Correction: ANKK1 is found in myogenic precursors and muscle fibers subtypes with glycolytic metabolism.

[This corrects the article DOI: 10.1371/journal.pone.0197254.].

ANKK1 is found in myogenic precursors and muscle fibers subtypes with glycolytic metabolism.

Ankyrin repeat and kinase domain containing 1 (ANKK1) gene has been widely related to neuropsychiatry disorders. The localization of ANKK1 in neural progenitors and its correlation with the cell cycle has suggested its participation in development. However, ANKK1 functions still need to be identified. Here, we have further characterized the ANKK1 localization in vivo and in vitro, by using immunolabeling, quantitative real-time PCR and Western blot in the myogenic lineage. Histologic investigations in mice and humans revealed that ANKK1 is expressed in precursors of embryonic and adult muscles. In mice embryos, ANKK1 was found in migrating myotubes where it shows a polarized cytoplasmic distribution, while proliferative myoblasts and satellite cells show different isoforms in their nuclei and cytoplasm. In vitro studies of ANKK1 protein isoforms along the myogenic progression showed the decline of nuclear ANKK1-kinase until its total exclusion in myotubes. In adult mice, ANKK1 was expressed exclusively in the Fast-Twitch muscles fibers subtype. The induction of glycolytic metabolism in C2C12 cells with high glucose concentration or treatment with berberine caused a significant increase in the ANKK1 mRNA. Similarly, C2C12 cells under hypoxic conditions caused the increase of nuclear ANKK1. These results altogether show a relationship between ANKK1 gene regulation and the metabolism of muscles during development and in adulthood. Finally, we found ANKK1 expression in regenerative fibers of muscles from dystrophic patients. Future studies in ANKK1 biology and the pathological response of muscles will reveal whether this protein is a novel muscle disease biomarker.

Osteopathic Manipulative Treatment Including Specific Diaphragm Techniques Improves Pain and Disability in Chronic Nonspecific Low Back Pain: A Randomized Trial.

OBJECTIVE: To investigate the effects of an osteopathic manipulative treatment (OMT), which includes a diaphragm intervention compared to the same OMT with a sham diaphragm intervention in chronic nonspecific low back pain (NS-CLBP). DESIGN: Parallel group randomized controlled trial. SETTING: Private and institutional health centers. PARTICIPANTS: Participants (N=66) (18-60y) with a diagnosis of NS-CLBP lasting at least 3 months. INTERVENTIONS: Participants were randomized to receive either an OMT protocol including specific diaphragm techniques (n=33) or the same OMT protocol with a sham diaphragm intervention (n=33), conducted in 5 sessions provided during 4 weeks. MAIN OUTCOME MEASURES: The primary outcomes were pain (evaluated with the Short-Form McGill Pain Questionnaire [SF-MPQ] and the visual analog scale [VAS]) and disability (assessed with the Roland-Morris Questionnaire [RMQ] and the Oswestry Disability Index [ODI]). Secondary outcomes were fear-avoidance beliefs, level of anxiety and depression, and pain catastrophization. All outcome measures were evaluated at baseline, at week 4, and at week 12. RESULTS: A statistically significant reduction was observed in the experimental group compared to the sham group in all variables assessed at week 4 and at week 12 (SF-MPQ [mean difference -6.2; 95% confidence interval, -8.6 to -3.8]; VAS [mean difference -2.7; 95% confidence interval, -3.6 to -1.8]; RMQ [mean difference -3.8; 95% confidence interval, -5.4 to -2.2]; ODI [mean difference -10.6; 95% confidence interval, -14.9 to 6.3]). Moreover, improvements in pain and disability were clinically relevant. CONCLUSIONS: An OMT protocol that includes diaphragm techniques produces significant and clinically relevant improvements in pain and disability in patients with NS-CLBP compared to the same OMT protocol using sham diaphragm techniques.

Generation of a disease-specific iPS cell line derived from a patient with Charcot-Marie-Tooth type 2K lacking functional GDAP1 gene.

Human CMT2-FiPS4F1 cell line was generated from fibroblasts of a patient with Charcot-Marie-Tooth disease harbouring the following mutations in the GDAP1 gene in heterozygosis: p.Q163X/p.T288NfsX3. This patient did not present mutations in the PM22, MPZ or GJB genes. Human reprogramming factors OCT3/4, KLF4, SOX2 and C-MYC were delivered using a non-integrative methodology that involves the use of Sendai virus.

Isolation Methods of Peripheral Blood Mononuclear Cells in Spanish Biobanks: An Overview.

The Spanish Hematic Derivatives Group, consisting of 26 biobanks, was established in 2011. We describe here the viability results of our publically available standard operating procedure to freeze and thaw peripheral blood mononuclear cells (PBMCs). Our protocol maximizes PBMC viability while avoiding where possible interbiobank and intrabiobank assay variability.

Monocytes and γδ T cells control the acute-phase response to intravenous zoledronate: insights from a phase IV safety trial.

Aminobisphosphonates (NBPs) are used widely against excessive bone resorption in osteoporosis and Paget's disease as well as in metastatic bone disease and multiple myeloma. Intravenous NBP administration often causes mild to severe acute-phase responses (APRs) that may require intervention with analgesics and antipyretics and lead to treatment noncompliance and nonadherence. We here undertook a phase IV safety trial in patients with osteoporosis to investigate the APR of otherwise healthy individuals to first-time intravenous treatment with the NBP zoledronate. This study provides unique insight into sterile acute inflammatory responses in vivo, in the absence of confounding factors such as infection or cancer. Our data show that both peripheral γδ T cells and monocytes become rapidly activated after treatment with zoledronate, which ultimately determines the clinical severity of the APR. Our study highlights a key role for IFN-γ in the zoledronate-induced APR and identifies pretreatment levels of monocytes and central/memory Vγ9/Vδ2 T cells as well as their responsiveness to zoledronate in vitro as predictive risk factors for the occurrence of subclinical and clinical symptoms. These findings have diagnostic and prognostic implications for patients with and without malignancy and are relevant for Vγ9/Vδ2 T-cell-based immunotherapy approaches.

[Erdheim-Chester disease: study of 12 cases]. / Enfermedad de Erdheim-Chester: estudio de 12 casos.

BACKGROUND AND OBJECTIVE: Erdheim-Chester disease (EC) is a rare form of non-Langerhans' cell histiocytosis. It is characterized by the xanthomatous infiltration of tissues with foamy CD68+/CD1a- histiocytes. We report a series of 12 patients diagnosed with EC. PATIENTS AND METHODS: We reviewed the clinical, pathological and therapeutic aspects of 12 cases diagnosed with EC at 7 tertiary teaching hospitals in Spain. Patients were included if tissue infiltration by histiocytes CD68+/CD1a- could be demonstrated in an appropriate clinical setting. RESULTS: Twelve patients (7 male) were included. Median follow-up was 36 months (IQR: 20-84). The median age at the time of clinical onset and pathological diagnosis was 49 (IQR: 28-61) and 56 years (IQR: 37-62), respectively. In 6 cases multiples biopsies were performed (skin, muscle, testicular) previous to diagnosis, which was confirmed in 3 cases after a carefully review of pathological tissues. Neurological involvement was independently associated with mortality (P<.05). Characteristic long bone osteosclerosis was detected in 9 patients. CONCLUSION: EC is a multisystemic and heterogeneous clinicopathological condition. A high index of suspicion and fluent communication between clinicians and pathologists is necessary to achieve a correct diagnosis.

Characterization of trisomic natural killer cell abnormalities in a patient with constitutional trisomy 8 mosaicism.

Malignancies found in children and adults with constitutional trisomy 8 mosaicism (CT8M) could be in part the consequence of dysfunction of trisomic immune cells. An adult patient exhibiting trisomy in the entire natural killer (NK) cell population has made possible the characterization of trisomy 8-positive NK cells. The study showed normal cytotoxic activity but predominance of an immunosenescent phenotype (CD56(dim)CD94/NKG2(bright)) characterized by a weak response to IL-2, increased upregulation of CD95/Fas, and impaired TNF-alpha production. As these defects may contribute to the escape and expansion of neoplastic cells, the authors hypothesize that cancer predisposition in CT8M may be partly a result of altered immunosurveillance.

Cross-linking of MHC class I molecules on human NK cells inhibits NK cell function, segregates MHC I from the NK cell synapse, and induces intracellular phosphotyrosines.

Engagement of major histocompatibility complex (MHC) class I molecules on immune cells, where they are usually highly expressed, induces signal transduction events of unclear significance. We show here that antibody-mediated cross-linking of MHC-I molecules on human natural killer (NK) cells inhibits their cytotoxic activity against tumor target cells. Inhibition by anti-MHC class I monoclonal antibody exhibits molecular specificity and is an isotype and Fc-independent process. Physical hindrance of specific molecular recognition, induction of apoptosis, or reciprocal NK cell killing, which could be induced by cross-linking of MHC I molecules, has also been ruled out as putative mechanisms of inhibition. Confocal microscopy analysis revealed that MHC class I molecules on the surface of NK cells colocalize constitutively with GM1, a marker of lipid rafts. Cross-linking of MHC class I resulted in the asymmetric redistribution of GM1-enriched raft domains, which are concentrated to the immunological synapse, and MHC I molecules, which segregate to the opposite pole. Also, the cross-linking of MHC I on NK cells induced intracellular tyrosine phosphorylations. These results suggest that MHC I molecules on NK cells could transmit inhibitory signals upon engagement with putative ligands expressed on the surface of those cells that need to be protected from natural cytotoxicity.