Regulation of stem cell function and neuronal differentiation by HERV-K via mTOR pathway.

Stem cells are capable of unlimited proliferation but can be induced to form brain cells. Factors that specifically regulate human development are poorly understood. We found that human stem cells expressed high levels of the envelope protein of an endogenized human-specific retrovirus (HERV-K, HML-2) from loci in chromosomes 12 and 19. The envelope protein was expressed on the cell membrane of the stem cells and was critical in maintaining the stemness via interactions with CD98HC, leading to triggering of human-specific signaling pathways involving mammalian target of rapamycin (mTOR) and lysophosphatidylcholine acyltransferase (LPCAT1)-mediated epigenetic changes. Down-regulation or epigenetic silencing of HML-2 env resulted in dissociation of the stem cell colonies and enhanced differentiation along neuronal pathways. Thus HML-2 regulation is critical for human embryonic and neurodevelopment, while it's dysregulation may play a role in tumorigenesis and neurodegeneration.

KMN-159, a novel EP4 receptor selective agonist, stimulates osteoblastic differentiation in cultured whole rat bone marrow.

KMN-159 is the lead compound from a series of novel difluorolactam prostanoid EP4 receptor agonists aimed at inducing local bone formation while avoiding the inherent side effects of systemic EP4 activation. KMN-159 is a potent, selective small molecule possessing pharmacokinetic properties amenable to local administration. Unfractionated rat bone marrow cells (BMCs) were treated once at plating with escalating doses of KMN-159 (1 pM to 10 µM). The resulting elevated alkaline phosphatase (ALP) levels measured 9 days post-dose are consistent with increased osteoblastic differentiation and exposure to KMN-159 at low nanomolar concentrations for as little as 30 min was sufficient to induce complete osteoblast differentiation of the BMCs from both sexes and regardless of age. ALP induction was blocked by an EP4 receptor antagonist but not by EP1 or EP2 receptor antagonists and was not induced by EP2 or EP3 receptor agonists. Addition of BMCs to plates coated with KMN-159 24 days earlier resulted in ALP activation, highlighting the chemical stability of the compound. The expression of phenotype markers such as ALP, type I collagen, and osteocalcin was significantly elevated throughout the osteoblastic differentiation timecourse initiated by KMN-159 stimulation. An increased number of tartrate-resistant acid phosphatase-positive cells was observed KMN-159 or PGE2 treated BMCs but only in the presence of exogenous receptor activator of nuclear factor kappa-Β ligand (RANKL). No change in the number of adipocytes was observed. KMN-159 also increased bone healing in a rat calvarial defect model with a healing rate equivalent to recombinant human bone morphogenetic protein-2. Our studies show that KMN-159 is able to stimulate osteoblastic differentiation with a very short time of exposure, supporting its potential as a therapeutic candidate for augmenting bone mass.

Factors associated with geographic variation in cost per episode of care for three medical conditions.

OBJECTIVE: To identify associations between market factors, especially relative reimbursement rates, and the probability of surgery and cost per episode for three medical conditions (cataract, benign prostatic neoplasm, and knee degeneration) with multiple treatment options. METHODS: We use 2004-2006 Medicare claims data for elderly beneficiaries from sixty nationally representative communities to estimate multivariate models for the probability of surgery and cost per episode of care as a function local market factors, including Medicare physician reimbursement for surgical versus non-surgical treatment and the availability of primary care and specialty physicians. We used Symmetry's Episode Treatment Groups (ETG) software to group claims into episodes for the three conditions (n = 540,874 episodes). RESULTS: Higher Medicare reimbursement for surgical episodes and greater availability of the relevant specialists are significantly associated with more surgery and higher cost per episode for all three conditions, while greater availability of primary care physicians is significantly associated with less frequent surgery and lower cost per episode. CONCLUSION: Relative Medicare reimbursement rates for surgical vs. non-surgical treatments and the availability of both primary care physicians and relevant specialists are associated with the likelihood of surgery and cost per episode.

Transcriptional activation by Oct4 is sufficient for the maintenance and induction of pluripotency.

Oct4 is an essential regulator of pluripotency in vivo and in vitro in embryonic stem cells, as well as a key mediator of the reprogramming of somatic cells into induced pluripotent stem cells. It is not known whether activation and/or repression of specific genes by Oct4 is relevant to these functions. Here, we show that fusion proteins containing the coding sequence of Oct4 or Xlpou91 (the Xenopus homolog of Oct4) fused to activating regions, but not those fused to repressing regions, behave as Oct4, suppressing differentiation and promoting maintenance of undifferentiated phenotypes in vivo and in vitro. An Oct4 activation domain fusion supported embryonic stem cell self-renewal in vitro at lower concentrations than that required for Oct4 while alleviating the ordinary requirement for the cytokine LIF. At still lower levels of the fusion, LIF dependence was restored. We conclude that the necessary and sufficient function of Oct4 in promoting pluripotency is to activate specific target genes.

Resident and fellow experiences after the introduction of endovascular aneurysm repair for abdominal aortic aneurysm.

OBJECTIVES: This study assessed trends in open and endovascular repair (EVAR) of intact and ruptured abdominal aortic aneurysm (AAA) in the Medicare population and evaluated recent trends in AAA repair at vascular fellowship training programs. METHODS: We identified all Medicare beneficiaries with a diagnosis of AAA who underwent repair or had a primary diagnosis of rupture (1995-2008). Cohorts were compared by type of repair (open vs EVAR) and presentation (intact vs ruptured AAA). Demographics of age, sex, and race were evaluated. We used unique hospital identifier codes to compare trends and 30-day mortality between hospitals that participate in vascular surgery fellowship training and those that do not. American Council on Graduate Medical Education data, only available for the years 1999 to 2008, were further used to better understand the changes in number of EVAR and open repairs of AAA performed each year for vascular fellows and general surgery residents, over time. RESULTS: We identified 449,122 patients (76% men), with 376,355 intact AAAs (84%) and 72,767 ruptured AAAs (16%). Mean age was 75.1 years. Use of EVAR for intact AAA rose to from 35% in 2001 to 63% in 2005 and comprised 78% of repairs by 2008. During the same period, the number of ruptured AAAs decreased by 40% overall, with nonoperative ruptured AAAs decreasing by 29% and EVAR increasing to 31% of rupture repairs. Hospitals training vascular fellows were quicker to adopt EVAR (2-year lag time) for intact AAA and had higher rates of EVAR for ruptured AAA (41.1% vs 29.2%; P = .001) than did hospitals without fellows. Mortality rates for open repairs of intact (4.0% vs 5.0%; P = .01) and ruptured AAA (34.1% vs 41.0%; P = .031) were lower at fellowship hospitals. The average number of open AAA repairs performed by vascular fellows dropped 50% (44.1 to 21.6/year) from 1999 to 2008. CONCLUSIONS: Contrary to the expectation of a plateau, use of EVAR for intact AAA continues to rise at fellowship and nonfellowship hospitals. Use of EVAR for rupture is being used more often at fellowship programs. The decline in open repairs performed by vascular fellows, and at fellowship and non-fellowship hospitals, may have important implications for future attending experience.

Sirolimus-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the SISR randomized trial.

CONTEXT: Although vascular brachytherapy is the only approved therapy for restenosis following bare-metal stent implantation, drug-eluting stents are now being used. Data on the relative merits of each are limited. OBJECTIVE: To determine the safety and efficacy of the sirolimus-eluting stent compared with vascular brachytherapy for the treatment of patients with restenosis within a bare-metal stent. DESIGN, SETTING, AND PATIENTS: Prospective, multicenter, randomized trial of 384 patients with in-stent restenosis who were enrolled between February 2003 and July 2004 at 26 academic and community medical centers. Data presented represent all follow-up as of June 30, 2005. INTERVENTIONS: Vascular brachytherapy (n = 125) or the sirolimus-eluting stent (n = 259). MAIN OUTCOME MEASURE: Target vessel failure (cardiac death, myocardial infarction, or target vessel revascularization) at 9 months postprocedure. RESULTS: Baseline patient characteristics were well matched. Lesion length was similar between vascular brachytherapy and sirolimus-eluting stent patients (mean [SD], 16.76 [8.55] mm vs 17.22 [7.97] mm, respectively; P = .61). Procedural success was 99.2% (124/125) in the vascular brachytherapy group and 97.3% (250/257) in the sirolimus-eluting stent group (P = .28). The rate of target vessel failure was 21.6% (27/125) with vascular brachytherapy and 12.4% (32/259) with the sirolimus-eluting stent (relative risk [RR], 1.7; 95% confidence interval [CI], 1.1-2.8; P = .02). Target lesion revascularization was required in 19.2% (24/125) of the vascular brachytherapy group and 8.5% (22/259) of the sirolimus-eluting stent group (RR, 2.3 [95% CI, 1.3-3.9]; P = .004). At follow-up angiography, the rate of binary angiographic restenosis for the analysis segment was 29.5% (31/105) for the vascular brachytherapy group and 19.8% (45/227) for the sirolimus-eluting stent group (RR, 1.5 [95% CI, 1.0-2.2]; P = .07). Compared with the vascular brachytherapy group, minimal lumen diameter was larger in the sirolimus-eluting stent group at 6-month follow-up (mean [SD], 1.52 [0.63] mm vs 1.80 [0.63] mm; P<.001), reflecting greater net lumen gain in the analysis segment (0.68 [0.60] vs 1.0 [0.61] mm; P<.001) due to stenting and no edge restenosis. CONCLUSION: Sirolimus-eluting stents result in superior clinical and angiographic outcomes compared with vascular brachytherapy for the treatment of restenosis within a bare-metal stent. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00231257.

Assessment of biomarkers of protein anabolism in skeletal muscle during the life span of the rat: sarcopenia despite elevated protein synthesis.

Loss of muscle strength is a principal factor in the development of physical frailty, a condition clinically associated with increased risk of bone fractures, impairments in the activities of daily living, and loss of independence in older humans. A primary determinant in the decline in muscle strength that occurs during aging is a loss of muscle mass, which could occur through a reduction in the rate of protein synthesis, an elevation in protein degradation, or a combination of both. In the present study, rates of protein synthesis and the relative expression and function of various biomarkers involved in the initiation of mRNA translation in skeletal muscle were examined at different times throughout the life span of the rat. It was found that between 1 and 6 mo of age, body weight increased fourfold. However, by 6 mo, gastrocnemius protein synthesis and RNA content per gram of muscle were lower than values observed in 1-mo-old rats. Moreover, the relative expression of two proteins involved in the binding of initiator methionyl-tRNA to the 40S ribosomal subunit, eukaryotic initiation factors (eIF)2 and eIF2B, as well as the 70-kDa ribosomal protein S6 kinase, S6K1, was lower at 6 mo compared with 1 mo of age. Muscle mass, protein synthesis, and the aforementioned biomarkers remained unchanged until approximately 21 mo. Between 21 and 24 mo of age, muscle mass decreased precipitously. Surprisingly, during this period protein synthesis, relative RNA content, eIF2B activity, relative eIF2 expression, and S6K1 phosphorylation all increased. The results are consistent with a model wherein protein synthesis is enhanced during aging in a futile attempt to maintain muscle mass.

Anal cancer in Alaska; a retrospective study of incidence, treatment, and outcomes.

Anal cancer is a rare tumor usually of squamous histology that is managed most often with concurrent chemotherapy and radiation therapy. Surgery is commonly reserved for those who fail primary treatment. We conducted a retrospective analysis of the medical records of patients with anal cancer seen in two radiation therapy centers in Alaska from the period of 1996 to mid-2001. Records were reviewed for diagnosis, sex, age, staging, treatment and outcomes. Twenty-four patients were identified with squamous cell carcinoma of the anus. Average age at diagnosis was 53. Tumor size was predominantly 2-5 centimeters. Four patients had nodal involvement and three had distant metastasis. Twenty patients received radiation. Nineteen received flourouracil and either cisplatin or mitomycin. Three patients underwent abdominoperineal resections. Ten were found to have no evidence of disease at an average of twenty-two months. These results are consistent with findings of larger studies elsewhere.

Case report: solitary pelvic osteochondroma presenting with L3 nerve root compression.

Osteochondroma is the most common benign bone tumor, comprising 40% of benign bone tumors. Typically they are found in adolescents growing on long bones such as the femur or radius and are clinically obvious. Very rarely, osteochondromas grow in the pelvis where they can reach a large size and present in more subtle ways. We describe an unusual case of a solitary osteochondroma in an otherwise healthy 29 year-old male presenting with signs and symptoms of an L3 nerve root compression.