Temozolomide (TMZ) is a chemotherapy agent used to treat Grade IV astrocytoma, also known as glioblastoma (GBM). TMZ treatment causes DNA damage that results in tumor cell apoptosis and increases the survival rate of GBM patients. However, chemoresistance as a result of TMZ‐induced autophagy significantly reduces this anticancer effects over time. Statins are competitive inhibitors of HMG‐CoA reductase, the rate‐limiting enzyme of the mevalonate (MEV) cascade. Statins are best known for their cholesterol (CH)‐lowering effect. Long‐term consumption of statins, prior to and in parallel with other cancer therapeutic approaches, has been reported to increase the survival rate of patients with various forms of cancers. In this study, we investigated the potentiation of TMZ‐induced apoptosis by simvastatin (Simva) in human GBM cell lines and patient GBM cells, using cell monolayers and three‐dimensional cell culture systems. The incubation of cells with a combination of Simva and TMZ resulted in a significant increase in apoptotic cells compared to cells treated with TMZ alone. Incubation of cells with CH or MEV cascade intermediates failed to compensate the decrease in cell viability induced by the combined Simva and TMZ treatment. Simva treatment inhibited the autophagy flux induced by TMZ by blocking autophago‐lysosome formation. Our results suggest that Simva sensitizes GBM cells to TMZ‐induced cell death in a MEV cascade‐independent manner and identifies the inhibition of autophagosome‐lysosome fusion as a promising therapeutic strategy in the treatment of GBM.

Background: hyperlipidemia as a major risk factor of atherosclerosis is treated with different drugs. Concerning length of therapy and vast majority of side effects, herbal medication may be suitable substitute for these drugs.

Background: Hallux valgus recurrence is an unsatisfactory complication, with many causes postulated. This study investigated the effect of pes planus on recurrence after scarf osteotomy. Methods: A total of 183 feet were retrospectively reviewed. All patients were treated with a scarf osteotomy and if required Akin osteotomy. We measured preoperative lateral talus first metatarsal angle (T1MA) to study pes planus; an angle of under −4 degrees was considered pes planus. We measured pre and postoperative hallux valgus angle (HVA), intermetatarsal angle (IMA), and sesamoid location. In total 164 feet were suitable for inclusion, with follow-up of at least 6 months (10 males and 154 females, mean age: 52 years). Results: Recurrence frequency (HVA greater than 15 degrees) was 27 feet (16%). Hallux valgus recurrence was not influenced by gender ( P value = .66) or preoperative IMA ( P value = .48). Preoperative HVA greater than 35 degrees was associated with increased frequency of recurrence ( P value = .004). Those with T1MA less than −10 degrees demonstrated progression in HVA and deterioration in sesamoid location up to 6 months postoperatively ( P value = .038). HVA did not progress beyond 6 months. The prevalence of recurrent hallux valgus with normal T1MA was 1%, in T1MA −4 to −10 degrees it was 29% and in T1MA less than −10 degrees it was 47% ( P value <.001). Breaks in T1MA less than −4 degrees were found at the naviculocuneiform joint in 68% of feet in this series. Conclusion: The prevalence of hallux valgus recurrence correlated with the severity of pes planus. Level of Evidence: Level III, retrospective cohort study.

Transient osteoporosis during pregnancy is a rare, self-limiting disease. We report on a 36-year-old woman who had bilateral subcapital femoral neck fractures during the 6th month of pregnancy. The diagnosis was made 4 days after delivery, because radiography was declined by the patient for fear of radiation. Fixation was not feasible owing to bone resorption, and 2-stage bipolar hemiarthroplasty was therefore performed. Magnetic resonance imaging is the best non-invasive investigative tool for pregnant women with hip pain. Early detection can prevent complications and resorting to major surgeries.

Chronic neuroinflammation driven by microglia is a characteristic feature associated with numerous neurodegenerative diseases. While acute inflammation can assist with recovery and repair, prolonged microglial pro-inflammatory responses are known to exacerbate neurodegenerative processes. Yet, detrimental outcomes of extended microglial activation are counterbalanced by beneficial outcomes including phagocytosis and release of trophic factors promoting neuronal viability. Our past work has shown that the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is a key signaling hub driving pro-inflammatory microglia responses, but the signaling pathway maintaining PARP-1 activation remains elusive. While best understood for its role in promoting DNA repair, our group has shown that PARP-1 activity can be stimulated via Ca 2+ influx-dependent ERK1/2-mediated phosphorylation. However, to date, the route of Ca 2+ entry responsible for stimulating PARP-1 has not been identified. A likely candidate is via Ca 2+ -permeable transient receptor potential melastatin 2 (TRPM2) channels activated downstream of PARP-1 in a cascade that involves ADP-ribose (ADPR) production by poly(ADP-ribose) glycohydrolase (PARG). Here we demonstrate that NMDA receptor (NMDAR) stimulation in primary cultured microglia induces their proliferation, morphological activation and release of pro-inflammatory mediators. These responses were contingent on the recruitment of PARP-1, PARG and Ca 2+ permeable TRPM2 channels. Furthermore, we show that Ca 2+ influx is necessary to activate PARP-1/TRPM2 signaling, in an ERK1/2-dependent, but DNA damage independent, manner. Our findings, showing that PARP-1/TRPM2 mediate the pro-inflammatory effects of NMDAR stimulation, provides a unifying mechanism linking elevated glutamate levels to chronic neuroinflammation.

Background:Musculoskeletal tumors are rare, but their descriptive data in any region are important to reduce mortality rate and improve their management.Materials and Methods:Retrospectively, 426 pathologic reports from 1997 to 2008 were reviewed in Shiraz University Orthopedic Hospitals which are the main referral centers for musculoskeletal tumors in south of Iran. We collected and analyzed data on age, gender, anatomical site, and histopathologic types of musculoskeletal tumors.Results:Of the 426 cases, 60.1% were men and 39.9% were women. The commonest malignant bone tumors were osteosarcoma (89; 50.6%), metastasis (30; 17.0%), Ewing's sarcoma (28; 15.9%), and chondrosarcoma (14; 8.0%). The most frequent benign bone tumors were osteochondroma (136; 63.9%), enchondroma (23; 10.8%), giant cell tumor (21; 9.9%), and osteoid osteoma (14; 6.6%). The femur was the most commonly involved site in musculoskeletal tumors. It was followed by the tibia in benign tumors and the humerus in malignant ones. Metastasis (28; 32.6%), soft tissue tumors (18; 20.9%), osteochondroma (10; 11.6%), and osteosarcoma (9; 10.5%) were the most diagnosed bone lesions in patients older than 40.Conclusion:There are no significant changes in epidemiology of musculoskeletal tumors in Shiraz, south of Iran, in comparison with other parts of the world.

It is clear that modifiable factors like quitting the habit of smoking and gaining more energy with better nutrition could reduce the mortality rate if hip fracture occurs in the elderly.

Statins are some of the most widely used drugs worldwide, but one of their major side effects is myotoxicity. Using mouse myoblast (C2C12) and human alveolar rhabdomyosarcoma cell lines (RH30) in 2-dimensional (2D) and 3-dimensional (3D) culture, we investigated the mechanisms of simvastatin's myotoxicity. We found that simvastatin significantly reduced cell viability in C2C12 cells compared to RH30 cells. However, simvastatin induced greater apoptosis in RH30 compared to C2C12 cells. Simvastatin-induced cell death is dependent on Geranylgeranyl pyrophosphate (GGPP) in C2C12 cells, while in RH30 cells it is dependent on both Farnesyl pyrophosphate (FPP) and GGPP. Simvastatin inhibited autophagy flux in both C2C12 and RH30 cells and inhibited lysosomal acidification in C2C12 cells, while autophagy inhibition with Bafilomycin-A1 increased simvastatin myotoxicity in both cell lines. Simvastatin induced more cell death in RH30 cells compared to C2C12 in 3D culture model with similar effects on autophagy flux as in 2D culture. Overall our results suggest that simvastatin-induced myotoxicity involves both apoptosis and autophagy, where autophagy serves a pro-survival role in both cell lines. The sensitivity to simvastatin myotoxicity is different in 2D versus 3D culture, demonstrating that the cellular microenvironment is a critical factor in regulating simvastatininduced cell death in myoblasts.