Updates on mesenchymal stem cell therapies for articular cartilage regeneration in large animal models.

There is an unmet need for novel and efficacious therapeutics for regenerating injured articular cartilage in progressive osteoarthritis (OA) and/or trauma. Mesenchymal stem cells (MSCs) are particularly promising for their chondrogenic differentiation, local healing environment modulation, and tissue- and organism-specific activity; however, despite early in vivo success, MSCs require further investigation in highly-translatable models prior to disseminated clinical usage. Large animal models, such as canine, porcine, ruminant, and equine models, are particularly valuable for studying allogenic and xenogenic human MSCs in a human-like osteochondral microenvironment, and thus play a critical role in identifying promising approaches for subsequent clinical investigation. In this mini-review, we focus on [1] considerations for MSC-harnessing studies in each large animal model, [2] source tissues and organisms of MSCs for large animal studies, and [3] tissue engineering strategies for optimizing MSC-based cartilage regeneration in large animal models, with a focus on research published within the last 5 years. We also highlight the dearth of standard assessments and protocols regarding several crucial aspects of MSC-harnessing cartilage regeneration in large animal models, and call for further research to maximize the translatability of future MSC findings.

Effects of the 2018 heat wave on health in the elderly: implications for adaptation strategies to climate change.

There has been growing concern over the effects of heat waves on health. However, the effects of heat waves on the health of individuals in vulnerable groups have rarely been examined. We aimed to investigate the acute health effects of heat waves in elderly individuals living in rural areas and to survey their adaptation capacity. Repeated measurements of body temperature (BT), blood pressure, sleep disturbance, and indoor temperature were conducted up to six times for each of 104 elderly individuals living in rural areas of South Korea during the 2018 heat wave. Changes in BT, systolic blood pressure (SBP), and diastolic blood pressure (DBP) according to variations in indoor and outdoor temperature were analyzed using linear mixed effect models controlling for age, sex, smoking, and drug use. We also surveyed heat wave adaptation capacity, heat wave shelters, and self-reported health problems. The average indoor temperature measured during the study period was 30.5°C (range: 22.9-38.3°C) and that of ambient temperature was 30.6°C (range: 24.6-36.3°C). BT significantly increased with indoor and outdoor temperatures. The effect on BT was greater in elderly women and the elderly with hypertension. DBP generally decreased with increasing indoor temperature, though the correlation was only statistically significant among the elderly with hypertension. Only 22 (21.2%) individuals used air conditioners during the heat wave. Most did not use an air conditioner mainly to avoid high electricity costs. Of the participants, 58.7% reported experiencing sleep disturbance, which was the most frequent self-reported health problem. Elderly individuals living in rural areas are directly exposed to high temperatures during heat waves, and their vital signs are sensitive to increases in indoor temperature due to poor adaptation capacity. Well-designed strategies for alleviating health-related stress during heat waves are necessary.

Cutaneous Melanoma in Asians.

Malignant melanoma is a rare disease in Asians but potentially the most aggressive form of skin cancer worldwide. It can occur in any melanocyte-containing anatomic site. Four main cutaneous melanoma subtypes are recognized: lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma (ALM), and nodular melanoma. Generally, excessive exposure to ultraviolet (UV) radiation increases the risk of melanoma. The exception is ALM, which is the most common melanoma subtype in Asians and is not associated with UV radiation. ALM presents as dark brownish to black, irregular maculopatches, nodules, or ulcers on the palms, soles, and nails. The lesions may be misdiagnosed as more benign lesions, such as warts, ulcers, hematomas, foreign bodies, or fungal infections, especially in amelanotic acral melanomas where black pigments are absent. The aim of this brief review is to improve understanding and the rate of early detection thereby reducing mortality, especially regarding cutaneous melanoma in Asians.

Bisphenol A exerts estrogenic effects by modulating CDK1/2 and p38 MAP kinase activity.

Bisphenol A (BPA) is considered to be an endocrine disruptor, but the mechanisms by which it disrupts endocrine functions are poorly understood. Here, we have shown that BPA binds both estrogen receptor (ER)-α and ER-beta (ER-ß) using a fluorescence polarization competitive binding assay. In addition, we found that BPA induced cell proliferation by modulating cell cycle-related genes in the MCF-7 human mammary cancer cell line. Moreover, using a BG1 luciferase ER transactivation assay, we found that BPA has estrogenic activity. Modulating the MAPK pathway by using an ERK inhibitor (PD98059) or a JNK inhibitor (SP600125) had no effect on the ability of BPA to induce estrogenic activity. However, the antiestrogen, ICI 182,780, and the p38 inhibitor, PD 169316 successfully blocked BPA-induced estrogenic activity. Our findings suggest that BPA mimics ER-dependent estrogenic activity by targeting proteins that regulate the cell cycle and p38 MAPK.

Dexamethasone increases fluid absorption via Na+/H+ exchanger (NHE) 3 activation in normal human middle ear epithelial cells.

The proper homeostasis of the liquid lining the surface of the middle ear cavity is vitally important for maintaining a fluid-free middle ear cavity. Disruption of this homeostasis leads to fluid collection in the middle ear cavity and results in otitis media with effusion. We demonstrated the molecular and functional expression of the Na+/H+ exchanger (NHE)s in normal human middle ear epithelial (NHMEE) cells. We also evaluated the role of NHEs in fluid absorption and the effect of dexamethasone on NHE function and NHE-dependent fluid absorption in NHMEE cells. Western blot analysis was performed for NHE1, -2, and -3 in NHMEE cells. The fluid absorption rate was measured after liquid application on the luminal surface of the cells. Intracellular pH (pHi) was measured using the pH-sensitive fluorescent probe bis-(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)-AM. NHE activity was determined as Na+-induced pHi recovery from an acid load achieved by luminal exposure to 40 mmol/l NH4Cl. NHE1, -2 and -3 were all expressed in the NHMEE cells. The pHi recovery rate was suppressed by inhibition of NHE2 and -3 with HOE694 at concentrations greater than 50 microM. Inhibition of NHE3 with 650 microM of HOE694 or S3226 significantly decreased the fluid absorption rate. Dexamethasone increased the Na+-induced pHi recovery rate which was reversed by the inhibition of NHE3 with 650 microM of HOE694. Dexamethasone treatment up-regulated NHE3 expression in a dose-dependent manner. The fluid absorption rate was increased by treatment with dexamethasone (10(-7) M) and reversed by the inhibition of NHE3. In summary, we have shown that NHE3 are involved in the regulation of both pHi and fluid absorption on the luminal surface of NHMEE cells. Dexamethasone stimulates NHE3 expression and NHE3-dependent fluid absorption in NHMEE cells. These findings provide a new insight into mechanisms that regulate periciliary fluid and the therapeutic mechanisms behind steroid treatment of otitis media with effusion.

Dichloro[(6R,7S,8S,14S)-(-)-sparteine-kappa2N,N']mercury(II).

In the title compound, [HgCl2(C15H26N2)], the chiral alkaloid (6R,7S,8S,14S)-(-)-L-sparteine acts as a bidentate ligand, with two Cl- ligands occupying the remaining coordination sites, producing a distorted tetrahedron. The N-Hg-N plane is twisted by 81.1 (2) degrees from the Cl-Hg-Cl plane. The mid-point of the N...N line does not lie exactly on the Cl-Hg-Cl plane but is tilted towards one of the N atoms by 0.346 angstroms. Similarly, the mid-point of the Cl...Cl line is tilted toward one of the Cl atoms by 0.163 angstroms. The packing structure shows that the complex is stabilized by two interatomic Cl...H contacts involving both Cl atoms and the methylene or methine H atoms of the (-)-sparteine ligand.