Chronic Fatigue Syndrome: US Federal Service

Marques A. · Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. · Infect Dis Clin North Am. · Pubmed #18452806 links to  free full text

Abstract: Studies have shown that most patients diagnosed with chronic Lyme disease either have no objective evidence of previous or current infection with Borrelia burgdorferi or are patients who should be classified as having post-Lyme disease syndrome, which is defined as continuing or relapsing nonspecific symptoms (such as fatigue, musculoskeletal pain, and cognitive complaints) in a patient previously treated for Lyme disease. Despite extensive study, there is currently no clear evidence that post-Lyme disease syndrome is caused by persistent infection with B burgdorferi. Four randomized placebo-controlled studies have shown that antibiotic therapy offers no sustained benefit to patients who have post-Lyme disease syndrome. These studies also showed a substantial placebo effect and a significant risk of treatment-related adverse events. Further research to elucidate the mechanisms underlying persistent symptoms after Lyme disease and controlled trials of new approaches to the treatment and management of these patients are needed.

Klimas NG, Koneru AO. · University of Miami Miller School of Medicine, 1201 NW 16th Street, VA Medical Center, 200 BMRC, 6th Floor, Miami, FL 33125, USA. · Curr Rheumatol Rep. · Pubmed #18177602 No free full text.

Abstract: Investigations into the underlying cause of chronic fatigue syndrome have advanced the field considerably in the past year. Gene microarray data have led to a better understanding of pathogenesis. Recent research has evaluated genetic signatures, described biologic subgroups, and suggested potential targeted treatments. Acute viral infection studies found that initial infection severity was the single best predictor of persistent fatigue. Genomic studies showed that persistent cases express Epstein Barr virus-specific genes and demonstrate abnormalities of mitochondrial function. Studies of immune dysfunction extended observations of natural killer cytotoxic cell dysfunction of the cytotoxic T cell through quantitative evaluation of intracellular perforins and granzymes. Other research has focused on a subgroup of patients with reactivated viral infection. These advances should result in targeted therapies that impact immune function, hypothalamic-pituitary-adrenal axis regulation, and persistent viral reactivation.

Agarwal R. · Division of Nephrology, Department of Medicine, Indiana University School of Medicine, and Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA. · Am J Nephrol. · Pubmed #17804903 No free full text.

Abstract: Iron deficiency anemia is common in people with chronic kidney disease (CKD) and its importance in supporting erythropoiesis is unquestioned especially in those patients treated with erythropoietin. Clinical symptomatology such as fatigability, cold intolerance, failure to concentrate and poor effort intolerance is often attributed to anemia or uremia. That iron deficiency, per se, can cause these symptoms is poorly recognized. Clinical and animal studies that support the benefits of iron supplementation, independent of increasing hemoglobin, such as those on immune function, physical performance, thermoregulation, cognition, and restless leg syndrome and aluminum absorption is the subject of this narrative review.

Chrousos GP, Kino T. · First Department of Pediatrics, Athens University Medical School, 11527 Athens, Greece. · Stress. · Pubmed #17514590 No free full text.

Abstract: Glucocorticoids contribute fundamentally to the maintenance of basal and stress-related homeostasis in all higher organisms. These hormones influence a large percentage of the expressed human genome and their effects spare almost no organs or tissues. Glucocorticoids influence many functions of the central nervous system, such as arousal, cognition, mood and sleep, the activity and direction of intermediary metabolism, the maintenance of a normal cardiovascular tone, the activity and quality of the immune and inflammatory reaction, including the manifestations of the sickness syndrome, as well as growth and reproduction. The numerous actions of glucocorticoids are mediated by a set of at least 16 glucocorticoid receptor (GR) isoforms forming homo- or hetero-dimers. The GRs consist of multifunctional domain proteins operating as ligand-dependent transcription factors that interact with many other cell signaling systems. The presence of multiple GR monomers and dimers expressed in a cell-specific fashion at different quantities with quantitatively and qualitatively different transcriptional activities suggests that the glucocorticoid signaling system is highly stochastic. Based on ample evidence, we present our conception that glucocorticoids are heavily involved in human pathophysiology and influence life expectancy. Common psychiatric and/or somatic complex disorders, such as anxiety, depression, insomnia, chronic pain and fatigue syndromes, obesity, the metabolic syndrome, essential hypertension, diabetes type 2, atherosclerosis with its cardiovascular sequelae, and osteoporosis, as well as autoimmune inflammatory and allergic disorders, all appear to have a glucocorticoid component.

Jones KD, Deodhar P, Lorentzen A, Bennett RM, Deodhar AA. · Division of Arthritis & Rheumatic Diseases, School of Medicine, Oregon Health & Science University School of Nursing, 3455 SW U.S. Veterans Hospital Road, Portland, OR 97239, USA. · Semin Arthritis Rheum. · Pubmed #17224178 No free full text.

Abstract: OBJECTIVE: Fibromyalgia (FM) is a syndrome characterized by chronic widespread pain, fatigue, disrupted sleep, depression, and physical deconditioning. In this article, we review the literature on the normal activity of the hypothalamic-pituitary-growth hormone-insulin-like growth factor-1 (HP-GH-IGF-1) axis and its perturbations in FM subjects. METHODS: Studies included in this review were accessed through an English language search of Cochrane Collaboration Reviews. Keyword MeSH terms included "fibromyalgia," "growth hormone" (GH), or "insulin-like growth factor-1" (IGF-1). RESULTS: Twenty-six studies enrolling 2006 subjects were reviewed. Overall, low levels of IGF-1 were found in a subgroup of subjects. Growth hormone stimulation tests often revealed a suboptimal response, which did not always correlate with IGF-1 levels. No consistent defects in pituitary function were found. Of the 3 randomized placebo controlled studies, only 9 months of daily injectable recombinant GH reduced FM symptoms and normalized IGF-1. CONCLUSIONS: These studies suggest that pituitary function is normal in FM and that reported changes in the HP-GH-IGF-1 axis are most likely hypothalamic in origin. The therapeutic efficacy of supplemental GH therapy in FM requires further study before any solid recommendations can be made.

Jackson JL, O'Malley PG, Kroenke K. · Department of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD 20814, USA. · CNS Spectr. · Pubmed #16575378 links to  free full text

Abstract: Somatic symptoms are common in primary care and clinicians often prescribe antidepressants as adjunctive therapy. There are many possible reasons why this may work, including treating comorbid depression or anxiety, inhibition of ascending pain pathways, inhibition of prefrontal cortical areas that are responsible for "attention" to noxious stimuli, and the direct effects of the medications on the syndrome. There are good theoretical reasons why antidepressants with balanced norepinephrine and serotonin effects may be more effective than those that act predominantly on one pathway, though head-to-head comparisons are lacking. For the 11 painful syndromes review in this article, cognitive-behavioral therapy is most consistently demonstrated to be effective, with various antidepressants having more or less randomized controlled data supporting or refuting effectiveness. This article reviews the randomized controlled trial data for the use of antidepressant and cognitive-behavior therapy for 11 somatic syndromes: irritable bowel syndrome, chronic back pain, headache, fibromyalgia, chronic fatigue syndrome, tinnitus, menopausal symptoms, chronic facial pain, noncardiac chest pain, interstitial cystitis, and chronic pelvic pain. For some syndromes, the data for or against treatment effectiveness is relatively robust, for many, however, the data, one way or the other is scanty.

Engel CC, Jaffer A, Adkins J, Riddle JR, Gibson R. · Department of Psychiatry, School of Medicine, Uniformed Services University, Bethesda, Md. 20814-4799, USA. · Adv Psychosom Med. · Pubmed #15248370 No free full text.

Abstract: In the 1991 Gulf War less than 150 of nearly 700,000 deployed US troops were killed in action. Today, however, over 1 in 7 US veterans of the war has sought federal healthcare for related-health concerns, and fully 17% of UK Gulf War veterans describe themselves as suffering from the 'Gulf War syndrome', a set of poorly defined and heterogeneous ailments consisting mainly of chronic pain, fatigue, depression and other symptoms. Even though over 250 million dollars of federally funded medical research has failed to identify a unique syndrome, the debate regarding potential causes continues and has included oil well smoke, contagious infections, exposure to chemical and biological warfare agents, and posttraumatic stress disorder. Historical analyses completed since the Gulf War have found that postwar syndromes consisting of chronic pain, fatigue, depression and other symptoms have occurred after every war in the 20th century. These syndromes have gone by a variety of names such as Da Costa's syndrome, irritable heart, shell shock, neurocirculatory asthenia, and battle fatigue. Though the direct causes of these syndromes are typically elusive, it is clear that war sets in motion an undeniable cycle of physical, emotional, and fiscal consequences for war veterans and for society. These findings lead to important healthcare questions. Is there a way to prevent or mitigate subsequent postwar symptoms and associated depression and disability? We argue that while idiopathic symptoms are certain to occur following any war, a population-based approach to postwar healthcare can mitigate the impact of postwar syndromes and foster societal, military, and veteran trust. This article delineates the model, describes its epidemiological foundations, and details examples of how it is being adopted and improved as part of the system of care for US military personnel, war veterans and families. A scientific test of the model's overall effectiveness is difficult, yet healthcare systems for combatants and their families are already being put to pragmatic tests as troops return from war in Iraq and Afghanistan and from other military challenges.

Goldstein DS, Robertson D, Esler M, Straus SE, Eisenhofer G. · Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 6N252, 10 Center Drive MSC-1620, Bethesda, MD 20892-1620, USA. · Ann Intern Med. · Pubmed #12416949 links to  free full text

Abstract: The term dysautonomia refers to a change in autonomic nervous system function that adversely affects health. The changes range from transient, occasional episodes of neurally mediated hypotension to progressive neurodegenerative diseases; from disorders in which altered autonomic function plays a primary pathophysiologic role to disorders in which it worsens an independent pathologic state; and from mechanistically straightforward to mysterious and controversial entities. In chronic autonomic failure (pure autonomic failure, multiple system atrophy, or autonomic failure in Parkinson disease), orthostatic hypotension reflects sympathetic neurocirculatory failure from sympathetic denervation or deranged reflexive regulation of sympathetic outflows. Chronic orthostatic intolerance associated with postural tachycardia can arise from cardiac sympathetic activation after "patchy" autonomic impairment or blood volume depletion or, as highlighted in this discussion, from a primary abnormality that augments delivery of the sympathetic neurotransmitter norepinephrine to its receptors in the heart. Increased sympathetic nerve traffic to the heart and kidneys seems to occur as essential hypertension develops. Acute panic can evoke coronary spasm that is associated with sympathoneural and adrenomedullary excitation. In congestive heart failure, compensatory cardiac sympathetic activation may chronically worsen myocardial function, which rationalizes treatment with beta-adrenoceptor blockers. A high frequency of positive results on tilt-table testing has confirmed an association between the chronic fatigue syndrome and orthostatic intolerance; however, treatment with the salt-retaining steroid fludrocortisone, which is usually beneficial in primary chronic autonomic failure, does not seem to be beneficial in the chronic fatigue syndrome. Dysautonomias are an important subject in clinical neurocardiology.

Engel CC, Adkins JA, Cowan DN. · Deployment Health Clinical Center, Walter Reed Army Medical Center, Washington, DC, USA. · Environ Health Perspect. · Pubmed #12194900 links to  free full text

Abstract: Medically unexplained physical symptoms (MUPS) are persistent idiopathic symptoms that drive patients to seek medical care. MUPS syndromes include chronic fatigue syndrome, fibromyalgia syndrome, and multiple chemical sensitivities. When MUPS occur after an environmental exposure or injury, an adversarial social context that we call "contested causation" may ensue. Contested causation may occur publicly and involve media controversy, scientific disagreement, political debate, and legal struggles. This adversarial social context may diminish the effectiveness of the provider-patient relationship. Contested causation also may occur privately, when disagreement over the causes of MUPS takes place in the patient-provider context. These patient-provider disagreements over causation often occur because of the enigmatic nature of MUPS. We suggest that a context of contested causation may have serious negative effects on healthcare for individuals with MUPS. Context plays a larger role in MUPS care than it does for most medical care because of the uncertain nature of MUPS, the reliance of standard MUPS therapies on a potentially tenuous patient-provider partnership, and the clinical need to rely routinely on subjective MUPS assessments that often yield discordant patient and provider conclusions. Contested causation may erode patient-provider trust, test the provider's self-assurance and capacity to share power with the patient, and raise problematic issues of compensation, reparation, and blame. These issues may distract patients and providers from therapeutic goals. In occupational and military settings, the adverse impact of contested causation on the patient-provider partnership may diminish therapeutic effectiveness to a greater degree than it does in other medical settings. Contested causation therefore raises questions regarding generalizability of standard therapies for MUPS and related syndromes to these settings. Future research is needed to learn whether intuitively sensible and evidence-based MUPS therapies benefit occupational and military medical patients who are afforded care in the context of contested causation.

Kerns RD, Kassirer M, Otis J. · VA Connecticut Healthcare System and Yale University, West Haven, CT 06516, USA. · J Rehabil Res Dev. · Pubmed #12051466 No free full text.

Abstract: Clinically significant pain has been found in as many as 65% of persons diagnosed with multiple sclerosis (MS). Acute pain conditions include trigeminal neuralgia, painful optic neuritis, and Lhermitte's syndrome. Chronic pain conditions such as dysesthesias in the limbs, joint pain, and other musculoskeletal or mechanical pain problems develop as a function of spasticity and deconditioning associated with MS. These painful conditions may respond to pharmacological, surgical, rehabilitation, and psychological interventions. However, unresolved pain, associated disability, and affective distress are common. In addition, efforts to manage MS and its associated symptoms, for example, may inadvertently cause osteoporosis and headache or other symptoms that may exacerbate pain and pain-related disability. Conversely, efforts to manage pain may have negative effects on the symptoms of MS (e.g., increased fatigue). A multidimensional approach to assessment and management that is guided by a comprehensive biopsychosocial model is recommended. Such an approach needs to consider the exacerbating nature of MS, MS-related pain, and interventions aimed at their management. Suggestions for future research on MS-related pain conclude the article.

Barkhuizen A. · Department of Medicine (L329A), Oregon Health Sciences University and Portland VA Medical Center, 3181 SW Sam Jackson Park Road, Portland, OR 97201, USA. · Curr Pain Headache Rep. · Pubmed #11403739 No free full text.

Abstract: Fibromyalgia is a chronic syndrome characterized by widespread pain, unrefreshed sleep, disturbed mood, and fatigue. Until such time as we have a clearer understanding of the trigger and/or pathophysiologic mechanisms producing these symptoms, pharmacologic treatment should be aimed at individual symptoms. Such treatment should ideally be offered as part of a multidisciplinary treatment program using both pharmacologic and nonpharmacologic treatment modalities. Critical components of any successful fibromyalgia treatment program include addressing physical fitness, work and other functional activities, and mental health, in addition to symptom-specific therapies. The main symptoms that should be addressed include pain, sleep disturbances including restless leg syndrome, mood disturbances, and fatigue. Pharmacologic therapy should also be considered for syndromes commonly associated with fibromyalgia including irritable bowel syndrome, interstitial cystitis, migraine headaches, temporomandibular joint dysfunction, dysequilibrium including neurally mediated hypotension, sicca syndrome, and growth hormone deficiency. This article provides general guidelines in initiating a successful pharmacologic treatment program for fibromyalgia.

Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. · Inflammatory Joint Diseases Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA. · Pharmacol Rev. · Pubmed #11121511 links to  free full text

Abstract: The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.

Greenlee JE, Rose JW. · Neurology Service, Veterans Affairs Medical Center and Department of Neurology, University of Utah Health Science Center, Salt Lake City 84148-001, USA. · Semin Neurol. · Pubmed #11051301 No free full text.

Abstract: The past several years have seen major advances in our understanding of neurological infectious diseases, their diagnosis, and their treatment. Along with these advances, however, new information about infectious agents and new therapeutic options have also introduced both uncertainty and controversy in the approach and management of patients with diseases of the central nervous system. Here, we discuss six such areas: the long-term efficacy of HAART therapy in treatment of HIV infection; the role of viral infection in chronic fatigue syndrome; Rasmussen's encephalitis as an infectious or autoimmune disease; the spectrum of neurological diseases caused by rickettsial infection; the role of Mycoplasma pneumoniae in human central nervous system disease; and the possible association of Chlamydia pneumoniae and human herpesvirus 6 with multiple sclerosis.

Friedlander AH, Walker LA, Friedlander IK, Felsenfeld AL. · Veterans Affairs Outpatient Clinic and Nursing Home, Sepulveda, Calif., USA. · J Am Dent Assoc. · Pubmed #10953534 links to  free full text

Abstract: BACKGROUND: Obstructive sleep apnea syndrome, or OSAS, is a common, but underdiagnosed, disorder that potentially is fatal. It is characterized by repetitive episodes of complete or partial upper airway obstruction leading to absent or diminished airflow into the lungs. These episodes usually last 10 to 30 seconds and result in loud snoring, a decrease in oxygen saturation, and chronic daytime sleepiness and fatigue. The obstruction is caused by the soft palate, base of the tongue or both collapsing against the pharyngeal walls because of decreased muscle tone during sleep. Potentially fatal systemic illnesses frequently associated with this disorder include hypertension, pulmonary hypertension, heart failure, nocturnal cardiac dysrhythmias, myocardial infarction and ischemic stroke. CLINICAL IMPLICATIONS: The classic signs and symptoms of OSAS may be recognizable by dental practitioners. Common findings in the medical history include daytime sleepiness, snoring, hypertension and type 2 diabetes mellitus. Common clinical findings include obesity; a thick neck; excessive fat deposition in the palate, tongue (enlarged) and pharynx; a long soft palate; a retrognathic mandible; and calcified carotid artery atheromas on panoramic and lateral cephalometric radiographs. CONCLUSIONS: Dentists cognizant of these signs and symptoms have an opportunity to diagnose patients with occult OSAS. After confirmation of the diagnosis by a physician, dentists can participate in management of the disorder by fabricating mandibular advancement appliances and performing surgical procedures that prevent recurrent airway obstruction.

O'Malley PG, Jackson JL, Santoro J, Tomkins G, Balden E, Kroenke K. · Department of Medicine, Walter Reed Army Medical Center, Washington, DC, USA. · J Fam Pract. · Pubmed #10628579 No free full text.

Abstract: OBJECTIVE: To determine the efficacy of antidepressant therapy for unexplained symptoms or symptom syndromes. SEARCH STRATEGIES: We identified original studies through searching MEDLINE, EMBASE, PsycLIT, the Federal Research in Progress database, and The Cochrane Library. We also searched the bibliographies of primary and review articles for additional studies. SELECTION CRITERIA: We excluded trials of patients with neuropathic, oncologic, or degenerative joint pain. Independent duplicate review of 392 articles identified 94 relevant reports of randomized trials involving 6595 patients across 6 symptom syndromes. Independent duplicate assessment was made for inclusion and data abstraction. Meta-analysis was performed on extractable placebo-controlled data. MAIN RESULTS: Of 94 included trials, most studied either tricyclic antidepressants, antiserotonin antidepressants, selective serotonin reuptake inhibitors (SSRIs), or multiple agents for the treatment of the following syndromes: headache (50), fibromyalgia (18), functional gastrointestinal syndromes (13), idiopathic pain (11), tinnitus (2), and chronic fatigue (2). The quality of the studies was fair (mean score = 4.8 on a scale of 0 to 8). A majority of the studies (69%) demonstrated benefit for at least one outcome measure. Symptom improvement typically did not correlate with depression response in the few studies where it was assessed. Meta-analysis of all extractable data showed a substantial benefit from antidepressants: For the dichotomous outcome of improvement, the odds ratio was 3.4 (95% confidence interval [CI], 2.6 - 4.5), and for continuous outcomes, the standardized mean difference was 0.87 (95% CI, 0.59-1.14). The absolute percentage difference in improvement between the antidepressant and placebo arms was 32%, yielding a number needed to treat of 3 to improve one person's symptoms. Meta-regression indicated no differential effect across the classes of antidepressants; however, onbivariate tally tricyclic studies were associated with a greater likelihood of efficacy than SSRI studies (P = .02). CONCLUSIONS: Antidepressants can be effective for various physical symptoms and symptom syndromes. The relation of outcome to depression and the efficacy of SSRIs needs further study.

Kreitman RJ, Squires DR, Stetler-Stevenson M, Noel P, FitzGerald DJ, Wilson WH, Pastan I. · Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bldg 5124b, 9000 Rockville Pike, Bethesda, MD 20892, USA. · J Clin Oncol. · Pubmed #16061911 No free full text.

Abstract: PURPOSE: To conduct a phase I trial of recombinant immunotoxin BL22, an anti-CD22 Fv fragment fused to truncated Pseudomonas exotoxin. PATIENTS AND METHODS: Forty-six pretreated patients with CD22+ non-Hodgkin's lymphoma (NHL; n = 4), chronic lymphocytic leukemia (CLL; n = 11), and hairy cell leukemia (HCL; n = 31) received 265 cycles at 3 to 50 microg/Kg every other day x 3 doses. RESULTS: BL22 was active in HCL, with 19 complete remissions (CRs; 61%) and six partial responses (PRs; 19%) in 31 patients. Of 19 CRs, 11 were achieved after one cycle and eight after two to 14 cycles. All 25 responders benefited clinically with one cycle. The CR rate was 86% in patients enrolled at > or = 40 microg/Kg every other day x 3, and 41% at lower doses (P = .011). The median duration for CR was 36 months (range, 5 to 66 months), and eight patients remain in CR at 45 months (range, 29 to 66 months). Lower but significant activity occurred in CLL. Neutralizing antibodies occurred in 11 (24%) of 46 patients (all HCL). A reversible hemolytic uremic syndrome requiring plasmapheresis was observed in one patient with NHL during cycle 1 and in four patients with HCL during cycle 2 or 3. The maximum-tolerated dose (MTD) evaluated at cycle 1 was 40 microg/Kg IV. QOD x 3. The most common toxicities at 30 to 50 microg/Kg every other day x 3 included hypoalbuminemia, transaminase elevations, fatigue, and edema. CONCLUSION: BL22 was well tolerated and highly effective in HCL, even after one cycle. Phase II testing is underway to define the efficacy with one cycle and to study safety when additional cycles are needed for optimal response.

Donta ST, Engel CC, Collins JF, Baseman JB, Dever LL, Taylor T, Boardman KD, Kazis LE, Martin SE, Horney RA, Wiseman AL, Kernodle DS, Smith RP, Baltch AL, Handanos C, Catto B, Montalvo L, Everson M, Blackburn W, Thakore M, Brown ST, Lutwick L, Norwood D, Bernstein J, Bacheller C, Ribner B, Church LW, Wilson KH, Guduru P, Cooper R, Lentino J, Hamill RJ, Gorin AB, Gordan V, Wagner D, Robinson C, DeJace P, Greenfield R, Beck L, Bittner M, Schumacher HR, Silverblatt F, Schmitt J, Wong E, Ryan MA, Figueroa J, Nice C, Feussner JR, Anonymous00161. · Veterans Affairs Medical Center, Boston, MA 02130, USA · Ann Intern Med. · Pubmed #15262663 links to  free full text

Abstract: BACKGROUND: It has been hypothesized that certain Mycoplasma species may cause Gulf War veterans' illnesses (GWVIs), chronic diseases characterized by pain, fatigue, and cognitive symptoms, and that affected patients may benefit from doxycycline treatment. OBJECTIVE: To determine whether a 12-month course of doxycycline improves functional status in Gulf War veterans with GWVIs. DESIGN: A randomized, double-blind, placebo-controlled clinical trial with 12 months of treatment and 6 additional months of follow-up. SETTING: 26 U.S. Department of Veterans Affairs and 2 U.S. Department of Defense medical centers. PARTICIPANTS: 491 deployed Gulf War veterans with GWVIs and detectable Mycoplasma DNA in the blood. INTERVENTION: Doxycycline, 200 mg, or matching placebo daily for 12 months. MEASUREMENTS: The primary outcome was the proportion of participants who improved more than 7 units on the Physical Component Summary score of the Veterans Short Form-36 General Health Survey 12 months after randomization. Secondary outcomes were measures of pain, fatigue, and cognitive function and change in positivity for Mycoplasma species at 6, 12, and 18 months after randomization. RESULTS: No statistically significant differences were found between the doxycycline and placebo groups for the primary outcome measure (43 of 238 participants [18.1%] vs. 42 of 243 participants [17.3%]; difference, 0.8 percentage point [95% CI, -6.5 to 8.0 percentage points]; P > 0.2) or for secondary outcome measures at 1 year. In addition, possible differences in outcomes at 3 and 6 months were not apparent at 9 or 18 months. Participants in the doxycycline group had a higher incidence of nausea and photosensitivity. LIMITATIONS: Adherence to treatment after 6 months was poor. CONCLUSION: Long-term treatment with doxycycline did not improve outcomes of GWVIs at 1 year.

Donta ST, Clauw DJ, Engel CC, Guarino P, Peduzzi P, Williams DA, Skinner JS, Barkhuizen A, Taylor T, Kazis LE, Sogg S, Hunt SC, Dougherty CM, Richardson RD, Kunkel C, Rodriguez W, Alicea E, Chiliade P, Ryan M, Gray GC, Lutwick L, Norwood D, Smith S, Everson M, Blackburn W, Martin W, Griffiss JM, Cooper R, Renner E, Schmitt J, McMurtry C, Thakore M, Mori D, Kerns R, Park M, Pullman-Mooar S, Bernstein J, Hershberger P, Salisbury DC, Feussner JR, Anonymous00179. · VA Medical Center, Boston, Mass, USA. · JAMA. · Pubmed #12636462 links to  free full text

Abstract: CONTEXT: Gulf War veterans' illnesses (GWVI), multisymptom illnesses characterized by persistent pain, fatigue, and cognitive symptoms, have been reported by many Gulf War veterans. There are currently no effective therapies available to treat GWVI. OBJECTIVE: To compare the effectiveness of cognitive behavioral therapy (CBT), exercise, and the combination of both for improving physical functioning and reducing the symptoms of GWVI. DESIGN, SETTING, AND PATIENTS: Randomized controlled 2 x 2 factorial trial conducted from April 1999 to September 2001 among 1092 Gulf War veterans who reported at least 2 of 3 symptom types (fatigue, pain, and cognitive) for more than 6 months and at the time of screening. Treatment assignment was unmasked except for a masked assessor of study outcomes at each clinical site (18 Department of Veterans Affairs [VA] and 2 Department of Defense [DOD] medical centers). INTERVENTIONS: Veterans were randomly assigned to receive usual care (n = 271), consisting of any and all care received from inside or outside the VA or DOD health care systems; CBT plus usual care (n = 286); exercise plus usual care (n = 269); or CBT plus exercise plus usual care (n = 266). Exercise sessions were 60 minutes and CBT sessions were 60 to 90 minutes; both met weekly for 12 weeks. MAIN OUTCOME MEASURES: The primary end point was a 7-point or greater increase (improvement) on the Physical Component Summary scale of the Veterans Short Form 36-Item Health Survey at 12 months. Secondary outcomes were standardized measures of pain, fatigue, cognitive symptoms, distress, and mental health functioning. Participants were evaluated at baseline and at 3, 6, and 12 months. RESULTS: The percentage of veterans with improvement in physical function at 1 year was 11.5% for usual care, 11.7% for exercise alone, 18.4% for CBT plus exercise, and 18.5% for CBT alone. The adjusted odds ratios (OR) for improvement in exercise, CBT, and exercise plus CBT vs usual care were 1.07 (95% confidence interval [CI], 0.63-1.82), 1.72 (95% CI, 0.91-3.23), and 1.84 (95% CI, 0.95-3.55), respectively. The OR for the overall (marginal) effect of receiving CBT (n = 552) vs no CBT (n = 535) was 1.71 (95% CI, 1.15-2.53) and for exercise (n = 531) vs no exercise (n = 556) was 1.07 (95% CI, 0.76-1.50). For secondary outcomes, exercise alone or in combination with CBT significantly improved fatigue, distress, cognitive symptoms, and mental health functioning, while CBT alone significantly improved cognitive symptoms and mental health functioning. Neither treatment had a significant impact on pain. CONCLUSION: Our results suggest that CBT and/or exercise can provide modest relief for some of the symptoms of chronic multisymptom illnesses such as GWVI.

McKenzie R, Reynolds JC, O'Fallon A, Dale J, Deloria M, Blackwelder W, Straus SE. · Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, Maryland , USA. · J Rheumatol. · Pubmed #10990237 No free full text.

Abstract: OBJECTIVE: While osteoporosis and bone fractures are clearly recognized side effects of high dose glucocorticoids, the effect of low dose glucocorticoids remains controversial. We investigated the effect of 3 months of low dose hydrocortisone on bone mineral density (BMD). METHODS: Subjects, 18 to 55 years old with chronic fatigue syndrome and no medical or psychiatric illness requiring medication, were randomized in a double blind, placebo controlled trial to receive oral hydrocortisone, 13 mg/m2 body surface area every morning and 3 mg/m2 every afternoon (25 to 35 mg/day, equivalent to about 7.5 mg prednisone/day) or placebo for 12 weeks. Before and after treatment BMD of the lumbar spine was measured by dual energy x-ray absorptiometry. RESULTS: We studied 23 subjects (19 women, 4 men). For the 11 hydrocortisone recipients there was a mean decrease in BMD: mean change from baseline of the lateral spine was -2.0% (95% CI -3.5 to -0.6. p = 0.03) and mean change of the anteroposterior spine was -0.8% (95% CI -1.5 to -0.1, p = 0.06). Corresponding changes for the 12 placebo recipients were +1.0% (95% CI -1.0 to 3.0, p = 0.34) and +0.2% (95% CI -1.4 to 1.5, p = 0.76). CONCLUSION: A 12 week course of low dose glucocorticoids given to ambulatory subjects with chronic fatigue syndrome was associated with a decrease in BMD of the lumbar spine. This decrease was statistically significant in lateral spine measurements and nearly so in anteroposterior spine measurements.

Kang HK, Li B, Mahan CM, Eisen SA, Engel CC. · Department of Veterans Affairs, Environmental Epidemiology Service, Washington DC 20420, USA. · J Occup Environ Med. · Pubmed #19322107 No free full text.

Abstract: OBJECTIVE: To assess periodically the health status of a cohort of 1991 Gulf War veterans by comparing various health outcomes with those of their military peers who were not deployed to the Gulf. METHODS: We conducted a follow-up health survey to collect health information among population-based samples of 30,000 veterans (15,000 Gulf War veterans and 15,000 Gulf Era veterans) using a structured questionnaire. RESULTS: Gulf veterans reported significantly higher rates of unexplained multi-symptom illness, chronic fatigue syndrome-like illness, posttraumatic stress disorder, functional impairment, health care utilization, a majority of selected physical conditions and all mental disorders queried during the survey than did Gulf Era veteran controls. CONCLUSIONS: Fourteen years after deployment, 1991 Gulf War veterans continue to report a higher prevalence of many adverse health outcomes, compared with Gulf Era veterans.

Anthenelli RM, Blom TJ, McElroy SL, Keck PE. · Tri-State Tobacco and Alcohol Research Center, Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA. · Addiction. · Pubmed #18339115 No free full text.

Abstract: AIMS: Study aims were threefold: (i) to determine the feasibility, potential efficacy and safety of topiramate as an aid to smoking cessation; (ii) to examine potential predictors of abstinence including gender; and (iii) to explore topiramate's effects on tobacco withdrawal and post-cessation weight gain. DESIGN: Randomized, double-blind, placebo-controlled, 11-week clinical trial with a 6-week dosage titration period and 5 weeks of maintenance treatment. SETTING: Single-site, out-patient, randomized clinical trial. PARTICIPANTS: Thirty-eight adult male and 49 female chronic smokers who smoked an average of > 10 cigarettes per day and who were motivated to try to quit smoking. INTERVENTION: Random assignment to receive either topiramate (n = 43) up to 200 mg daily in divided doses or placebo (n = 44) orally combined with brief counseling over an 11-week period. MEASUREMENTS: Carbon monoxide (CO)-confirmed 4-week prolonged abstinence rate during weeks 8-11. Changes in tobacco withdrawal, body weight and safety parameters were also assessed. FINDINGS: Overall, no significant increase in the prolonged abstinence rate was detected, but logistic regression analysis indicated significant gender-specific differences. Men treated with topiramate were nearly 16 times more likely to quit smoking than women on topiramate [37.5% versus 3.7%; odds ratio (OR) = 15.6; P = 0.016] and were roughly four times more likely to quit smoking than placebo-treated men (37.5% versus 13.6%; OR = 3.8; P = 0.098). Topiramate-treated men reported significantly lower tobacco withdrawal scores than both women taking topiramate and men on placebo. On average, male cessators on placebo gained 3.30 kg, whereas topiramate led to a 0.72 kg weight loss (P = 0.03). Study discontinuation rates due to adverse events (AEs) were significantly higher in the topiramate group (topiramate 23% versus placebo 2%). The most commonly reported AEs in the topiramate arm were paraesthesia, fatigue, difficulty with concentration/attention and nervousness. CONCLUSIONS: Topiramate produced gender-specific effects on smoking cessation. Male smokers had markedly greater quit rates than female smokers and men were roughly four times more likely to quit smoking when treated with topiramate as compared to placebo. Topiramate was fairly well tolerated, although higher discontinuation rates were seen. Topiramate's triple effects aiding smoking abstinence, attenuating nicotine withdrawal and preventing post-cessation weight gain might make it a promising agent for treating tobacco addiction, at least in men.

Cook DB, O'Connor PJ, Lange G, Steffener J. · Department of Veterans Affairs-William S. Middleton Memorial Veterans Hospital, Madison, WI 53706, USA. · Neuroimage. · Pubmed #17408973 No free full text.

Abstract: The neural mechanisms underlying feelings of fatigue are poorly understood. The primary purpose of the study was to use functional magnetic resonance imaging (fMRI) to determine the association between feelings of mental fatigue and blood oxygen level dependent (BOLD) brain responses during a mentally fatiguing cognitive task. Healthy, non-fatigued controls and chronic fatigue syndrome (CFS) patients were included to determine the influence of chronic levels of fatigue on brain responses. We hypothesized that mental fatigue would be significantly related to brain activity during a fatiguing cognitive task but not during either a non-fatiguing motor (finger tapping) or cognitive (auditory monitoring) task. Patients (n=9) and controls (n=11) completed a finger tapping task, a simple auditory monitoring task and a challenging working memory task, designed to induce mental fatigue, while undergoing fMRI. Fatigue was measured prior to scanning and following each task during fMRI data collection. Results showed that mental fatigue was significantly related to brain activity during the fatiguing cognitive task but not the finger tapping or simple auditory monitoring tasks. Significant (p< or =0.005) positive relationships were found for cerebellar, temporal, cingulate and frontal regions. A significant (p=0.001) negative relationship was found for the left posterior parietal cortex. CFS participants did not differ from controls for either finger tapping or auditory monitoring tasks, but exhibited significantly greater activity in several cortical and subcortical regions during the fatiguing cognitive task. Our results suggest an association between subjective feelings of mental fatigue and brain responses during fatiguing cognition.

Hawk C, Jason LA, Torres-Harding S. · Hines VA Hospital, Hines, Illinois, USA. · Int J Behav Med. · Pubmed #17078775 No free full text.

Abstract: The goal of this study was to identify variables that successfully differentiated patients with chronic fatigue syndrome, major depressive disorder, and controls. Fifteen participants were recruited for each of these three groups, and discriminant function analyses were conducted. Using symptom occurrence and severity data from the Fukuda et al. (1994) definitional criteria, the best predictors were postexertional malaise, unrefreshing sleep, and impaired memory-concentration. Symptom occurrence variables only correctly classified 84.4% of cases, whereas 91.1% were correctly classified when using symptom severity ratings. Finally, when using percentage of time fatigue reported, postexertional malaise severity, unrefreshing sleep severity, confusion-disorientation severity, shortness of breath severity, and self-reproach to predict group membership, 100% were classified correctly.

Lincoln AE, Helmer DA, Schneiderman AI, Li M, Copeland HL, Prisco MK, Wallin MT, Kang HK, Natelson BH. · War-Related Illness and Injury Study Center, Washington DC Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA. · Mil Med. · Pubmed #16895119 No free full text.

Abstract: Combat veterans often return from deployment having experienced a wide range of exposures, symptoms, and medical conditions. The Department of Veterans Affairs established war-related illness and injury study centers to serve combat veterans with unexplained illnesses. We report the exposures, clinical status, and utilization of 53 combat veterans who participated in the National Referral Program (NRP) from January 2002 until March 2004. Participants were primarily male (81%) and served in the Persian Gulf War (79%). Common diagnoses were chronic fatigue syndrome (n = 23, 43%), neurotic depression (n = 21, 40%), and post-traumatic stress disorder (n = 20, 38%). Self-reported exposures related to weaponry, disease prophylaxis, environmental hazards, stress, and poor hygiene. A small increase in mean SF-36V mental component scores (2.8 points, p = 0.009) and use of rehabilitation therapies (1.6 additional visits, p = 0.018) followed the NRP referral. The small gain in mental function suggests that the NRP may benefit combat veterans with long and complex medical histories.

Hunsaker DH, Riffenburgh RH. · Department of Otolaryngology, Naval Medical Center San Diego, San Diego, California 92109, USA. · Otolaryngol Head Neck Surg. · Pubmed #16647530 No free full text.

Abstract: OBJECTIVE: To analyze the impact of snoring, independent of obstructive sleep apnea syndrome on patients referred for home sleep studies and to report a new technology for the reporting of snoring, using sophisticated sound collection and noise-canceling technology. STUDY DESIGN AND SETTING: A retrospective statistical review of consecutive anonymous data compiled from questionnaires and digital data of snoring loudness and duration measured at the upper lip during unattended home sleep studies in 4,860 patients referred for snoring and sleep-disturbed breathing. RESULTS: A strong relationship exists between a history of snoring and complaints of daytime sleepiness (80%), obesity (73%), and chronic fatigue (78%) (all yield P<0.001). By contrast, only 42% to 48% of patients without these symptoms complain of snoring. In 3 multiple-regression analyses, the percent of time snoring, average loudness, and peak loudness are all significantly predicted by the apnea hypopnea index (all P<0.003), body mass index (all P<0.001), and age (P=0.014). Daytime sleepiness was strongly predicted by percent time snoring (P=0.014), weakly by average loudness (P=0.046), and not at all by peak loudness (P=0.303). CONCLUSION: By using a pair of microphones placed at the upper lip, one that samples breath sounds and the other ambient sound and artifact noise, the NovaSOM QSG measures snoring while canceling ambient noise. The clinical impact of snoring on the patient as well as the bed partner, independent of obstructive sleep apnea syndrome, is an unrecognized factor in sleep-disturbed breathing. SIGNIFICANCE: Measurable criteria to define snoring are suggested. Snoring loudness is not measured in most laboratory Polysomnograms. EBM rating: B-3b.