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.     

Revised cutoff values of serum aminotransferase in detecting viral hepatitis among CAPD patients: experience from Taiwan, an endemic area for hepatitis B

BACKGROUND: To determine the best cutoff values of aspartate aminotransferase (AST) and alanine amino-transferase (ALT) in detecting viral hepatitis C infection among patients of continuous ambulatory peritoneal dialysis (CAPD). METHODS: 90 (44 male and 46 female) CAPD patients and 526 adult controls (266 male, 260 female) were enrolled. Serum AST and ALT were measured by an auto-analyser monthly. Serum HBsAg was examined using a RIA method and anti-HCV by an second-generation EIA method. The best cutoff values of AST and ALT for detecting viral hepatitis were obtained from the ROC (receiver-operating characteristic) curve. RESULTS: The prevalence of anti-HCV(+) was significantly higher in CAPD patients (16.7%) than in normal controls (4.9%), while that of HBsAg(+) was similar in both groups. CAPD patients had significantly lower levels of serum aminotransferases compared to normal controls. Mean AST were 23.8 IU/l in normal control and 18.8 IU/l in the CAPD patients (P < 0.001). Mean ALT were 21.9 IU/l in normal controls and 15.3 IU/l in the CAPD patients (P < 0.001). CAPD patients with HCV infection had higher serum AST and ALT levels than those without. However, HBV infection did not cause significant serum aminotransferase elevation in patients. The conventional cutoff values of AST (40 IU/l) and ALT (40 IU/l) for detecting viral hepatitis yielded only a sensitivity of 27.3 and 18.2% respectively; on the contrary, our revised cutoff values of AST (24 IU/l) and ALT (17 IU/l) had better sensitivities (AST, 72.7%; ALT, 63.6%). For serial aminotransferase values, the sensitivity of AST and ALT for detecting HCV were 36.4 and 27.3% by conventional criteria, and were both 81.8%, by our newly revised criteria. CONCLUSIONS: Serum aminotransferase cutoff values should be modified for screening viral hepatitis in a CAPD population. Our new cutoff criteria had important clinical implications in providing benefits of earlier detection and possible prevention from chronic hepatic deteriorations.     

Use of an intravascular T1 contrast agent to improve MR cine myocardial-blood pool definition in man

The feasibility of improving myocardial/blood pool contrast in MR cine images through use of an intravascular contrast agent (Ferumoxtran, Advanced Magnetics, Inc., Cambridge, MA) was tested in four subjects. The contrast-to-noise ratio (CNR) demonstrated a trend toward improvement in the short axis and improved significantly in the long axis cine by an average of 128% (P < .05). Image intensity gradients at the myocardial/blood pool interface increased significantly in both the short and long axis (P < .01). It is expected that larger image intensity gradients at the endocardial border should improve the capabilities of automated segmentation algorithms, reducing the uncertainty and need for manual editing.     

Early patterning of prelimbic cortical axons to the striatal patch compartment in the neonatal mouse

The striatum receives excitatory input from virtually the entire cerebral cortex. In the adult, this input is segregated into two functionally distinct compartments of the striatum, the patch (striosome) and matrix regions. This study determined whether the patterning of corticostriatal afferents from the prelimbic cortex to the striatal patch compartment develops during the early period of collateral formation or instead at the time of peak synaptogenesis. Initial formation of corticostriatal axon collaterals was observed by embryonic day (E) 19. Quantification of corticostriatal collaterals revealed a significant increase in the number and complexity of collateral branches at postnatal day 6 as compared to E19. Concomitant with the increase in collateral branching, a heterogeneous pattern of collateralization consisting of parallel rows of corticostriatal collaterals was observed in the medial striatum. In addition to the rows, clusters of corticostriatal axons occurred more laterally. These clusters colocalized with patches of dense tyrosine hydroxylase-positive fibers, a marker for the striatal patch compartment in the neonatal mouse. Together, these data indicate that corticostriatal patterning occurs during the period of early axon collateralization resulting in a segregation of corticostriatal axon collaterals from the prelimbic cortex to the striatal patch compartment.     

Exclusion of BMP6 as a candidate gene for cleidocranial dysplasia

Cleidocranial dysplasia (CCD) is an autosomal dominant, generalized skeletal dysplasia in humans that has been mapped to the short arm of chromosome 6. We report linkage of a CCD mutation to 6p21 in a large family and exclude the bone morphogenetic protein 6 gene (BMP6) as a candidate for the disease by cytogenetic localization and genetic recombination. CCD was linked with a maximal two-point LOD score of 7.22 with marker D6S452 at theta = 0. One relative with a recombination between D6S451 and D6S459 and another individual with a recombination between D6S465 and CCD places the mutation within a 7 cM region between D6S451 and D6S465 at 6p21. A phage P1 genomic clone spanning most of the BMP6 gene hybridized to chromosome 6 in band region p23-p24 using FISH analysis, placing this gene cytogenetically more distal than the region of linkage for CCD. We derived a new polymorphic marker from this same P1 clone and found recombinations between the marker and CCD in this family. The results confirm the map position of CCD on 6p21, further refine the CCD genetic interval by identifying a recombination between D6S451 and D6S459, and exclude BMP6 as a candidate gene.     

The impact of hypothermia on dilutional coagulopathy

The control of hemorrhage in hypothermic patients with platelet and clotting factor depletion is often impossible. Determining the cause of coagulopathic bleeding (CB) will enable physicians to appropriately focus on rewarming, clotting factor repletion, or both. Objective: To determine the contribution of hypothermia in producing CB and ascertain if simultaneous hypothermia and dilutional coagulopathy (DC) interact synergistically. Method: Prothrombin time, partial thromboplastin time, and platelet function were determined at assay temperatures of 29 degrees to 37 degrees C on normal and critically ill, noncoagulopathic (NC) individuals. Dilutional coagulopathy was created using buffered saline and the assays repeated. Results: Hypothermic assay at < or = 35 degrees C significantly prolonged coagulation times. The effect of hypothermia on NC and DC samples was not different. Conclusion: Assays performed at 37 degrees C underestimate coagulopathy in hypothermic patients. The effect of hypothermia on NC and DC is not different, indicating the lack of a synergistic effect. Normalization of clotting requires both rewarming and clotting factor repletion.     

The histologic anatomy of the volar plate

The EU Concerted Action Workshop on 11q23 Abnormalities in Hematological Malignancies collected 550 patients with abnormalities involving 11q23. Of these, 53 patients had a translocation involving chromosome 11, breakpoint q23, and chromosome 19, breakpoint p13. Karyogram review enabled each patient to be further defined as t(11;19)(q23;p13.1) (21 patients) or t(11;19)(q23;p13.3) (32 patients). There was a marked difference between the type of banding and the translocation identified: t(11;19)(q23;p13.1) was detected predominantly by R-banding, whereas t(11;19)(q23;p13.3) was detected almost solely by G-banding. Additional change was extremely rare in patients with t(11;19)(q23;p13.1) but occurred in nearly half of the patients with t(11;19)(q23;p13.3). Patients with t(11;19)(q23;p13.1) all had leukemia of a myeloid lineage, mostly acute myeloid leukemia (AML), and were predominantly adult. In contrast patients with t(11;19)(q23;p13.3) had malignancies of both myeloid and lymphoid lineage and were mainly infants less than 1 year old. The survival of both groups of patients was generally poor, over 50% of t(11;19)(q23;p13.1) patients died within 2 years of diagnosis and the median survival of acute lymphoblastic leukemia (ALL) patients with t(11;19)(q23;p13.3) was 17.6 months.     

Diagnostic and prognostic relevance of malignancy-associated changes in cervical smears

OBJECTIVE: For approximately 15 years, malignancy-associated changes (MACs) have been consistently found by means of high-resolution cytometry in different tissues, especially in visually normal appearing cervical cells. Their biologic nature is not yet fully understood. The aim of this investigation was to assess the expression of MACs in cervical smears and to evaluate their prognostic relevance. STUDY DESIGN: This study was performed on normal intermediate cells obtained from 53 cytologically positive and 78 cytologically negative cervical smears. From a second sample, 31 cases showing negative cytology were selected for a prospective longitudinal study. Densitometric and texture features were generated, and MACs were described on the basis of multivariate discriminant analysis. RESULTS: Discrimination between positive and negative cases was possible, with a correct classification rate of approximately 80%. After a mean period of 29.5 months, we noted no statistically significant increase in the incidence of cervical intraepithelial neoplasia in the group of healthy but MAC-positive women as compared to those who were MAC negative. CONCLUSION: MACs were constantly expressed in the epithelium of the cervix. Although their prognostic relevance remains unclear, MACs play an important role in the effort to automate cervical cytology.     

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.