Chronic Fatigue Syndrome: Maryland

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.

Auwaerter PG. · Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Clin Infect Dis. · Pubmed #17578771 No free full text.

Abstract: It is not well understood why some patients develop a subjective syndrome that includes considerable fatigue, musculoskeletal aches, and neurocognitive dysfunction after receiving standard antibiotic courses for the treatment of Lyme disease. Some practitioners use the term "chronic Lyme disease" and order prolonged courses of oral and parenteral antibiotics, believing that persistent infection with Borrelia burgdorferi is responsible. However, well-performed prospective studies have found neither evidence of chronic infection nor a benefit worthy of long-term antibiotic therapy for these patients. Such extended antibiotic therapy poses hazards and cannot be viewed as acceptable. The term "chronic Lyme disease" should be discarded as misleading; rather, the term "post-Lyme disease syndrome" better reflects the postinfectious nature of this condition. Further research is necessary to understand possible mechanisms of these chronic symptoms following Lyme disease as well as to find effective therapies.

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.

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.

Geier MR, Geier DA. · The Genetic Centers of America, MedCon, Inc., Silver Spring, Maryland 20905, USA. · Clin Exp Rheumatol. · Pubmed #15638050 No free full text.

Abstract: OBJECTIVES: Adverse events and positive re-challenge of symptoms reported in the scientific literature and to the Vaccine Adverse Event Reporting System (VAERS) following hepatitis B vaccination (HBV) were examined. METHODS: The VAERS and PubMed (1966-2003) were searched for autoimmune conditions including arthritis, rheumatoid arthritis, myelitis, optic neuritis, multiple sclerosis (MS), Guillain Barré Syndrome (GBS), glomerulonephritis, pancytopenia/thrombocytopenia, fatigue, and chronic fatigue, and Systemic Lupus Erythematous (SLE) following HBV. RESULTS: HBV was associated with a number of serious conditions and positive re-challenge or significant exacerbation of symptoms following immunization. There were 415 arthritis, 166 rheumatoid arthritis, 130 myelitis, 4 SLE, 100 optic neuritis, 101 GBS, 29 glomerulonephritis, 283 pancytopenia/thrombocytopenia, and 183 MS events reportedfollowing HBV A total of 465 positive re-challenge adverse events were observed following adult HBV that occurred sooner and with more severity than initial adverse event reports. A case-report of arthritis occurring in identical twins was also identified. CONCLUSIONS: Evidence from biological plausibility, case-reports, case-series, epidemiological, and now for positive re-challenge and exacerbation of symptoms, and events in identical twins was presented. One would have to consider that there is causal relationship between HBV and serious autoimmune disorders among certain susceptible vaccine recipients in a defined temporal period following immunization. In immunizing adults, the patient, with the help of their physician, should make an informed consent decision as to whether to be immunized or not, weighing the small risks of the adverse effects of HBV with the risk of exposure to deadly hepatitis B virus.

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.

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.

Shoemaker RC, House DE. · Chronic Fatigue Center, 500 Market Street, Suite 103, Pocomoke City, MD 21851, USA. <> · Neurotoxicol Teratol. · Pubmed #17010568 No free full text.

Abstract: Occupants of water-damaged buildings (WDBs) with evidence of microbial amplification often describe a syndrome involving multiple organ systems, commonly referred to as "sick building syndrome" (SBS), following chronic exposure to the indoor air. Studies have demonstrated that the indoor air of WDBs often contains a complex mixture of fungi, mycotoxins, bacteria, endotoxins, antigens, lipopolysaccharides, and biologically produced volatile compounds. A case-series study with medical assessments at five time points was conducted to characterize the syndrome after a double-blinded, placebo-controlled clinical trial conducted among a group of study participants investigated the efficacy of cholestyramine (CSM) therapy. The general hypothesis of the time series study was that chronic exposure to the indoor air of WDBs is associated with SBS. Consecutive clinical patients were screened for diagnosis of SBS using criteria of exposure potential, symptoms involving at least five organ systems, and the absence of confounding factors. Twenty-eight cases signed voluntary consent forms for participation in the time-series study and provided samples of microbial contaminants from water-damaged areas in the buildings they occupied. Twenty-six participants with a group-mean duration of illness of 11 months completed examinations at all five study time points. Thirteen of those participants also agreed to complete a double-blinded, placebo-controlled clinical trial. Data from Time Point 1 indicated a group-mean of 23 out of 37 symptoms evaluated; and visual contrast sensitivity (VCS), an indicator of neurological function, was abnormally low in all participants. Measurements of matrix metalloproteinase 9 (MMP9), leptin, alpha melanocyte stimulating hormone (MSH), vascular endothelial growth factor (VEGF), immunoglobulin E (IgE), and pulmonary function were abnormal in 22, 13, 25, 14, 1, and 7 participants, respectively. Following 2 weeks of CSM therapy to enhance toxin elimination rates, measurements at Time Point 2 indicated group-means of 4 symptoms with 65% improvement in VCS at mid-spatial frequency-both statistically significant improvements relative to Time Point 1. Moderate improvements were seen in MMP9, leptin, and VEGF serum levels. The improvements in health status were maintained at Time Point 3 following a 2-week period during which CSM therapy was suspended and the participants avoid re-exposure to the WDBs. Participants reoccupied the respective WDBs for 3 days without CSM therapy, and all participants reported relapse at Time Point 4. The group-mean number of symptoms increased from 4 at Time Point 2 to 15 and VCS at mid-spatial frequency declined by 42%, both statistically significant differences relative to Time Point 2. Statistically significant differences in the group-mean levels of MMP9 and leptin relative to Time Point 2 were also observed. CSM therapy was reinstated for 2 weeks prior to assessments at Time Point 5. Measurements at Time Point 5 indicated group-means of 3 symptoms and a 69% increase in VCS, both results statistically different from those at Time Points 1 and 4. Optically corrected Snellen Distance Equivalent visual acuity scores did not vary significantly over the course of the study. Group-mean levels of MMP9 and leptin showed statistically significant improvement at Time Point 5 relative to Time Points 1 and 4, and the proportion of participants with abnormal VEGF levels was significantly lower at Time Point 5 than at Time Point 1. The number of participants at Time Point 5 with abnormal levels of MMP9, leptin, VEGF, and pulmonary function were 10, 10, 9, and 7, respectively. The level of IgE was not re-measured because of the low incidence of abnormality at Time Point 1, and MSH was not re-measured because previously published data indicated a long time course for MSH improvement. The results from the time series study supported the general study hypothesis that exposure to the indoor air of WDBs is associated with SBS. High levels of MMP9 indicated that exposure to the complex mixture of substances in the indoor air of the WDBs triggered a pro-inflammatory cytokine response. A model describing modes of action along a pathway leading to biotoxin-associated illness is presented to organize current knowledge into testable hypotheses. The model links an inflammatory response with tissue hypoxia, as indicated by abnormal levels of VEGF, and disruption of the proopiomelanocortin pathway in the hypothalamus, as evidenced by abnormalities in leptin and MSH levels. Results from the clinical trial on CSM efficacy indicated highly significant improvement in group-mean number of symptoms and VCS scores relative to baseline in the 7 participants randomly assigned to receive 2 weeks of CSM therapy, but no improvement in the 6 participants assigned placebo therapy during that time interval. However, those 6 participants also showed a highly significant improvement in group-mean number of symptoms and VCS scores relative to baseline following a subsequent 2-week period of CSM therapy. Because the only known benefit of CSM therapy is to enhance the elimination rates of substances that accumulate in bile by preventing re-absorption during enterohepatic re-circulation, results from the clinical trial also supported the general study hypothesis that SBS is associated with exposure to WDBs because the only relevant function of CSM is to bind and remove toxigenic compounds. Only research that focuses on the signs, symptoms, and biochemical markers of patients with persistent illness following acute and/or chronic exposure to WDBs can further the development of the model describing modes of action in the biotoxin-associated pathway and guide the development of innovative and efficacious therapeutic interventions.

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.

Dang CV. · Ross Research Bldg, Room 1025, Johns Hopkins University School of Medicine, 720 Rutland Ave, Baltimore, MD 21205, USA. · JAMA. · Pubmed #11495622 No free full text.

Abstract: Macrocytic anemia occurring in patients with fatigue suggests numerous diagnoses, ranging from nutritional deficiencies to a myelodysplastic syndrome. A careful history-taking is critically important for recognition of runner's anemia, which is due to plasma volume expansion, with hemolysis from the pounding of feet on pavement, and hemoglobinuria. Gastrointestinal blood loss may also contribute to anemia in long-distance runners. Early recognition of runner's anemia in patients with a complex presentation of anemia is important in circumventing many diagnostic tests. Runner's anemia should be considered when, amidst a constellation of signs and symptoms, mild anemia is well tolerated by an avid runner.

Rowe PC, Calkins H, DeBusk K, McKenzie R, Anand R, Sharma G, Cuccherini BA, Soto N, Hohman P, Snader S, Lucas KE, Wolff M, Straus SE. · Departments of Pediatrics and Medicine, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287, USA. · JAMA. · Pubmed #11150109 links to  free full text

Abstract: CONTEXT: Patients with chronic fatigue syndrome (CFS) are more likely than healthy persons to develop neurally mediated hypotension (NMH) in response to prolonged orthostatic stress. OBJECTIVE: To examine the efficacy of fludrocortisone acetate as monotherapy for adults with both CFS and NMH. DESIGN: Randomized, double-blind, placebo-controlled trial conducted between March 1996 and February 1999. SETTING: Two tertiary referral centers in the United States. PATIENTS: One hundred individuals aged 18 to 50 years who satisfied Centers for Disease Control and Prevention criteria for CFS and had NMH provoked during a 2-stage tilt-table test. Eighty-three subjects had adequate outcome data to assess efficacy. INTERVENTION: Subjects were randomly assigned to receive fludrocortisone acetate, titrated to 0.1 mg/d (n = 50) or matching placebo (n = 50) for 9 weeks, followed by 2 weeks of observation after discontinuation of therapy. MAIN OUTCOME MEASURE: Proportion of subjects in each group with at least a 15-point improvement on a 100-point global wellness scale. RESULTS: Baseline demographic and illness characteristics between the groups were similar; CFS had been present for at least 3 years in 71%. Using an intention-to-treat analysis, 7 subjects (14%) treated with fludrocortisone experienced at least a 15-point improvement in their wellness scores compared with 5 (10%) among placebo recipients (P =.76). No differences were observed in several other symptom scores or in the proportion with normal follow-up tilt test results at the end of the treatment period. CONCLUSIONS: In our study of adults with CFS, fludrocortisone as monotherapy for NMH was no more efficacious than placebo for amelioration of symptoms. Failure to identify symptomatic improvement with fludrocortisone does not disprove the hypothesis that NMH could be contributing to some of the symptoms of CFS. Further studies are needed to determine whether other medications or combination therapy are more effective in treating orthostatic intolerance in patients with CFS.

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.

Revicki DA, Rentz AM, Luo MP, Wong RL, Doward LC, McKenna SP. · Center for Health Outcomes Research, United Biosource Corporation, Bethesda, MD, USA. · Health Qual Life Outcomes. · Pubmed #19183482 links to  free full text

This publication has no abstract.

Warren JW, Howard FM, Cross RK, Good JL, Weissman MM, Wesselmann U, Langenberg P, Greenberg P, Clauw DJ. · Department of Medicine, Epidemiology and Preventive Medicine, and Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA. · Urology. · Pubmed #18995888 No free full text.

Abstract: OBJECTIVES: Probing for clues to the pathogenesis of interstitial cystitis/painful bladder syndrome (IC/PBS), we sought antecedent nonbladder syndromes that distinguished incident IC/PBS cases from matched controls. METHODS: Female incident IC/PBS cases were recruited nationally, and their IC/PBS onset date (index date) was established. The controls were recruited by national random digit dialing and matched to the cases by sex, age, region, and interval between the (assigned) index date and interview. The prevalence of 24 nonbladder syndromes before the index date was assessed, 7 by multiple methods. RESULTS: The cases with IC/PBS had greater antecedent prevalence of 11 syndromes, and 243 of 313 cases (78%) vs 145 of 313 controls (45%) had multiple syndromes (P < .001). Fibromyalgia-chronic widespread pain (FM-CWP), chronic fatigue syndrome, sicca syndrome, and irritable bowel syndrome were associated with each other by pairwise and factor analyses using numerous assumptions. Cases with FM-CWP, chronic fatigue syndrome, sicca syndrome, and/or irritable bowel syndrome (n = 141, 45%) were more likely to have other syndromes (ie, migraine, chronic pelvic pain, depression, and allergy). Three other syndrome clusters were identified; each was associated with this FM-CWP cluster. CONCLUSIONS: Eleven antecedent syndromes were more often diagnosed in those with IC/PBS, and most syndromes appeared in clusters. The most prominent cluster comprised FM-CWP, chronic fatigue syndrome, sicca syndrome, and irritable bowel syndrome; most of the other syndromes and identified clusters were associated with it. Among the hypotheses generated was that some patients with IC/PBS have a systemic syndrome and not one confined to the bladder.

Kuo DZ, Cheng TL, Rowe PC. · Maple Avenue Pediatrics, Fair Lawn, New Jersey, USA. · Pediatrics. · Pubmed #18055669 links to  free full text

Abstract: We report on the successful collaborative care of an adolescent with chronic fatigue syndrome between a primary care pediatrician and an academic chronic fatigue syndrome specialist located in different cities. Regular telephone and e-mail communication and clearly defined patient-care roles allowed for timely management of symptoms and marked clinical improvement. We discuss ways to improve the collaboration of primary care and subspecialty physicians for patients with chronic fatigue syndrome and children with special health care needs.

Catassi C, Kryszak D, Louis-Jacques O, Duerksen DR, Hill I, Crowe SE, Brown AR, Procaccini NJ, Wonderly BA, Hartley P, Moreci J, Bennett N, Horvath K, Burk M, Fasano A. · Mucosal Biology Research Center and Division of Pediatric Gastroenterology and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. · Am J Gastroenterol. · Pubmed #17355413 No free full text.

Abstract: BACKGROUND: Celiac disease (CD) is one of the most common lifelong disorders in western countries. However, most cases remain currently undiagnosed in North America, mostly due to poor awareness of CD by primary care physicians. OBJECTIVES: The aims of this study were (a) to determine whether an active case-finding strategy in primary care could increase the frequency of CD diagnosis and (b) to determine the most common clinical presentations of the condition. METHODS:This was a multicenter, prospective study involving adult subjects during the years 2002-2004, attending one of the participating practices. All individuals with symptoms or conditions known to be associated with CD were tested for immunoglobulin A anti-transglutaminase (tTG) antibodies, and those with elevated anti-tTG were subsequently tested for IgA antiendomysial antibodies (EMA). All subjects who were positive for EMA were advised to undergo an intestinal biopsy and HLA typing. RESULTS: The study group included 737 women and 239 men, with a median age of 54.3 yr. A positive anti-tTG test was found in 30 out of 976 investigated subjects (3.07%, 95% CI 1.98-4.16). CD was diagnosed in 22 patients (18 women, 4 men). The most frequent reasons for CD screening in these 22 cases were bloating (12/22), thyroid disease (11/22), irritable bowel syndrome (7/22), unexplained chronic diarrhea (6/22), chronic fatigue (5/22), and constipation (4/22). The prevalence of CD in the serologically screened sample was 2.25% (95% CI 1.32-3.18). The diagnostic rate was low at baseline (0.27 cases per thousand visits, 95% CI 0.13-0.41) and significantly increased to 11.6 per thousand visits (95% CI 6.8-16.4, P < 0.001) following active screening implementation. CONCLUSIONS: This study demonstrates that an active case-finding strategy in the primary care setting is an effective means to improve the diagnostic rate of CD in North America.

Mazzocco MM, Henry AE, Kelly RI. · Kennedy Krieger Institute, Baltimore, MD 21211, USA. · J Dev Behav Pediatr. · Pubmed #17353728 No free full text.

Abstract: OBJECTIVE: Barth syndrome is a rare, X-linked recessive disorder that affects only boys. The cardinal characteristics include growth retardation, cardioskeletal myopathy, chronic or cyclic neutropenia, and 3-methylglutaconic aciduria. A preliminary study of five young boys with Barth syndrome suggested a distinct cognitive phenotype. METHODS: The present study was designed to explore whether additional evidence for a cognitive phenotype emerged from a larger sample. A psychoeducational assessment battery was administered to 15 boys with Barth syndrome. Data from these boys were compared to data from 15 typically developing boys individually matched on age and grade in school to each of the 15 boys with Barth syndrome. RESULTS: Although boys with Barth syndrome had age-appropriate performance on all measures of reading-related skills, their performance on mathematics and visual spatial tasks was significantly lower than that of boys in the comparison group. Moreover, specific aspects of visual short-term memory also differed from available norms. CONCLUSION: Our findings support the validity of the preliminary findings and reflect a higher incidence of cognitive difficulties in boys with Barth syndrome relative to boys in the comparison group. Coupled with the fatigue regularly experienced by boys with Barth syndrome, our findings indicate that educational support should be implemented during the early school-age years for children with Barth syndrome.

Brooks JK, Francis LA. · Department of Diagnostic Sciences and Pathology, Baltimore College of Dental Surgery, Dental School, University of Maryland, Baltimore, MD 21201, USA. · J Am Dent Assoc. · Pubmed #16637478 links to  free full text

Abstract: BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a chronic, relatively common autonomic disorder typically affecting younger females. It is distinguished by a dramatic increase in heart rate on the assumption of an upright posture from the supine position. METHODS: The authors provide an overview of the demographics, clinical assessment, diagnostic features, differential diagnoses, pathogeneses and medical treatment of patients with POTS, with an emphasis on the clinical treatment of the dental patient affected by the syndrome. CONCLUSION: Patients frequently exhibit symptoms of lightheadedness, fatigue, palpitations and syncope. Patients with POTS may have Ehlers-Danlos syndrome, mitral valve prolapse, chronic fatigue syndrome or, rarely, the Brugada syndrome. Despite widespread dissemination of information regarding POTS in the medical literature, scant information on it has appeared in dental publications. PRACTICE IMPLICATIONS: Dentists need to be familiar with the clinical features of POTS and be prepared to treat patients at risk of developing syncope.

Fostel J, Boneva R, Lloyd A. · National Center for Toxicogenomics, NIEHS MD F1-05, 111 Alexander Drive, PO Box 12233, Research Triangle Park, NC 27709-2233, USA. · Pharmacogenomics. · Pubmed #16610954 No free full text.

Abstract: OBJECTIVE: To identify biomarkers of chronic fatigue syndrome (CFS) and related disorders through analysis of microarray data, pathology test results and self-report symptom profiles. METHOD: To empirically derive the symptom domains of the illnesses, factor analysis was performed on responses to self-report questionnaires (multidimensional fatigue inventory, Centers for Disease Control and Prevention (CDC) symptom inventory and Zung depression scale) before validation with independent datasets. Gene expression patterns that distinguished subjects across each factor dimension were then sought. RESULTS: A four-factor solution was favored, featuring 'fatigue' and 'mood disturbance' factors. Scores on these factors correlated with measures of disability on the Short Form (SF)-36. A total of 57 genes that distinguished subjects along each factor dimension were identified, although the separation was significant only for subjects beyond the extreme (15th and 85th) percentiles of severity. Clustering of laboratory parameters with expression of these genes revealed associations with serum measurements of pH, electrolytes, glucose, urea, creatinine, and liver enzymes (aspartate amino transferase [AST] and alanine amino transferase [AST]); as well as hematocrit and white cell count. CONCLUSION: CFS is a complex syndrome that cannot simply be associated with changes in individual laboratory tests or expression levels of individual genes. No clear association with gene expression and individual symptom domains was found. However, analysis of such multifacetted datasets is likely to be an important means to elucidate the pathogenesis of CFS.

Carmel L, Efroni S, White PD, Aslakson E, Vollmer-Conna U, Rajeevan MS. · National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA. · Pharmacogenomics. · Pubmed #16610948 No free full text.

Abstract: OBJECTIVES: To identify the underlying gene expression profiles of unexplained chronic fatigue subjects classified into five or six class solutions by principal component (PCA) and latent class analyses (LCA). METHODS: Microarray expression data were available for 15,315 genes and 111 female subjects enrolled from a population-based study on chronic fatigue syndrome. Algorithms were developed to assign gene scores and threshold values that signified the contribution of each gene to discriminate the multiclasses in each LCA solution. Unsupervised dimensionality reduction was first used to remove noise or otherwise uninformative gene combinations, followed by supervised dimensionality reduction to isolate gene combinations that best separate the classes. RESULTS: The authors' gene score and threshold algorithms identified 32 and 26 genes capable of discriminating the five and six multiclass solutions, respectively. Pair-wise comparisons suggested that some genes (zinc finger protein 350 [ZNF350], solute carrier family 1, member 6 [SLC1A6], F-box protein 7 [FBX07] and vacuole 14 protein homolog [VAC14]) distinguished most classes of fatigued subjects from healthy subjects, whereas others (patched homolog 2 [PTCH2] and T-cell leukemia/lymphoma [TCL1A]) differentiated specific fatigue classes. CONCLUSION: A computational approach was developed for general use to identify discriminatory genes in any multiclass problem. Using this approach, differences in gene expression were found to discriminate some classes of unexplained chronic fatigue, particularly one termed interoception.

Engel CC. · Department of Psychiatry, F. Edward Hebert School of Medicine of Uniformed Services University of Health Sciences, Bethesda, MD 20814-4799, USA. · CNS Spectr. · Pubmed #16575379 links to  free full text

Abstract: In recent years, research-methods literature mainly addressing controlled clinical trials has arisen regarding explanatory and pragmatic treatment trials. Explanatory trials tend to examine causal mechanisms and questions of efficacy and value internal validity (creating optimal study conditions) over generalizability (using study results to understand treatment effects in real-life patient populations). In contrast, pragmatic trials value "external relevance" (generalizability) of study results over "internal elegance" so that clinicians and health policymakers can better understand how treatments might impact their patients and policies. This review draws inspiration from these contrasting explanatory and pragmatic perspectives and develops them for clinical and research pertaining to idiopathic physical symptoms and related syndromes (eg, somatization disorder, chronic fatigue syndrome, multiple chemical sensitivities, irritable bowel syndrome). Explanatory and pragmatic perspectives are used to examine these idiopathies with regard to causation, case definition, labels, and treatment. It is concluded that idiopathic symptom syndromes are fundamentally pragmatic clinical and research challenges. For epidemiologic and methodologic reasons, the complex explanations for these syndromes remain largely elusive. Even so, scientific and clinical pragmatism offers the opportunity to reduce disagreement between competing medical disciplines and between clinicians and affected patients with regard to irreconcilable etiologic questions and to remain evidence-based in the care of patients.

Chrousos GP, Kaltsas G. · Athens University, Athens, Greece and National Institutes of Health, Bethesda, MD, USA. · Clin Endocrinol (Oxf). · Pubmed #16181227 No free full text.

This publication has no abstract.

Sullivan SD, Hanauer J, Rowe PC, Barron DF, Darbari A, Oliva-Hemker M. · Department of Pediatric Gastroenterology, The Johns Hopkins University School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #15795588 No free full text.

Abstract: BACKGROUND: The term orthostatic intolerance is used to describe symptoms of hemodynamic instability such as lightheadedness, fatigue, impaired cognition and syncope that develop on assuming an upright posture. Common forms of orthostatic intolerance in childhood include postural tachycardia syndrome and neurally mediated hypotension. OBJECTIVE: A descriptive report of the clinical characteristics of patients presenting with gastrointestinal symptoms who are ultimately found to have orthostatic intolerance. METHODS: A medical record review of all patients referred to the pediatric gastroenterology service at the Johns Hopkins Children's Center who had an abnormal tilt table test between June 1996 and December 2000. RESULTS: Of 24 eligible subjects aged 9-17 years (mean, 14.3 years), four had postural tachycardia syndrome, eight had both postural tachycardia and neurally mediated hypotension, and 12 had neurally mediated hypotension alone. The most common presenting gastrointestinal symptoms were abdominal pain, nausea and vomiting. Median number of gastrointestinal symptoms per patient was 3 (range, 1-7), and 87% of the patients experienced gastrointestinal symptoms for more than 1 year and 48% experienced gastrointestinal symptoms for more than 3 years. Follow-up information was available on 18 patients. Seventy-eight percent of patients (14 of 18) had complete resolution of symptoms with treatment of orthostatic intolerance. CONCLUSION: Pediatric patients with chronic upper gastrointestinal symptoms may have underlying orthostatic intolerance. In patients with upper gastrointestinal symptoms and orthostatic intolerance, treatment of orthostatic intolerance may result in resolution of gastrointestinal symptoms.