Development of Bone Targeting Drugs.

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca(2+). The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments

Effects of climate change on coastal fresh groundwater resources

This study evaluates the impacts of climate change on fresh groundwater resources specifically salinity intrusion in water resources stressed coastal aquifers. Our assessment used the Hadley Centre climate model, HadCM3 with high and low emission scenarios (SRES A2 and B2) for years 2000-2099. In both scenarios, the annual fresh groundwater resources losses indicate an increasing long-term trend in all stressed areas, except in the northern Africa/Sahara region. We also found that precipitation and temperature individually did not show good correlations with fresh groundwater loss. However, the relationship between the aridity index and fresh groundwater loss exhibited a strong negative correlation. We also discuss the impacts of loss of fresh groundwater resources on socio-economic activities, mainly population growth and per capita fresh groundwater resources

Effects of climate and land use changes on groundwater resources in coastal aquifers

To estimate the freshwater loss in coastal aquifers due to salinisation, a numerical model based on the sharp interface assumption has been introduced. The developed methodology will be useful in areas where limited hydrological data are available. This model will elaborate on the changes in fresh groundwater loss with respect to climate change, land use pattern and hydrologic soil condition. The aridity index has been introduced to represent the variations in precipitation and temperature. The interesting finding is that the deforestation leads to increase groundwater recharge in arid areas, because deforestation leads to reduce evapotranspiration even though it favors runoff. The combined climate and land use scenarios show that when the aridity index is less than 60, the agricultural lands give higher groundwater recharge than other land use patterns for all hydrologic soil conditions. The calculated recharge was then used to estimate the freshwater–saltwater interface and percentage of freshwater loss due to salinity intrusion. We found that in arid areas, the fresh groundwater loss increases as the percentage of forest cover increases. The combined effects of deforestation and aridity index on fresh groundwater loss show that deforestation causes an increase in the recharge and existing fresh groundwater resource in areas having low precipitation and high temperature (arid climates)

Synthesis of Amphiphilic Three-Armed Star Random Copolymers via Living Radical Polymerization and their Unimolecular Folding Properties in Water

Amphiphilic three-armed star random copolymers were synthesized by ruthenium-catalyzed living radical copolymerization of hydrophilic poly(ethylene glycol) methyl ether methacrylate (PEGMA) and hydrophobic dodecyl methacrylate (DMA). Their amphiphilic star random copolymers with 10-50 mol% DMA efficiently self-folded in water with intramolecular hydrophobic interaction to form compact unimolecular micelles. Owing to PEG segments, star copolymers were thermoresponsive to induce lower critical solution temperature-type phase separation in water

Strategies for Regenerating Striatal Neurons in the Adult Brain by Using Endogenous Neural Stem Cells

Currently, there is no effective treatment for the marked neuronal loss caused by neurodegenerative diseases, such as Huntington's disease (HD) or ischemic stroke. However, recent studies have shown that new neurons are continuously generated by endogenous neural stem cells in the subventricular zone (SVZ) of the adult mammalian brain, including the human brain. Because some of these new neurons migrate to the injured striatum and differentiate into mature neurons, such new neurons may be able to replace degenerated neurons and improve or repair neurological deficits. To establish a neuroregenerative therapy using this endogenous system, endogenous regulatory mechanisms that can be co-opted for efficient regenerative interventions must be understood, along with any potential drawbacks. Here, we review current knowledge on the generation of new neurons in the adult brain and discuss their potential for use in replacing striatal neurons lost to neurodegenerative diseases, including HD, and to ischemic stroke

Vietnam's Rural-to-Urban Migrant Families: Educational and Social Inequalities in a Transitional Society

This dissertation explores the challenges, especially those relating to education and to social marginalization, that are being faced every day by underprivileged migrant families residing in Hanoi, the capital of Vietnam. It also reveals the coping mechanisms they must devise in order to stay afloat financially in a nation that is rapidly urbanizing and thereby changing at a dizzying speed. Drawing primarily upon my interviews with and observations of migrant families and associated community members, and secondarily upon scholarly and governmental research, this study shows how these families' survival strategies reveal those patterns of resource mobilization that are intimately linked to their social relations to, and ties with, others in the destination area. In the wake of the economy's marketization that began in the mid-1980s, Vietnam has undergone massive social changes, including a vast upsurge in free migration, an increased bargaining power of cash, and rising levels of social segregation. On the one hand, the advent of the market-oriented economy and nominal relaxation of the state controls over population mobility have opened up new paths down which migrants can pursue economic opportunities in their urban destinations, and have given people on the move some room for negotiation with the state. On the other hand, their status as non-permanent residents of Hanoi has continued to hinder them from gaining access to public services and government-sponsored care, equal to that enjoyed by their permanent-resident counterparts. Perhaps the chief consequence of the latter adverse trend is that migrant children not meeting the financial and/or regulatory conditions that all students are expected to meet if they wish to enter mainstream, formal education are inclined to seek learning opportunities in the other sphere of alternative, informal education. Thus migrant families have essentially been trapped, socioeconomically, in the informal sector; they have little prospect of upward social mobility, and they are compelled to adopt a stance of self-reliance with respect to resource mobilization. Then too, the everyday and governmental discourses that too often portray migrants as being disorderly at best and criminal at worst, and thus as constituting a deleterious social presence, have served not only to vindicate the state's ongoing adherence to the preexisting household-registration system but to disguise its ineffectiveness at managing rural-urban migration and its failure to redress Vietnam's ever-widening social inequalities and increasingly inequitable resource distribution. The permeation of such discourse among the city residents, and its internalization by the migrants themselves, have only served to exacerbate the stigmatization and peripheralizing of migrants. Serving to at least somewhat counteract the latter negative trend is the migrants' resourcefulness in settling into the city and forming social safety-nets, mutual-aid arrangements often based on sharing the same village of origin. Unfortunately, the social solidarity of village-based relations often goes hand in hand with exclusivity and thus with discrimination against all those who fall outside the inner circles, thereby further distancing the migrants from the mainstream of city life. Ultimately the study points to the need for some structural transformations in the Vietnamese government, changes reflective of the fact that migrants are not mere "social evils" but to the contrary, part and parcel of the state's growth. Only when such steps have been taken will the discourse about migrants shift from vilification to praise or even concern, and will Vietnamese society no longer be "transitional" because it has become inclusive and cohesive

Polymeric pseudo-crown ether for cation recognition via cation template-assisted cyclopolymerization.

Cyclopolymerization is a chain polymerization of bifunctional monomers via alternating processes of intramolecular cyclization and intermolecular addition, to give soluble linear polymers consisting of in-chain cyclic structures. Though cyclopolymers comprising in-chain multiple large rings potentially show unique functionality, they generally require the elaborate design of bifunctional monomers. Here we report cation template-assisted cyclopolymerization of poly(ethylene glycol) dimethacrylates as an efficient strategy directly yielding polymeric pseudo-crown ethers with large in-chain cavities (up to 30-membered rings) for selective molecular recognition. The key is to select a size-fit metal cation for the spacer unit of the divinyl monomers to form a pseudo-cyclic conformation, where the two vinyl groups are suitably positioned for intramolecular cyclization. The marriage of supramolecular chemistry and polymer chemistry affords efficient, one-pot chemical transformation from common chemical reagents with simple templates to functional cyclopolymers

Disposition Kinetics of Taxanes in Peritoneal Dissemination

Treatment of cancers in the abdominal cavity, such as peritoneal dissemination, is difficult, but in principle intraperitoneal administration of anticancer drugs is expected to be preferable to systemic administration. Taxane anticancer drugs are used to treat gastric cancer patients with peritoneal dissemination. They are administered as micellar preparations, Taxol and Taxotere, which consist of paclitaxel in Cremophor EL (crEL) and docetaxel in Polysorbate-80 (PS-80), respectively. In this paper we review the disposition kinetics of taxane anticancer drugs after intraperitoneal administration in peritoneal dissemination patients and animal models and also discuss the effect of the surfactant vehicle on the behavior of taxanes

Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects

AbstractPurposeThe objective of these studies was to evaluate the pharmacokinetic profile, safety, and tolerability of mirabegron, a β3-adrenoceptor agonist for the treatment of overactive bladder, including food effects (low- or high-fat meals) and sex, in healthy East Asian subjects.MethodsIn total, 5 pharmacokinetic studies of mirabegron were conducted in healthy East Asian subjects. Food effects were assessed in 3 randomized, single-dose studies in young Japanese male subjects (study 1), male and female subjects (study 2), and young Taiwanese male and female subjects (study 3). In the other 2 single- and multiple-dose studies in young Chinese male and female subjects (study 4 and study 5), mirabegron was administered as a single dose under fasted conditions. After the washout period, mirabegron was administered once daily under fed conditions for 8 days. Pharmacokinetic parameters were determined using noncompartmental methods. Safety and tolerability assessments included physical examinations, vital signs, 12-lead ECG, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event monitoring.FindingsAfter administration of single oral doses of mirabegron, exposure under fed conditions was lower than under fasted conditions in Japanese and Taiwanese subjects. In Japanese subjects, a greater reduction in mirabegron Cmax and AUC0–∞ was observed after a low-fat meal compared with a high-fat meal. In Chinese subjects, Cmax was reached at approximately 4.0 hours after single oral doses. Mirabegron accumulated 2- to 3-fold on once-daily dosing of multiple-dose relative to single-dose data. Steady state was reached within 7 days. After administration of mirabegron, mean values for Cmax and AUC in female subjects were higher than those in male subjects. Mirabegron was well tolerated in Japanese, Taiwanese, and Chinese subjects.ImplicationsOur studies confirm the higher exposure levels of mirabegron in female compared with male East Asian subjects as found earlier in Western subjects. Furthermore, the effects of food on the pharmacokinetic profiles appeared to be similar among the 3 populations tested in our studies. The findings suggest that there are no significant pharmacokinetic differences among the Japanese, Taiwanese, and Chinese populations