Randomised controlled trial of brief intervention with biofeedback and hypnotherapy in patients with refractory irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a common disorder associated with profoundly impaired quality of life and emotional distress. The management of refractory IBS symptoms remains challenging and non-pharmacological therapeutic approaches have been shown to be effective. We compared brief interventions with biofeedback and hypnotherapy in women referred by their GP with refractory IBS symptoms. Patients were randomised to one of two treatment groups, biofeedback or hypnotherapy, delivered as three one-hour sessions over 12 weeks. Symptom assessments were undertaken using validated, self-administered questionnaires. Two of the 128 consecutive IBS patients suitable for the study declined to consider nonpharmacological therapy and 29 patients did not attend beyond the first session. Of the 97 patients randomised into the study, 21 failed to attend the therapy session; 15 of 76 patients who attended for therapy dropped out before week 12 post-therapy. The mean (SD) change in IBS symptom severity score 12 weeks post-treatment in the biofeedback group was -116.8 (99.3) and in the hypnotherapy group -58.0 (101.1), a statistically significant difference between groups (difference=-58.8, 95% confidence interval [CI] for difference [-111.6, -6.1], p=0.029). In 61 patients with refractory IBS, biofeedback and hypnotherapy were equally effective at improving IBS symptom severity scores, total non-gastrointestinal symptom scores and anxiety and depression ratings during 24 weeks follow-up. Biofeedback may prove to be the more cost-effective option as it requires less expertise.

Transfectant mosaic spheroids: a new model for evaluation of tumour cell killing in targeted radiotherapy and experimental gene therapy.

BACKGROUND: We describe an in vitro tumour model for targeted radiotherapy and gene therapy that incorporates cell population heterogeneity. MATERIALS AND METHODS: Transfectant mosaic spheroids (TMS) and transfected mosaic monolayers (TMM) are composed of two cell populations derived from a single cell line. The cells of one population were transfected with the noradrenaline transporter gene (NAT), allowing active uptake of a radiolabelled targeting agent meta-[131I]iodobenzylguanidine ([131I]MIBG); the other population of cells was derived from the same parent line and transfected with a marker gene - green fluorescent protein (GFP). After treatment with [131I]MIBG, cell kill was determined in TMM by clonogenic assay and in TMS by clonogenic assay and spheroid growth delay. RESULTS: We have used the TMS model to assess the 'radiological bystander effect' (radiation cross-fire) conferred by the beta-emitting radiopharmaceutical [131I] MIBG whose cellular uptake is facilitated by the transfected gene encoding NAT. We show that cell killing by [131I]MIBG in both TMS and TMM cultures increased in direct proportion to the fraction of NAT-transfected cells and that the degree of cell killing against fraction transfected was greater in TMS, suggestive of a greater bystander effect in the three-dimensional culture system. CONCLUSIONS: TMS provide a useful model for assessment of the effectiveness of targeted radiotherapy in combination with gene therapy when less than 100% of the target cell population is expressing the NAT transgene. Further, this novel model offers the unique opportunity to investigate radiation-induced bystander effects and their contribution to cell cytotoxicity in radiotherapy and other gene therapy applications.

Organochlorine pesticide and polychlorinated biphenyl residues in Canada geese (Branta canadensis) from Chicago, Illinois.

Breast muscle samples, with or without overlying adipose tissue and skin, were obtained from Canada geese collected in northeastern illinois while undergoing feather molt. Specimens were evaluated for contaminant concentrations to determine if they would be acceptable as human food provided through government-subsidized programs. Samples were baked, allowing fat to drip free, and assayed for persistent organochlorine pesticides and polychlorinated biphenyls. Residues of heptachlor epoxide, dieldrin, DDE and PCBs (as Arochlor 1248) were detected. The specimens contained relatively low concentrations of contaminants, such that US Department of Agriculture residue limits for meat were exceeded in only 1 sample. Baking of breast muscle without the overlying skin and adipose tissue resulted in reductions in concentrations of detectable compounds. Fewer samples baked with the skin attached had detectable concentrations of heptachlor epoxide, dieldrin and PCB then samples cooked without skin; however, the converse was true for DDE. Periodic monitoring for environmental contaminants such as PCBs, exclusion of geese from localities where samples have contaminants such as PCBs, exclusion of geese from localities where samples have contaminants at concentrations that exceed recommended dietary limits, the use of processing and/or cooking methods which remove large amounts of lipid, and advisories that provide information on known health risks are recommended if wild resident Canada geese from the Chicago area are provided as food for underprivileged humans.

Diagnosis and management of human B virus (Herpesvirus simiae) infections in Michigan.

Three men who had worked at the same animal research facility and had had contact with macaque monkeys were infected with B virus (Herpesvirus simiae). Their clinical presentations varied from self-limited aseptic meningitis syndrome to fulminant encephalomyelitis and death. Patient 1 was treated only after a respiratory arrest and other signs of advanced brain stem dysfunction had occurred. He died 8 days after hospital admission, despite treatment with acyclovir. Patient 2 presented with subtle signs and symptoms of brain stem encephalitis. He received antiviral therapy with intravenous ganciclovir. Patient 3 had a headache without meningismus and was also treated with acyclovir. Both patients 2 and 3 survived and did not have objective sequelae. Viral culturing, ELISA and western blot antibody testing, and magnetic resonance imaging all proved useful in the diagnosis of these patients' conditions.

Hepatosplenic candidiasis: successful treatment with fluconazole.

PURPOSE: To determine if fluconazole is effective treatment for hepatosplenic candidiasis that has not resolved with amphotericin B and flucytosine treatment. PATIENTS AND METHODS: Six patients (ages 3 to 44) with acute leukemia and hepatosplenic candidiasis who did not respond to prior antifungal therapy were treated with fluconazole. RESULTS: All six patients had fever and three had nausea and vomiting; computed tomographic (CT) scan showed lucencies in the liver in six, lucencies in the spleen in five, and lucencies in the kidneys in three. Prior therapy with 1.6 to 4 g of amphotericin B in the five adults and 526 mg of amphotericin B in the child (with the addition of flucytosine in four) failed to improve clinical symptoms or lucencies in the liver, spleen, and kidneys seen on CT scan. Fluconazole was given at a dose of 200 to 400 mg daily (70 to 100 mg in the child) for 2 to 14 months. All patients had resolution of fever and other symptoms in 2 to 8 weeks. Improvement of the lesions noted on CT scan was seen in 4 to 8 weeks in all patients. Total resolution of lesions noted on CT scan occurred by 4 weeks in two patients, but took 4 to 5 months for three patients and 13 months for one patient. Three patients had relapse of their acute leukemia and two died, presumably cured of their candidiasis. Two patients underwent successful bone marrow transplantation without relapse of their candidiasis. CONCLUSION: Fluconazole appears to be useful in the treatment of hepatosplenic candidiasis that has not resolved with amphotericin B and flucytosine therapy.

Apparent zearalenone intoxication in a dairy herd from feeding spoiled acid-treated corn.

High-moisture corn was treated with a propionic acid preservative and stored in a 40,000 bushel steel bin. This corn heated and spoiled in storage and subsequently was retreated with the preservative. The out-of-condition corn was used as an ingredient in the ration for a dairy herd of cows and replacement heifers. The finished feed was cultured for fungi and assayed for mycotoxins. Results were 750,000 Fusarium spp colonies/g of feed, and 1.5 mg zearaleonone and 1.0 mg deoxynivalenol/kg of feed. Frequent episodes of behavioral estrus of 2 to 5 d duration, that were not synchronized with the ovarian cycle, were observed. Cows in the second and third trimester of pregnancy also has episodes of behavioral estrus. Idiopathic vaginitis was diagnosed. Mammary development occurred in the prepubertal heifers. Cows bred in true estrus were found in true estrus 35 to 55 d later. All of the heifers with precocious mammary development were subsequently culled from the herd because of sterility.

Acute aflatoxicosis in feeder pigs, resulting from improper storage of corn.

Aflatoxicosis was diagnosed in 600 feeder pigs, of which 400 died, 150 were destroyed, and 50 were marketed. The pigs were exposed to 2,500 to 3,500 micrograms of aflatoxins/kg of feed. Drought-stressed damaged corn infected with Aspergillus flavus was stored under ambient conditions in a glass-lined silo, and this storage environment provided conditions that favored rapid fungal growth and mycotoxin production.

Assembly of the membrane attack complex promotes decay of the alternative pathway C3 convertase on Neisseria gonorrhoeae.

C3, C4, factor B, properdin, and C2 binding to serum-sensitive and serum-resistant gonococci was quantitated in C8-deficient and normal human serum by using fluorescein-conjugated antibodies and 3H-labeled components. Organism and serum-specific differences were noted, the most striking of which involved factor B and properdin binding to the serum-sensitive strains in the different sera. C3 binding to these organisms was quantitatively and kinetically equivalent in C8-deficient and normal human serum. In contrast, factor B and properdin binding reached a plateau after 5 min in C8-deficient serum but peaked and fell to control values in normal human serum. Identical results were obtained with normal human serum immunochemically depleted of C8. Between 7 and 15% of the bound C3 participated in formation of the alternative pathway convertase C3bBb/P. Reconstitution of the C cascade by adding purified C8 to C8-deficient serum led to the loss of factor B previously bound to the organisms. Factor B loss occurred coincident with bacterial killing and membrane disruption as observed by electron microscopy. Prevention of membrane disruption by depleting normal human serum of lysozyme had no effect on killing and failed to prevent factor B loss. Stabilization of the C3bBb complex with Ni2+ prevented factor B loss as well as gross membrane disruption but not bacterial killing. C2 (the classical pathway analog of factor B) binding to gonococci was equivalent in C8-deficient and normal human serum peaking within 2.5 min and falling to control values in both sera thereafter. We conclude that the assembly of the membrane attack complex promotes decay of C3bBb/P with release of factor B and properdin but not C3 from the organism surface. Membrane disruption does not appear to be required for this effect. This activity may represent a mechanism to limit continued C consumption.

Killing of Neisseria meningitidis by human neutrophils: implications for normal and complement-deficient individuals.

The contributions of complement-dependent phagocytosis and serum bactericidal activity (SBA) to the killing of 62 strains of meningococci were examined by using C8-depleted or pooled human serum (PHS). The complement-dependent nature of killing by neutrophils was confirmed by restoring survival to control values by using heated serum. Serogroups B and 29E, but not A, C, Y, and W135, were ingested and killed by neutrophils in C8-depleted PHS (PHS-C8Dep; 41.7% +/- 7.3% and 60.5% +/- 17.8% vs. greater than or equal to 100% survival, respectively, at 30 min). Group B meningococci were resistant to complement-mediated SBA, whereas group Y were susceptible. Deposition of C3 on serogroups B and Y was similar (28.5 +/- 2.9 vs. 23.5 +/- 2.7 C3 fluorescence units; P greater than .05); however, susceptibility to complement-dependent phagocytosis and complement-mediated SBA of serogroups B and Y did not correlate. We also examined meningococcal phagocytosis by using serum from a C8-deficient patient. In contrast to PHS-C8Dep, this serum supported rapid phagocytic killing of serogroups A, C, Y, and W135 meningococci. This finding suggests that vaccinating individuals deficient in late-complement components may shift the burden of host defense from SBA to phagocytosis.

Glycosaminoglycan composition of tight skin and control mouse skins.

Tight skin (TSK) mouse skin has previously been shown to contain increased amounts of collagen and glycosaminoglycans (GAG). We now report on the GAG composition of TSK mouse skin. Using an electrophoretic and an enzymatic HPLC method, skin from 99 TSK and control mice (newborn, 1 month-old, and 6 months-old) were analyzed for GAG composition. There was no significant difference between TSK and control GAG.

Staphylococcus aureus meningitis: a broad-based epidemiologic study.

In an effort to ascertain important epidemiologic and prognostic risk factors, we analyzed 33 cases of Staphylococcus aureus meningitis occurring over an 8-year period (1976 to 1984). Staphylococcus aureus caused 6% of all bacterial meningitis at our University Hospital. Fifty percent of cases were pediatric and included 7 newborn infants, of whom 71% were either premature or had low birth weight. Major underlying diseases were: central nervous system (CNS) disorders (55%), endocarditis (21%, predominantly intravenous drug abusers), other sites of infection (27%), and prematurity (24%). Fifty-seven percent of patients were bacteremic and 41% of those had concomitant bacteriuria. Hypoglycorrhachia was present in 27% of cases, positive cerebrospinal fluid (CSF) Gram stain in 20%, disseminated intravascular coagulation (DIC) in 19%, and methicillin-resistant organisms in 18%. Cerebrospinal fluid cultures remained positive for a protracted period (mean, 6.7 days) regardless of the presence or absence of a CNS shunt. Overall mortality was 21%. Favorable outcomes were associated with the eventual presence of sterile CSF (15.4% vs. 100% mortality) and the removal of foreign bodies (10% vs. 67% mortality). Mortality was also associated (p less than 0.5) with the presence of diabetes mellitus, age greater than 60, obtundation or coma on presentation, bacteremia, or DIC. Cure correlated (p less than .05) with CNS shunt-associated infections, age less than 1, normal neurologic examinations on presentation, or the absence of DIC or bacteremia.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of intravenous immunoglobulin on E. coli opsonization in multiple myeloma.

Infections are a major source of morbidity in multiple myeloma; E. coli is now the leading pathogen. Intravenous IgG may be a modality which could ameliorate the opsinopathy of multiple myeloma. We infused 6 patients with multiple myeloma with IgG (100 mg/kg) and compared E. coli opsonophagocytosis pre- and post-IgG infusions. Log phase, broth grown E. coli K12 (5 X 10(6)/ml) and normal, dextran-sedimented human neutrophils (5 X 10(6)/ml) were combined in 10% heat inactivated, pre- or post-IgG infusion multiple myeloma serum with 5% agammaglobulinemic serum as a complement source and incubated at 37 degrees C for 30 min. Phagocytosis was quantified as percentage survival of the inoculum. Control survival in heat inactivated normal serum + complement + neutrophils was 1.7 +/- 0.8%. Pre- and post-IgG infusion sera were equally abnormal opsonin sources with 14.3 +/- 6.5% and 17.5 +/- 3.0% survivals. Individually, patients with poor opsonophagocytosis improved with IgG (e.g., pre = 45.2 +/- 3.7%; post = 29.5 +/- 2.3% survival), whereas patients with good opsonophagocytosis showed a deleterious effect (e.g., pre = 2.3 +/- 0.9%; post 23.3 +/- 6.3% survival). To explain these data, we measured deposited IgM and IgG on E. coli by pre- and post-IgG infusion sera in a fluorescence immunoassay. Pre- and post-IgG infusion sera had equally depressed IgM deposition (pre = 13.7 +/- 2.1%; post = 14.5 +/- 2.6% of normal serum), and also equal IgG deposition (pre = 96.8 +/- 6.5%; post = 94.6 +/- 4.8% of normal serum).(ABSTRACT TRUNCATED AT 250 WORDS)

Hidden 19S IgM rheumatoid factor in adults with juvenile rheumatoid arthritis onset.

Forty-eight adult patients with juvenile rheumatoid arthritis (JRA) (onset before age 16 years) were evaluated at the age of 17 years or more for the presence of hidden 19S IgM rheumatoid factors (RF), i.e., 19S IgM RF that can be detected by the complement-dependent haemolytic assay in the IgM-containing fraction after separation of the serum by acid gel filtration. The average age of the patients was 25.3 years. The mean duration of disease was 16.5 years. Thirty-two of 48 patients (67%) showed the presence of hidden 19S IgM RF in their serum. Disease activity correlated with hidden RF titres in 62% (55/88) of the evaluations. The results indicate that patients with seronegative JRA onset continue to have significant titres of hidden 19S IgM RF in their sera into early adulthood.

Opsonophagocytosis of Neisseria gonorrhoeae: interaction of local and disseminated isolates with complement and neutrophils.

The phagocytosis of serum-sensitive (SS) and serum-resistant (SR) gonococci by neutrophils was examined. SS strains were more rapidly and completely ingested and killed than were SR strains (8.8% +/- 3.4% vs. 64.4% +/- 7.7% survival at 30 min [P less than .005]) in C8-deficient serum or C8-depleted normal serum. Opsonic requirements of the two types of isolates differed. Heat-labile and -stable serum factors played an important role in the phagocytosis of SS but not SR strains. Indeed, killing of SR strains by polymorphonuclear neutrophils did not vary over a 1,000-fold change in serum concentration. SS strains consumed and fixed C3 more rapidly and in greater amounts than did SR strains (83.3% +/- 17.4% vs. 20.8% +/- 5.0% at 10 min [P less than .01]). However, this difference in C3 consumption and fixation did not completely account for the difference in phagocytosis because killing of SS strains was still greater than that of SR strains under conditions of equal C3 fixation.

Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency.

Inherited deficiencies of the complement proteins are rare in unselected populations. Examination of patients with the clinical correlates of complement deficiency (autoimmune disease and certain bacterial infections) shows the frequency of inherited complement deficiency to rise enormously (5.9% of patients with systemic lupus erythematosus, 10 to 25% of adults with sporadic meningococcal disease). Autoimmune diseases of all types, but especially systemic lupus erythematosus, discoid lupus and glomerulonephritis, are seen in all categories of complement deficiency, most typically in those of the early classical pathway (C1, C4, C2). Pneumococcal infections are characteristic of deficiencies of the early classical pathway, as well. Deficiencies of C3 are associated with severe disease including autoimmune phenomena, pneumococcal and neisserial infections. C3-deficient patients become ill substantially earlier in life. Infections with N. meningitidis and N. gonorrhoeae are most typical of the late component deficiencies, with over 40% of homozygotes affected. Despite the presence of this deficiency from birth and the peak age-specific incidence of meningococcal disease in the general population at ages 3-8 months, the median age of first infection in the late component-deficient patients is 17 years. Relapse of infection is ten times more common in these patients, and discrete recurrences are seen in 45% of affected individuals. An unusual and unexplained predilection for infection with serogroup Y N. meningitidis exists. Despite an immune deficiency, and problems with ascertainment bias, it appears that persons with late component complement deficiency enjoy less mortality than normals who contract meningococcal disease. Attempts to explain the pathogenesis of neisserial infection in late component deficiencies have focused on the concept that normally non-pathogenic serum-sensitive bacteria are etiologic in the absence of serum bactericidal activity. Data to support this concept remain to be developed and contrary data exist. A separate mechanism may predispose properdin-deficient patients to meningococcal infection, since they appear to develop fulminant infections with high mortality.

Glycosaminoglycan content in the lung of the tight-skin mouse.

Morphologic and physiologic pulmonary changes have been described in the tight-skin (TSK) mouse, but no biochemical studies have been done. We performed qualitative and quantitative analyses of glycosaminoglycans (GAG) on lungs of the TSK mouse. Total GAG were determined by cetylpyridinium chloride precipitation in whole lung specimens from TSK mice and normal (N) mice of different age groups: 1, 6, and 12 months old. There was no significant difference in total GAG, GAG concentration, or dry lung weight between TSK and N mice in any of the 3 age groups. In addition, fractionation of the GAG by electrophoresis revealed similar amounts of individual GAG (predominantly dermatan sulfate and heparin) in TSK and N mice within each age group. Therefore, structural abnormalities in the TSK mouse lung were not demonstrated to be due to qualitative or quantitative changes in GAG.