hundred nanomolar CT also stimulated alkaline phosphatase specific activity by 33% (P less than 0.05). Thus, CT stimulates cAMP, [Ca2+]i, and inositol phosphate second messengers in UMR 106-06 cells. However, in contrast to other agents which elevate intracellular cAMP levels, CT does not suppress DNA synthesis. These results suggest that the linkage of CT receptor second messengers to effects on cell function differ from those of PTH and/or that CT may produce additional second messenger(s) which antagonize the antiproliferative effect of increased cAMP levels in UMR-106-06 cells.