Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: a randomized controlled trial.

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.

Bacteremia and skin/bone infections in two patients with X-linked agammaglobulinemia caused by an unusual organism related to Flexispira/Helicobacter species.

Two patients with Bruton's X-linked agammaglobulinemia are described with bacteremia and skin/bone infection due to an organism which by 16S rRNA gene sequence analysis was most closely related to "Flexispira" rappini (and thus designated a Flexispira-like organism, FLO) and more distantly related to the Helicobacter species. The organism required microaerobic conditions and, supplemental H(2) gas for growth and was reliably stained with acridine orange. In common with Helicobacter cinaedi infections, the focus of the FLO infection was in one case in the blood vessels or lymphatics of an extremity and in the other case in the skin and adjacent bone of an extremity. In both cases, prolonged IV antibiotic therapy was necessary to clear the infection. The susceptibility of XLA patients to FLO infection appears to be related to the fact that XLA is associated with severe B cell (humoral) immunodeficiency and thus these patients have difficulty with intravascular or intralymphatic infection. These findings elucidate the nature of FLO infections in humans and point the way to their detection and treatment.

Recurrent bacteremia caused by a "Flexispira"-like organism in a patient with X-linked (Bruton's) agammaglobulinemia.

Helicobacter spp., except for Helicobacter cinaedi, have only rarely been reported in cases of septicemia. A patient with X-linked (Bruton's) agammaglobulinemia was found to have persistent sepsis with a Helicobacter-like organism despite multiple courses of antibiotics. His periods of sepsis were associated with leg swelling thought to be consistent with cellulitis. The organism was fastidious and required a microaerophilic environment containing H(2) for growth. Optimal growth was observed at 35 to 37 degrees C on sheep blood, CDC anaerobe, and Bordet-Gengou agars. Serial subcultures every 4 to 5 days were required to maintain viability. The organism was strongly urease positive and showed highest relatedness to Helicobacter-like organisms with the vernacular name "Flexispira rappini" by 16S rRNA gene sequence analysis. Genomic DNA hybridization studies, however, found 24 to 37% relatedness to "F. rappini" and even less to other Helicobacter spp. Although the organism phenotypically resembles "Flexispira" and Helicobacter, it is thought to represent a new taxon. The patient's infection was eventually cleared with a prolonged (5-month) course of intravenous imipenem and gentamicin.

Intestinal lymphangiectasia, a disease characterized by selective loss of naive CD45RA+ lymphocytes into the gastrointestinal tract.

Intestinal lymphangiectasia (InL) is a disease characterized by hypoproteinemia and lymphocytopenia resulting from blocked intestinal lymphatics and loss of lymph fluid into the gastrointestinal tract. This leads to immunologic abnormalities including hypogammaglobulinemia, skin anergy and impaired allograft rejection. In the present study, we evaluated whether the above immunologic abnormalities are secondary to a quantitative or qualitative disorder of T cells. In initial studies we demonstrated that adult InL patients' peripheral blood contain strikingly (and significantly) reduced numbers of CD4+/CD45RA+ T cells, whereas the numbers of CD4+/CD45RO+ T cells were only moderately (and not significantly) reduced. In addition, the CD4+/CD45RO+ T cell population contained an increased percentage of highly differentiated and previously sensitized cells, as demonstrated by decreased CD27 and CD31 expression and increased HLA-DR and CD69 expression. In subsequent functional studies, we showed that the InL CD4+/CD45RO+ T cells, when stimulated in vitro, proliferate fivefold less than control CD4+/CD45RO+ T cells and produce fourfold more IL-4 and threefold less IFN-gamma and IL-2. Thus, this cytokine production profile also reflects the highly differentiated nature of the residual cell population. Overall, these studies provide new information on the trafficking of naive/mature and Th1/Th2 T cell populations in this disease model.

Defects of monocyte interleukin 12 production and humoral immunity in Whipple's disease.

BACKGROUND & AIMS: Whipple's disease (WD) is a systemic infection in which the causative bacteria typically accumulate within macrophages. The aim of this study was to test whether this macrophage dysfunction is the cause or result of previously shown T-cell defects. METHODS: In vitro production of interleukin (IL)-12, IL-10, tumor necrosis factor alpha, interferon gamma (IFN-gamma), and transforming growth factor beta (TGF-beta) from purified monocytes and peripheral blood mononuclear cells, cytokine expression on duodenal biopsy specimens, and serum cytokine and immunoglobulin (Ig) levels were tested in 9 patients with WD. RESULTS: Reduced monocyte IL-12 production and decreased IFN-gamma secretion by peripheral blood mononuclear cells in vitro were found, as well as reduced immunohistological staining for IL-12 and IFN-gamma, but no decrease in other cytokines in patients with WD. A similar but less severe defect in 2 relatives with WD argued for a genetic basis of this abnormality. Serum IgG2, an IFN-gamma-dependent Ig subclass, and serum TGF-beta levels were reduced in patients with WD. CONCLUSIONS: The described monocyte defects in WD may result in a secondary reduction of IFN-gamma production and IgG2 serum levels. This provides a rationale for additive immunotherapy in patients with antibiotic-refractory WD.

Musculoskeletal symptoms among electricians.

This study ascertained the presence of musculoskeletal symptoms among electricians, in order to evaluate the prevalence of cumulative trauma disorders (CTD) in this population. We adapted the CTD surveillance questionnaire used by National Institute for Occupational Safety and Health (NIOSH) to assess the prevalence of neck, shoulder, elbow, hand/wrist, back, and knee symptoms in the year prior to the survey. Questionnaires were completed by 308 apprentices and journeymen enrolled in training classes at the local union hall. The participants were relatively young individuals, and 86% of the participants were currently working as electricians. Participants reported a high prevalence of symptoms which occurred more than three times during the past year or which lasted more than 1 week. Back symptoms and hand/wrist symptoms were experienced most frequently, by about half the population, while elbow symptoms were reported by only 15% of participants. Symptom prevalence was lower, but still notable, when defined as symptoms which had occurred at least once a month or lasted more than a week in the past year. Eighty-two percent of participants reported at least one musculoskeletal symptom using the most inclusive definition, while 57% reported two or more symptoms. This survey highlights that: 1) low back discomfort is common in young construction workers, and resulted in medical care, missed work, or light duty for almost 35% of the participants; 2) neck discomfort is also very common and required doctor visits or work modification for almost one quarter of the participants; 3) these construction workers continued to work with symptoms that are classifiable as a CTD; and 4) history of injury is correlated with the subsequent prevalence of musculoskeletal symptoms.

Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure.

We have treated 6 chronic alcoholics and identified an additional 19 reported in the literature who developed severe hepatotoxicity from acetaminophen taken in apparently moderate doses. The clinical disease in these 25 patients had a characteristic pattern: mild to moderate jaundice; mild to severe coagulopathy; and strikingly abnormal aminotransferase levels, values inconsistent with either acute alcoholic hepatitis or viral hepatitis. The possible causes for the injury from ostensibly nontoxic drug levels appear to be either the induction by chronic alcohol intake of the cytochrome P-450 system responsible for converting acetaminophen to a toxic metabolite, or the effect of alcoholism and the associated malnutrition in reducing the glutathione concentration, responsible normally for preventing hepatotoxicity by conjugation with the toxic metabolite. The research data pertaining to the apparent enhanced toxicity from chronic alcoholism are reviewed. Despite the low frequency of ethanol-potentiated acetaminophen hepatotoxicity, alcoholics should be cautioned about the use of acetaminophen while they persist in heavy consumption of alcohol.

Does primary biliary cirrhosis in men differ from primary biliary cirrhosis in women?

Primary biliary cirrhosis is infrequently diagnosed in men, so that the clinical, biochemical and histopathological spectrum of this disease in men has not been evaluated. Therefore, we studied 30 men who had a histological diagnosis of primary biliary cirrhosis and had positive tests for antimitochondrial antibodies. Five patients had no hepatobiliary symptoms, and two of these patients had neither biochemical nor histological evidence of cholestasis. These 30 male patients' findings were compared with the findings in 30 age-matched women who also had primary biliary cirrhosis and antimitochondrial antibodies. Six of these patients were asymptomatic. Clinical findings and symptomatic status, in addition to biochemical and histopathological features, were generally similar in both male and female patients. The possible significance of higher serum alkaline phosphatase activities and lower frequency of occurrence of piecemeal necrosis in men with primary biliary cirrhosis, as compared with women, requires further study.

Stability of aspartate aminotransferase and alanine aminotransferase activities.

Because there are conflicting data regarding the effect of different temperatures and durations of storage on the stability of the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), a new study has been conducted to re-examine this important issue. Blood obtained from patients with varying aminotransferase levels was centrifuged, the resultant serum was divided into aliquots, the samples were stored at room, refrigerator, and freezer temperatures, and the aminotransferases measured on days 0, 1, 2, 3, 4, and 30. In all but one circumstance, both AST and ALT activities declined markedly beginning within 24 hr of venipuncture; the temperature of storage did not significantly affect the rate or degree of loss of enzyme activity. The exception was the evidence that ALT activity in samples obtained from individuals with initially normal values showed a rise during the first 3 to 4 days, followed thereafter by a decline to below baseline values. Thus, to ensure accuracy of aminotransferase measurement, testing of samples should be conducted on the day of venipuncture.