Future research on MS-related fatigue may consider a longitudinal design with a carefully selected self-report instrument to advance understanding of the underlying pathological mechanisms.

Co-transcriptional splicing takes place in the context of a highly dynamic chromatin architecture, yet the role of chromatin restructuring in coordinating transcription with RNA splicing has not been fully resolved. To further define the contribution of histone modifications to pre-mRNA splicing in Saccharomyces cerevisiae, we probed a library of histone point mutants using a reporter to monitor pre-mRNA splicing. We found that mutation of H3 lysine 36 (H3K36) -a residue methylated by Set2 during transcription elongation -exhibited phenotypes similar to those of pre-mRNA splicing mutants. We identified genetic interactions between genes encoding RNA splicing factors and genes encoding the H3K36 methyltransferase Set2 and the demethylase Jhd1 as well as point mutations of H3K36 that block methylation. Consistent with the genetic interactions, deletion of SET2, mutations modifying the catalytic activity of Set2 or H3K36 point mutations significantly altered expression of our reporter and reduced splicing of endogenous introns. These effects were dependent on the association of Set2 with RNA polymerase II and H3K36 dimethylation. Additionally, we found that deletion of SET2 reduces the association of the U2 and U5 snRNPs with chromatin. Thus, our study provides the first evidence that H3K36 methylation plays a role in co-transcriptional RNA splicing in yeast.Abbreviations: (H3K36), histone H3 lysine 36; (ChIP), chromatin immunoprecipitations; (RT-qPCR), reverse transcription PCR; (snRNP), small nuclear ribonucleprotein; (RNA Pol II), RNA polymerase II

Hypocortisolism has been reported in chronic fatigue syndrome (CFS), with the significance of this finding to disease etiology unclear. This study examined cortisol levels and their relationships with symptoms in a group of 108 individuals with CFS. CFS symptoms examined included fatigue, pain, sleep difficulties, neurocognitive functioning, and psychiatric status. Alterations in cortisol levels were examined by calculation of mean daily cortisol, while temporal variation in cortisol function was examined by means of a regression slope. Additionally, deviation from expected cortisol diurnal pattern was determined via clinical judgment. Results indicated that fatigue and pain were associated with salivary cortisol levels. In particular, variance from the expected pattern of cortisol was associated with increased levels of fatigue. The implications of these findings are discussed.Keywords salivary cortisol; chronic fatigue syndrome; cognitive functioning; pain; fatigue Chronic fatigue syndrome (CFS) is an illness characterized by severe, disabling fatigue that is not alleviated with rest, and by flu-type symptoms including sore throats, muscle pain, joint pain, headaches, memory/concentration difficulties, unrefreshing sleep, and postexertional malaise (Fukuda, et al. 1994). The causes of CFS are currently unknown, and, as of yet, no clear diagnostic marker for this illness has emerged. Physiological studies have suggested the presence of dysfunction in the immune, endocrine, and neurological systems, NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript and researchers have found numerous abnormalities in these systems. However, many of these physiological abnormalities have not been replicated across studies, and a confusing picture still exists regarding the pathophysiology of this illness. Most recently, it has been suggested that individuals with CFS constitute a heterogeneous population, and little progress in clearly delineating the physiology of this illness may have resulted because of the presence of distinct subgroups within this larger umbrella diagnosis (Jason, Corradi, Torres-Harding, Taylor, & King, 2005).However, some abnormalities have been more consistently reported in the literature as affecting a subset of individuals with CFS. One finding frequently reported is a dysfunction of the hypothalamic-pituitary-adrenal axis, (HPA) with resulting hypocortisolism (Addington, 2000;Cleare, 2003). Cortisol, a glucocorticoid, is the major end product of the HPA axis and is involved in regulation of several bodily systems. Some researchers have noted that approximately 20-25% of individuals with CFS and related disorders such as fibromyalgia or post-traumatic stress disorder have exhibited hypocortisolism and downregulation of the HPA axis (Fries, Hesse, Hellhammer, & Hellhammer, 2005). Cleare (2003), in a review of the literature examining HPA dysfunction in CFS, found that many, but not all, studies of cortisol in CFS found lower levels of baseline cortisol and changes in sen...

Kindling might represent a heuristic model for understanding the etiology of Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Kindling occurs when an organism is exposed repeatedly to an initially sub-threshold stimulus resulting in hypersensitivity and spontaneous seizure-like activity. Among patients with ME/CFS, chronically repeated low-intensity stimulation due to an infectious illness might cause kindling of the limbic-hypothalamic-pituitary axis. Kindling might also occur by high-intensity stimulation (e.g., brain trauma) of the limbic-hypothalamic-pituitary axis. Once this system is charged or kindled, it can sustain a high level of arousal with little or no external stimulus and eventually this could lead to hypocortisolism. Seizure activity may spread to adjacent structures of the limbic-hypothalamic-pituitary axis in the brain, which might be responsible for the varied symptoms that occur among patients with ME/CFS. In addition, kindling may also be responsible for high levels of oxidative stress, which has been found in patients with ME/CFS.