Further validation of the Multidimensional Fatigue Inventory in a US adult population sample

Background  

The Multidimensional Fatigue Inventory (MFI-20) was developed in 1995. Since then, it has been widely used in cancer research and cancer-related illnesses but has never been validated in fatiguing illnesses or in a large US population-selected sample. In this study, we sought to examine the reliability and validity of the MFI-20 in the population of the state of Georgia, USA. Further, we assessed whether the MFI-20 could serve as a complementary diagnostic tool in chronically fatigued and unwell populations.     

Persistent paranoid delusions following the September 11 terrorist attacks in a man with no pre-existing mental illness

The effects of modern day terrorism on mental health are not well understood. Described here is a 51-year-old male with no pre-existing mental illness who developed paranoid delusions related to the September 11, 2001, terrorist attacks shortly after they occurred. After about two years of treatment with quetiapine the patient was no longer delusional about terrorism but experienced extensive paranoid delusions about commonly encountered persons, requiring treatment which continues to the current time. Clinicians should be aware of the possible impact of terrorist activities on the mental health of vulnerable individuals.     

tPA Activates LDL Receptor-Related Protein 1-Mediated Mitogenic Signaling Involving the p90RSK and GSK3β Pathway

In renal fibrosis, interstitial fibroblasts have an increased proliferative phenotype, and the numbers of interstitial fibroblasts closely correlate with the extent of kidney damage. The mechanisms underlying proliferation and resulting expansion of the interstitium remain largely unknown. Here we define the intracellular signaling events by which tissue plasminogen activator (tPA) promotes renal interstitial fibroblast proliferation. tPA promoted the proliferation of renal interstitial fibroblasts independent of its protease activity. The mitogenic effect of tPA required Tyr⁴⁵⁰⁷ phosphorylation of the cytoplasmic tail of its receptor LDL receptor–related protein 1. tPA triggered sequential proliferative signaling events involving Erk1/2, p90RSK, GSK3β phosphorylation, and cyclin D1 induction. Blockade of Erk1/2 activation or knockdown of p90RSK suppressed tPA-induced GSK3β phosphorylation, cyclin D1 expression, and fibroblast proliferation. In contrast, expression of constitutively active Mek1 mimicked tPA in inducing GSK3β phosphorylation and cyclin D1 expression. Ectopic overexpression of an uninhibitable GSK3β mutant eliminated tPA-induced cyclin D1 expression. In the murine obstruction model, tPA deficiency reduced renal GSK3β phosphorylation and induction of PCNA and FSP-1. These findings show that tPA induces Tyr⁴⁵⁰⁷ phosphorylation of LDL receptor–related protein 1, which in turn leads to the downstream phosphorylation of Erk1/2, p90RSK, and GSK3β, followed by the induction of cyclin D1 in murine interstitial fibroblasts. This study implicates tPA as a mitogen that promotes interstitial fibroblast proliferation, leading to expansion of these cells.The hallmark of chronic kidney disease is renal interstitial fibrosis, which is characterized by avid inflammation, proliferation of interstitial cells, extensive deposition of extracellular matrix components, and the eventual destruction of normal kidney structure.^1–3 In general, the extent of tubulointerstitial fibrosis largely predicts the prognosis of patients with chronic kidney disease.^1,2,4 Interstitial fibroblasts are considered to be the primary matrix-producing cells and principal mediators of renal fibrosis associated with progressive renal failure.^2,5,6 The size of the interstitial fibroblast population closely correlates with the extent of interstitial injuries.^6–8 In the fibrotic kidney, fibroblasts display an increased proliferative phenotype and expand in the interstitial region.^7,9,10 However, the underlying mechanisms and the regulation of the fate of these cells remain largely unknown.Recent studies demonstrate that tPA is actually a molecule with dual functions.^11–13 As a member of the serine protease family, tPA participates in the activation of various zymogens and certain growth factors and plays a pivotal role in the homeostasis of blood coagulation/fibrinolysis and matrix regulation.^14–17 As a cytokine, tPA executes multiple biological functions by binding to its membrane receptor, the LDL receptor–related protein-1 (LRP-1) and triggering profound intracellular signaling events.^11–14,18 In the unilateral ureteral obstruction (UUO) model, the expression of tPA and LRP-1 in the obstructed kidney are significantly increased compared with control kidney, suggesting that tPA signaling is up-regulated during kidney injury.^12,13 In addition, tPA-deficient mice are protected from obstruction induced fibrotic injury and demonstrate significantly fewer activated fibroblasts than wild-type mice.^12,19 Thus, we hypothesized that tPA may be an endogenous factor governing the fate of interstitial fibroblasts and controlling the size of these cells population.LRP-1 functions as a tPA receptor and mediates most of the cytokine actions of tPA.^11–14,20 Mature LRP-1 consists of an extracellular 515-kDa α subunit and an 85-kDa β subunit with a transmembrane segment and cytoplasmic tail. The cytoplasmic tail of the β subunit contains numerous tyrosine residues in the vicinity of two NPXY motifs.^20,21 Phosphorylation of the tyrosine residue(s) is believed to be required for the binding of signaling adaptor proteins that mediate the signal transduction of its ligands,^22,23 although the exact role of tyrosine phosphorylation in tPA signaling remains undefined.In the present study, we demonstrate that tPA acts as a mitogen to promote the proliferation of renal interstitial fibroblasts. The mitogenic effect of tPA is mediated by the phosphorylation of Tyr⁴⁵⁰⁷ within the distal NPXY motif of LRP-1, initiating a cascade of proliferative signaling events involving phosphorylation of Erk1/2, p90RSK, GSK3β, and induction of cyclin D1.     

Acute stress disorder, depression, and tobacco use in disaster workers following 9/11

Early posttraumatic psychiatric disorders have not been well studied in disaster workers. This study examined the rates of probable acute stress disorder (ASD), probable depression, increased tobacco use, and their associated risk factors in 9/11 World Trade Center disaster workers. Surveys were obtained from 90 disaster workers (e.g., medical personnel, police, firefighters, search and rescue) 2-3 weeks after 9/11. Nearly 15% of disaster workers had probable ASD and 26% had probable depression. Probable ASD and depression were highly related to functional impairment. The risk for ASD was increased for those with 9/11-specific disaster exposures, more pre-9/11 trauma exposures, and the peritraumatic dissociative symptom of altered sense of time. Disaster workers who were younger, non-White, or who had increasing numbers of peritraumatic dissociative symptoms were more likely to have probable depression. More than half of tobacco users increased their tobacco use after 9/11. Additionally, all tobacco users with probable ASD and almost all tobacco users with probable depression increased tobacco use. Rapid mobilization of resources for early screening and intervention and health promotion campaigns aimed at improving adverse health-related behaviors may be helpful for this high-risk group.     

Non-lateralised deficits in anti-saccade performance in patients with hemispatial neglect

We tested patients suffering from hemispatial neglect on the anti-saccade paradigm to assess voluntary control of saccades. In this task participants are required to saccade away from an abrupt onset target. As has been previously reported, in the pro-saccade condition neglect patients showed increased latencies towards targets presented on the left and their accuracy was reduced as a result of greater undershoot. To our surprise though, in the anti-saccade condition, we found strong bilateral effects: the neglect patients produced large numbers of erroneous pro-saccades to both left and right stimuli. This deficit in voluntary control was present even in patients whose lesions spared the frontal lobes. These results suggest that the voluntary control of action is supported by an integrated network of cortical regions, including more posterior areas. Damage to one or more components within this network may result in impaired voluntary control.