Human iPSC-Derived Neurons as A Platform for Deciphering the Mechanisms behind Brain Aging.

With an increased life expectancy among humans, aging has recently emerged as a major focus in biomedical research. The lack of in vitro aging models-especially for neurological disorders, where access to human brain tissues is limited-has hampered the progress in studies on human brain aging and various age-associated neurodegenerative diseases at the cellular and molecular level. In this review, we provide an overview of age-related changes in the transcriptome, in signaling pathways, and in relation to epigenetic factors that occur in senescent neurons. Moreover, we explore the current cell models used to study neuronal aging in vitro, including immortalized cell lines, primary neuronal culture, neurons directly converted from fibroblasts (Fib-iNs), and iPSC-derived neurons (iPSC-iNs); we also discuss the advantages and limitations of these models. In addition, the key phenotypes associated with cellular senescence that have been observed by these models are compared. Finally, we focus on the potential of combining human iPSC-iNs with genome editing technology in order to further our understanding of brain aging and neurodegenerative diseases, and discuss the future directions and challenges in the field.

Disruption of Cytosolic Folate Integrity Aggravates Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Modulates Metastatic Properties in Non-Small-Cell Lung Cancer Cells.

Patients with advanced-stage non-small-cell lung cancer (NSCLC) are susceptible to malnutrition and develop folate deficiency (FD). We previously found that folate deprivation induces drug resistance in hepatocellular carcinoma; here, we assessed whether disrupted cytoplasmic folate metabolism could mimic FD-induced metastasis and affect the sensitivity of NSCLC cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We examined whether cytosolic folate metabolism in NSCLC cells was disrupted by FD or the folate metabolism blocker pemetrexed for 1-4 weeks. Our results revealed an increase in NF-κB overexpression-mediated epithelial-mesenchymal transition biomarkers: N-cadherin, vimentin, matrix metalloproteinases (MMPs), SOX9, and SLUG. This finding suggests that the disruption of folate metabolism can drastically enhance the metastatic properties of NSCLC cells. Cytosolic FD also affected EGFR-TKI cytotoxicity toward NSCLC cells. Because SLUG and N-cadherin are resistance effectors against gefitinib, the effects of SLUG knockdown in folate antagonist-treated CL1-0 cells were evaluated. SLUG knockdown prevented SLUG/NF-κB/SOX9-mediated invasiveness and erlotinib resistance acquisition and significantly reduced pemetrexed-induced gelatinase activity and MMP gene expression. To summarize, our data reveal two unprecedented adverse effects of folate metabolism disruption in NSCLC cells. Thus, the folic acid status of patients with NSCLC under treatment can considerably influence their prognosis.

N-butylidenephthalide attenuates Alzheimer's disease-like cytopathy in Down syndrome induced pluripotent stem cell-derived neurons.

Down syndrome (DS) patients with early-onset dementia share similar neurodegenerative features with Alzheimer's disease (AD). To recapitulate the AD cell model, DS induced pluripotent stem cells (DS-iPSCs), reprogrammed from mesenchymal stem cells in amniotic fluid, were directed toward a neuronal lineage. Neuroepithelial precursor cells with high purity and forebrain characteristics were robustly generated on day 10 (D10) of differentiation. Accumulated amyloid deposits, Tau protein hyperphosphorylation and Tau intracellular redistribution emerged rapidly in DS neurons within 45 days but not in normal embryonic stem cell-derived neurons. N-butylidenephthalide (Bdph), a major phthalide ingredient of Angelica sinensis, was emulsified by pluronic F127 to reduce its cellular toxicity and promote canonical Wnt signaling. Interestingly, we found that F127-Bdph showed significant therapeutic effects in reducing secreted Aß40 deposits, the total Tau level and the hyperphosphorylated status of Tau in DS neurons. Taken together, DS-iPSC derived neural cells can serve as an ideal cellular model of DS and AD and have potential for high-throughput screening of candidate drugs. We also suggest that Bdph may benefit DS or AD treatment by scavenging Aß aggregates and neurofibrillary tangles.

Strontium ranelate in fracture healing and joint pain improvement in a rheumatoid arthritis patient.

Rheumatoid arthritis is a chronic inflammatory disease characterized by cartilage and bone destruction leading to functional disability. Patients with rheumatoid arthritis also are inclined to have lower bone density and to develop osteoporosis, a condition that leaves them more prone to fractures. With improper care, these incapacitated patients can develop increased morbidity and mortality. Strontium ranelate, currently prescribed for osteoporosis, can be especially helpful in rheumatoid arthritis by strengthening bone quality, reducing fracture risks, and promoting fracture healing. We report a 62-year-old woman with rheumatoid arthritis who suffered a periprosthetic fracture of the femur. After five months of treatment with systemic administration of strontium ranelate, she achieved pain-free ambulation and near union of the aforementioned fracture. In addition, she reported a significant improvement of her polyarthralgia, so that she could stop taking analgesics for her underlying condition in the second month of strontium ranelate therapy. Given this unexpected result, we propose that besides its already known pharmacological effects, strontium ranelate could have an additional benefit in improving polyarthralgia in rheumatoid arthritis patients.

Chylous hip joint effusion and bone absorption after total hip arthroplasty in a patient with chylocolporrhoea: a case of Gorham's disease.

Chyle is a sterile, milky fluid consisting of lymph and emulsified fats that is formed in the small intestines and taken up by lymph vessels. Chylous effusions usually occur after destruction or obstruction of lymphatic channels, and chylous joint effusions have been reported in association with rheumatoid and/or septic arthritis, and as the result of penetrating trauma to subsynovial fatty tissue and the intra-articular fat pad. We report a case of bone absorption and lytic change in the femur associated with a chylous hip joint effusion after a total hip arthroplasty (THA) in a patient with chylocolporrhoea and a history of chylous ascites.

Directional/acidic dissolution kinetics of (OH,F,Cl)-bearing apatite.

Directional dissolution of a natural (OH,F,Cl)-bearing apatite has been studied at various solution pH values (0-3) and 30 degrees C. This apatite showed abnormally high O--H stretching frequencies due to the substitution of Cl for OH. The advance of dissolution front indicated that steady-state directional dissolution for pH = 0-2 followed an apparent rate law of Rate = ka(H+) (n) (in mole/m(2)h), where the rate constants (k) are 2.15 and 1.61; and the rate orders (n) are 1.44 and 1.30 for [0001] and <1,120> directions, respectively. Previous study, however, indicated a smaller n value (n = 0.55-0.70) for fluorapatite powders at higher pHs. A nonlinear pH dependence of logarithmic dissolution rate at a wide pH range implied that the surface active sites and/or rate-determining steps have changed when the acidity of solution and/or the composition of the apatite were changed. The opening of etch pits on basal planes further indicated that the dissolution rates along the three principal directions have the following relationship: [0001] > <1,120> > <1,010> for pH=0-1, but the order was reversed for pH > 3.

A sonography assisted technique for the removal of a femoral interlocking nail--a technical note.

BACKGROUND: Open methods for removal of femoral interlocking nails involve an incision (up to 10 cm) over the trochanter to find the tip of the nail. The distal locking screws are some times difficult to palpate and an incision (up to about 5 cm) is often needed for exposure. Intra-operative fluoroscopy is often used as an adjunct technique to minimize the surgical wound. However, patients and surgeons are exposed to a radiation hazard. Sonography can provide a real-time and efficient alternative to fluoroscopy. METHODS: Sonography of soft tissue has been established to identify a foreign body. A metallic implant has a hyperechoic image; therefore, we can identify the correct position of the screws preoperatively and intraoperatively. RESULTS: We have developed a technique using sonography and minimal incisions for the removal of a femoral interlocking nail. The proximal wound is 2.5 cm in length and the wound is 0.5 cm in length for each distal locking screw. CONCLUSION: The sonography can be used to minimize the length of incision and prevent radiation exposure in the removal of intramedullary femoral nails.

Complications of locked nailing in humeral shaft fractures.

BACKGROUND: The purpose of this study was to investigate the complications of humeral locked nailing. METHODS: Between 1994 and 2000, 161 humeral shaft fractures (98 acute fractures and 63 delayed unions or nonunions) in 159 patients treated with humeral locked nails were followed up for an average of 25.4 months. There were 89 men and 70 women, with an average age of 53.5 years. Acute fractures included 68 closed, 18 type I, 8 type II, 3 type IIIA, and 1 type IIIB open fractures. Thirty-six nonunions had previous operations. In general, acute fractures were treated with closed nailing and nonunions were treated with open nailing with bone grafting. Since 1998, interfragmentary wiring has been added in nonunions to compress the fracture. RESULTS: In total, 30 patients had 31 significant complications. Nine of them were persistent nonunions, six from acute fractures and three from nonunions. Fracture gap was associated with a significantly higher risk of nonunion. The risk of operative comminution was significantly higher in retrograde nailing, and operative comminution resulted in a significantly higher risk of nonunion. Seven of the nine nonunions underwent revisional nailing and achieved eventual union. Removal of the protruded screws was performed in two cases. Other complications included shoulder impairment, elbow impairment, angular malunion, and post-nailing radial nerve palsy. CONCLUSION: Many complications of humeral locked nailing can be prevented by improving the implant design or surgical techniques. The patients with persistent nonunion can be reliably treated by revisional nailing and bone grafting.