Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group

BACKGROUND: There is no satisfactory medical therapy for patients with primary sclerosing cholangitis. Ursodiol (ursodeoxycholic acid) benefits patients with primary biliary cirrhosis, another cholestatic liver disease. METHODS: From May 1989 to July 1995, we enrolled 105 patients with well-documented primary sclerosing cholangitis in a randomized, double-blind study comparing ursodiol (13 to 15 mg per kilogram of body weight per day in divided doses) with placebo. The primary outcome was the time to treatment failure, defined as death; liver transplantation; histologic progression by two stages (of four) or progression to cirrhosis; the development of varices, ascites, or encephalopathy; sustained quadrupling of the serum bilirubin concentration; marked worsening of fatigue or pruritus; inability to tolerate the drug; or voluntary withdrawal from the study. RESULTS: We analyzed data on the 51 patients in each group with at least 3 months of follow-up; the median follow-up was 2.2 years. There was no significant difference between the groups in time to treatment failure (relative risk of treatment failure in the ursodiol group, 1.01; 95 percent confidence interval, 0.6 to 1.7). During the first two years of follow-up, treatment was unsuccessful in 17 of 32 patients (53 percent) in the placebo group and 16 of 31 (52 percent) in the ursodiol group. There were also no differences in time to treatment failure for patients with early-stage disease or in time to liver transplantation. Ursodiol, but not placebo, was associated with improvement in serum alkaline phosphatase, aspartate aminotransferase, bilirubin, and albumin levels at one and two years. CONCLUSIONS: In a group of patients with well-defined primary sclerosing cholangitis, ursodiol provided no clinical benefit.     

Enhanced performance feedback to strengthen biofeedback treatment outcome with childhood migraine

The activity of rifabutin (LM 427) against Mycobacterium leprae was evaluated in armadillos inoculated earlier with human-derived M. leprae. Rifabutin was administered daily at a dose of 6 mg/kg body weight/day. The effect of rifabutin on M. leprae harvested from armadillos was determined by measuring the intracellular levels of ATP (an indicator of metabolic activity) of M. leprae and also their ability to multiply in the mouse footpads and in vitro in DH medium. Within 2 weeks of initiating the treatment, ATP levels declined to 21% of the original (pre-treatment level) and these M. leprae failed to multiply in the footpads of mice as well as in the in vitro culture system. This suggests that rifabutin was able to kill all M. leprae within 2 weeks. After 8 weeks the treatment was terminated and results showed that M. leprae from the treated armadillos remained non-viable in the mouse footpad system as well as in the in vitro system, indicating bactericidal action of rifabutin. The results suggest that rifabutin can be a substitute for rifampin in the leprosy multi-drug therapy regimen.     

Heme oxygenase 1 is required for mammalian iron reutilization

Stressed mammalian cells up-regulate heme oxygenase 1 (Hmox1; EC 1.14.99.3), which catabolizes heme to biliverdin, carbon monoxide, and free iron. To assess the potential role of Hmox1 in cellular antioxidant defense, we analyzed the responses of cells from mice lacking functional Hmox1 to oxidative challenges. Cultured Hmox1(-/-) embryonic fibroblasts demonstrated high oxygen free radical production when exposed to hemin, hydrogen peroxide, paraquat, or cadmium chloride, and they were hypersensitive to cytotoxicity caused by hemin and hydrogen peroxide. Furthermore, young adult Hmox1(-/-) mice were vulnerable to mortality and hepatic necrosis when challenged with endotoxin. Our in vitro and in vivo results provide genetic evidence that up-regulation of Hmox1 serves as an adaptive mechanism to protect cells from oxidative damage during stress.     

The nature of the signals regulating CD8 T cell proliferative responses to CD8alpha+ or CD8alpha- dendritic cells

The CD8alpha(-)-expressing dendritic cells (DC) of mouse spleen have been shown to be poor inducers of interleukin (IL)-2 production by CD8 T cells when compared to the CD8- DC. As a consequence, CD8 T cells give a more prolonged proliferative response to CD8- DC than to CD8+ DC. The possible mechanisms underlying these functional differences in DC subtype have been investigated. Inadequate co-stimulation did not underlie the poor T cell response to allogeneic CD8+ DC. Equivalent levels of B7-1 (CD80) and B7-2 (CD86) were found on the two DC subtypes and co-stimulator assays did not reveal any functional differences between them. Although CD8+ DC were found to die more rapidly in culture than CD8- DC, this did not explain their reduced stimulatory ability. Neither prolonging DC survival in culture nor renewing the stimulator cells by repeated addition of freshly isolated DC had any significant effect on the T cell responses. Furthermore, later addition to the cultures of DC of the opposite type to the initiating DC did not reverse or eliminate the differential response to the initiating DC. The role of DC-derived soluble factors was examined by addition to the cultures of supernatants derived from freshly isolated or stimulated DC of the opposite type. This neither enhanced the poor stimulatory capacity of CD8+ DC nor inhibited the stimulation by CD8- DC. Furthermore, addition of a series of cytokines that might have been produced by the DC did not eliminate the differences in T cell proliferation. Only the addition to the cultures of the growth factors IL-2 and IL-4 overcame the stimulatory difference between the two DC populations, confirming that the difference in T cell proliferative responses was a consequence of differences in induced cytokine production. The difference in the response of CD8 T cells to CD8+ and CD8- DC is therefore determined by direct DC-T cell contact during the earliest stages of the culture and involves an undetermined and possibly new signaling system.     

Effect of antenatal administration of thyrotrophin releasing hormone on fetal flow velocity waveforms

AIM: To determine whether antenatal administration of thyrotrophin releasing hormone (TRH), to promote lung maturation, alters blood flow through the fetal middle cerebral, umbilical artery, or ductus arteriosus and through the maternal uterine arteries. METHODS: The effect of transplacentally administered TRH on the fetal circulation was prospectively evaluated in 30 patients between 24 and 34 weeks' gestation. TRH (400 micrograms) was given to the mother intravenously either as a bolus or an infusion. Fetal effects were determined by measuring the maximum velocity and pulsatility index (PI) in middle cerebral artery, ductus arteriosus, uterine artery and umbilical artery Doppler waveforms. Measurements were made immediately before, and 10 and 60 minutes after maternal TRH administration. RESULTS: Intravenous injection of TRH had no significant effect on PI in the uterine, umbilical, or middle cerebral artery and the ductus arteriosus within 60 minutes of administration in either group. CONCLUSION: The antenatal use of TRH in conjunction with steroids for fetal lung maturity does not affect utero-placental or fetal haemodynamic variables, as measured by Doppler. These findings, therefore, do not support the suggestion that antenatal intravenous administration of TRH either as bolus or infusion may have immediate adverse vascular effects in the fetus.     

Evaluation of bovine-derived bone protein with a natural coral carrier as a bone-graft substitute in a canine segmental defect model

The efficacy of a bone-graft substitute (bovine-derived bone protein in a carrier of natural coral) in the healing of a segmental defect of a weight-bearing long bone was evaluated. Twenty dogs, divided into two groups, underwent bilateral radial osteotomies with creation of a 2.5 cm defect. On one side of each dog, the defect was filled with autogenous cancellous bone graft. Contralateral defects received, in a blinded randomized fashion, cylindrical implants consisting of natural coral (calcium carbonate) or calcium carbonate enhanced with a standard dose of bovine-derived bone protein (3.0 mg/implant; 0.68 mg bone protein/cm3). The limbs were stabilized with external fixators, and all animals underwent monthly radiographs. They were killed at 12 (group 1) or 24 (group 2) weeks, and regenerated bone was studied by biomechanical testing and histology. Radiographic union developed in all 20 radii with autogenous cancellous bone grafts and in all 10 of the radii with the composite implants. None of the radii with implants of calcium carbonate alone showed radiographic evidence of union. This represented a statistically significant difference between implant types. In addition, calcium carbonate implants both with and without bone protein demonstrated radiographic evidence of near total resorption of the radiodense carrier by 12 weeks. This resorption facilitated radiographic evaluation of healing. Mean values for biomechanical parameters of radii with the composite implants exceeded those for the contralateral controls at 12 and 24 weeks; the difference was statistically significant at 12 weeks. Histology revealed scant residual calcium carbonate carrier at either time in the defects with calcium carbonate implants; however, a moderate amount was present in defects with the composite implants. In these specimens, the residual carrier was completely surrounded by newly formed bone that may have insulated the calcium carbonate from further degradation. The present study used a carrier of granular calcium carbonate reconstituted with bovine type-I collagen to deliver an osteoinductive protein to the defect site. This carrier is of nonhuman origin (eliminating the risk of disease transmission or antigenicity) and resorbs rapidly. In this model, bovine-derived bone protein in a natural coral carrier performed consistently better than the gold standard autogenous cancellous bone graft in terms of the amount of bone formation and strength of the healed defect. This may have implications for removal of hardware or resumption of weight-bearing in certain clinical situations. These data also indicate that coralline calcium carbonate alone represents a poor option as a bone-graft substitute in this critical-sized segmental defect model.     

Randomized study of prophylactic platelet transfusion threshold during induction therapy for adult acute leukemia: 10,000/microL versus 20,000/microL

PURPOSE: We designed and conducted a randomized single-institution trial comparing two common prophylactic platelet transfusion thresholds in patients undergoing induction therapy for acute leukemia. PATIENTS AND METHODS: Seventy-eight patients undergoing induction therapy for acute leukemia were randomized to receive prophylactic apheresis platelet concentrates when the platelet count was either < or = 10,000/microL or < or = 20,000/microL. RESULTS: There was no significant difference in the total number of bleeding episodes per patient with a median of four in the < or = 10,000/microL arm and two in the < or = 20,000/microL arm (25th to 75th percentiles of 2, 7 and 1, 5, respectively; P = .12). Patients randomized to the < or = 10,000/microL arm received more platelet transfusions for bleeding [one (0, 2) v zero (0, 0); P = .0003]. In contrast, patients on the < or = 20,000/microL arm received more platelet transfusions for prophylactic indications [10 (5, 14) v six (3, 8); P = 0.001], as would be expected, but less for bleeding. Nevertheless, the total number of platelet transfusions given to patients on the < or = 20,000/microL arm was higher and nearly significant [11 (6, 15) v seven (5, 11); P = .07]. There were no statistically significant differences between the groups with regard to RBC transfusion requirements, febrile days, days hospitalized, days thrombocytopenic, need for HLA-matched platelets, remission rate, or death during induction chemotherapy. No patient in either group died from hemorrhage or underwent major surgery for bleeding complications. CONCLUSION: Giving prophylactic platelets at a threshold of < or = 10,000/microL compared with < or = 20,000/microL can decrease the total utilization of platelets with only a small adverse effect on bleeding, and no statistically significant effect on morbidity.     

Astrocytic neurotransmitter receptors in situ and in vivo

In the brain, astrocytes are associated intimately with neurons and surround synapses. Due to their close proximity to synaptic clefts, astrocytes are in a prime location for receiving synaptic information from released neurotransmitters. Cultured astrocytes express a wide range of neurotransmitter receptors, but do astrocytes in vivo also express neurotransmitter receptors and, if so, are the receptors activated by synaptically released neurotransmitters? In recent years, considerable efforts has gone into addressing these issues. The experimental results of this effort have been compiled and are presented in this review. Although there are many different receptors which have not been identified on astrocytes in situ, it is clear that astrocytes in situ express a number of different receptors. There is evidence of glutamatergic, GABAergic, adrenergic, purinergic, serotonergic, muscarinic, and peptidergic receptors on protoplasmic, fibrous, or specialized (Bergmann glia, pituicytes, Müller glia) astrocytes in situ and in vivo. These receptors are functionally coupled to changes in membrane potential or to intracellular signaling pathways such as activation of phospholipase C or adenylate cyclase. The expression of neurotransmitter receptors by astrocytes in situ exhibits regional and intraregional heterogeneity and changes during development and in response to injury. There is also evidence that receptors on astrocytes in situ can be activated by neurotransmitter(s) released from synaptic terminals. Given the evidence of extra-synaptic signaling and the expression of neurotransmitter receptors by astrocytes in situ, direct communication between neurons and astrocytes via neurotransmitters could be a widespread form of communication in the brain which may affect many different aspects of brain function, such as glutamate uptake and the modulation of extracellular space.     

Significance of a false-positive trisomy 18 multiple-marker screening test

We report our results in 24 children with malignant primary bone tumours of the distal femur treated with a Stanmore extendible endoprosthesis (SEER). This consists of a femoral component that can be lengthened, a constrained knee and an uncemented sliding tibial component which crosses the proximal tibial physeal plate perpendicularly. The average age of the patients at diagnosis was ten years and the mean follow-up was 4.7 years (2.5 to 7.9). The mean growth of the affected tibia was 76% (18 to 136) and of the fibula 83% (15 to 750) of the growth of the unaffected limb. Measurement of growth arrest lines showed that the mean growth of the proximal tibial physis on the affected side was 69% (43 to 100) of that of the normal side. The great variability in the growth of the physis cannot yet be explained.