The treatment of migraines and tension-type headaches with intravenous and oral niacin (nicotinic acid): systematic review of the literature

BACKGROUND: Migraine and tension-type headaches impose a tremendous economic drain upon the healthcare system. Intravenous and oral niacin has been employed in the treatment of acute and chronic migraine and tension-type headaches, but its use has not become part of contemporary medicine, nor have there been randomized controlled trials further assessing this novel treatment. We aimed to systematically review the evidence of using intravenous and/or oral niacin as a treatment for migraine headaches, tension-type headaches, and for headaches of other etiologic types. METHODS: We searched English and non-English language articles in the following databases: MEDLINE (1966–February 2004), AMED (1995–February 2004) and Alt HealthWatch (1990–February 2004). RESULTS: Nine articles were found to meet the inclusion criteria and were included in this systematic review. Hypothetical reasons for niacin's effectiveness include its vasodilatory properties, and its ability to improve mitochondrial energy metabolism. Important side effects of niacin include flushing, nausea and fainting. CONCLUSION: Although niacin's mechanisms of action have not been substantiated from controlled clinical trials, this agent may have beneficial effects upon migraine and tension-type headaches. Adequately designed randomized trials are required to determine its clinical implications

Ghrelin Indirectly Activates Hypophysiotropic CRF Neurons in Rodents

Ghrelin is a stomach-derived hormone that regulates food intake and neuroendocrine function by acting on its receptor, GHSR (Growth Hormone Secretagogue Receptor). Recent evidence indicates that a key function of ghrelin is to signal stress to the brain. It has been suggested that one of the potential stress-related ghrelin targets is the CRF (Corticotropin-Releasing Factor)-producing neurons of the hypothalamic paraventricular nucleus, which secrete the CRF neuropeptide into the median eminence and activate the hypothalamic-pituitary-adrenal axis. However, the neural circuits that mediate the ghrelin-induced activation of this neuroendocrine axis are mostly uncharacterized. In the current study, we characterized in vivo the mechanism by which ghrelin activates the hypophysiotropic CRF neurons in mice. We found that peripheral or intra-cerebro-ventricular administration of ghrelin strongly activates c-fos – a marker of cellular activation – in CRF-producing neurons. Also, ghrelin activates CRF gene expression in the paraventricular nucleus of the hypothalamus and the hypothalamic-pituitary-adrenal axis at peripheral level. Ghrelin administration directly into the paraventricular nucleus of the hypothalamus also induces c-fos within the CRF-producing neurons and the hypothalamic-pituitary-adrenal axis, without any significant effect on the food intake. Interestingly, dual-label immunohistochemical analysis and ghrelin binding studies failed to show GHSR expression in CRF neurons. Thus, we conclude that ghrelin activates hypophysiotropic CRF neurons, albeit indirectly

Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology

Supported by the Office of International Affairs, National Cancer Institute (NCI), the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc) and the United States Food and Drug Administration (FDA) to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a) to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b) to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations

MYD88 L265P somatic mutation in Waldenstrom’s Macroglobulinemia

Background: Waldenstrom’s Macroglobulinemia (WM) is an incurable, IgM secreting lymphoplasmacytic lymphoma (LPL) with overlapping clinicopathological features to IgM secreting monoclonal gammopathy of unknown significance (MGUS), marginal zone lymphoma (MZL) and myeloma (MM). The underlying mutation for WM remains to be delineated. Methods: Whole genome sequencing (WGS) of bone marrow (BM) LPL cells was performed for 30 WM patients and included sequencing of paired normal/tumor tissues for 10 patients. Sanger sequencing was used to validate these findings in samples from an expanded cohort of patients with LPL, other overlapping B-cell disorders, and healthy donors. Results: A somatic variant (T→C) in LPL cells was identified at position 38182641 at 3p22.2 in all 10 paired, and 17/20 unpaired WM patients which predicted for an amino acid change (L265) in MYD88, a mutation which triggers IRAK/MAPK/NF-κβ signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49/54 WM and 3/3 non-IgM secreting LPL patients (91.2% of all LPL patients). MYD88 L265P was absent in normal paired tissues from WM/LPL patients, healthy donor B-cells, and absent or rarely expressed in samples from MM, MZL or IgM MGUS patients. Mutations in ARID1A (5/30; 17%) leading to premature stop or frameshift were also identified, which associated with greater disease burden. Lastly, 2 of 3 WM patients with wild type MYD88 had variants in MLL2. Conclusions: MYD88 L265P is a highly recurring mutation in WM/LPL patients, which can aid in differentiating WM/LPL from overlapping B-cell disorders, and provides a novel target for the development of therapeutics for WM/LPL

Establishment of BCWM.1 cell line for Waldenström's macroglobulinemia with productive in vivo engraftment in SCID-hu mice

A significant impairment in understanding the biology and advancing therapeutics for Waldenstrom's macroglobulinemia (WM) has been the lack of a representative cell line and animal model. We, therefore, report on the establishment of the BCWM.1 cell line, which was derived from the long-term culture of CD19 + selected bone marrow lymphoplasmacytic cells isolated from an untreated patient with WM. BCWM.1 cells morphologically resemble lymphoplasmacytic cells (LPC) and propagate in RPMI-1640 medium supplemented with 10% fetal bovine serum. Phenotypic characterization by flow cytometric analysis demonstrated typical WM LPC characteristics: CD5 -, CD10 -, CD19 +, CD20 +, CD23 +, CD27 -, CD38 +, CD138 +, CD40 +, CD52 +, CD70 +, CD117 +, cIgM +, cIgG -, cIgA -, cκ -, cλ +, as well as the survival proteins APRIL and BLYS, and their receptors TACI, BCMA and BAFF-R. Enzyme-linked immunosorbent assay studies demonstrated secretion of IgMλ and soluble CD27. Karyotypic and multicolor fluorescence in situ hybridization studies did not demonstrate cytogenetic abnormalities. Molecular analysis of BCWM.1 cells confirmed clonality by determination of IgH rearrangements. Inoculation of BCWM.1 cells in human bone marrow chips implanted in severe combined immunodeficient-hu mice led to rapid engraftment of tumor cells and serum detection of human IgM, λ, and soluble CD27. These studies support the use of BCWM.1 cells as an appropriate model for the study of WM, which in conjunction with the severe combined immunodeficient-hu mouse model may be used as a convenient model for studies focused on both WM pathogenesis and development of targeted therapies for WM. © 2007 ISEH - Society for Hematology and Stem Cells.link_to_subscribed_fulltex

Ghrelin plays a role in various physiological and pathophysiological brain functions

The ghrelin receptor is now known to play an important role in regulating physiological responses to stress. In particular, ghrelin acting at the growth hormone secretagogue receptor (ghrelin receptor) may promote anxious behaviours under non-stressed conditions, and attenuate anxiety under conditions of stress. Dysregulation of the ghrelin system therefore has significant consequences for stress-related mood disorders such as anxiety and depression; disorders that pose a substantial problem for human health. These effects of the ghrelin system on mood are of particular concern in obese populations, where the likelihood of a mood disorder is higher and the ghrelin system disrupted. Studies in humans are still revealing conflicting roles for ghrelin and the ghrelin receptor in anxiety and depression, but these, and studies in animal models, offer evidence that ghrelin may influence its receptor at extra-hypothalamic brain regions to exert indirect control over central responses to stress and over brain pathways related to anxiety and depression. In this chapter, I discuss the background and potential mechanisms for ghrelin and ghrelin receptor's role in regulating stress and stress-related mood disorders