Uroporphyria induced by 5-aminolaevulinic acid alone in Ahrd SWR mice

In mice, depression of hepatic uroporphyrinogen decarboxylase (UROD) leading to porphyrin accumulation (uroporphyria) occurs with chlorinated ligands of the aryl hydrocarbon (AH) receptor especially after iron overload. However, in the absence of chlorinated ligands, iron itself will eventually cause uroporphyria, but this response is not associated with the Ahr genotype. These effects are potentiated by administration of the haem precursor 5-aminolaevulinate (ALA). The aim of this study was to investigate the effects of ALA alone. Prolonged administration of 2 mg ALA/mL in the drinking water to SWR mice also led to decarboxylase insufficiency (11% of control) and uroporphyria by 8 weeks, whereas DBA/2 mice did not show reduced enzyme activity. Both strains are considered AH nonresponsive and analysis of the Ahr gene using restriction fragment length polymorphism was consistent with SWR, like DBA/2, possessing the Ahrd allele. Exposure of isolated hepatocytes to ALA (150-500 microM) for up to 48 hr showed a significant accumulation of both uroporphyrin and coproporphyrin in the medium, which for uroporphyrin particularly was significantly greater with SWR than with DBA/2 cells. Basal in vivo CYP1A2 activity, measured as microsomal methoxyresorufin dealkylation, was significantly greater in SWR than in DBA/2 mice (1.3-fold), but it was unclear whether this was sufficient to explain the marked difference in sensitivities of the two strains. Despite SWR mice being AH nonresponsive, uroporphyria and decarboxylase depression after an initial iron overload and ALA for 3 weeks were greatly potentiated by a single dose (100 mg/kg) of hexachlorobenzene (a weak AH ligand). The results demonstrate that there is a genetic difference in mice independent of the Ahr genotype and response to iron, which influences the susceptibility to ALA-induced uroporphyria. Thus chemicals, iron and ALA can act independently, but also together, to cause porphyria in susceptible individuals.     

The effect of unilateral varus rotational osteotomy with or without pelvic osteotomy on the contralateral hip in patients with perinatal static encephalopathy

The hexane fractions from methanolic extracts of Anetheum graveolens L. (Umbelliferae) and Acorus gramineus Soland. (Araceae), revealed potent inhibitory activities against the resistance of multi-drug resistant Staphylococcus aureus SA2 when combined with ampicillin (Am) or chloramphenicol (Cm). As active principles, carvone and the liquid mixture containing carvone from Anetheum graveolens L. and a liquid mixture mainly consisting of benzoic acid phenylmethyl ester (benzyl benzoate) from Acorus gramineus Soland, were identified. They showed resistance inhibition at the level of 20-50 micrograms/ml when combined with 100 or 50 micrograms/ml of Am or Cm, respectively.     

Control of testicular vasomotion by testosterone and tubular factors in rats

We have compared the pharmacological and molecular characteristics of 2 cell lines derived from the C6 rat glioblastoma, and selected for resistance either to doxorubicin (C6 0.5 line) or to vincristine (C6 IV line). Each line displays a preferential 400-fold resistance towards the drug used for selection, the C6 IV line being especially weakly resistant to doxorubicin (13-fold). Verapamil completely restored doxorubicin sensitivity in the C6 IV line as well as vincristine resistance in the C6 0.5 line, but could not completely reverse doxorubicin resistance in the C6 0.5 line or vincristine resistance in the C6 IV line. This suggests that specific mechanisms of resistance against each drug were added to a common P-glycoprotein-mediated multidrug-resistance mechanism. Doxorubicin efflux was total within 2 hr in the C6 IV line, whereas it remained 8 to 10% of drug in the C6 0.5 line 4 hr after drug removal, despite a more rapid efflux of the drug in the first 30 min. This 2-compartment behavior could be related to a special sub-cellular distribution of doxorubicin in C6 0.5 cells. Northern and Western blot analysis of the mdrI gene and of the P-glycoprotein expressed by the 2 resistant cell lines made it possible to quantify their degree of over-expression; when compared with the C6 wild strain, the C6 0.5 line over-expressed both the mdrI gene and the P-glycoprotein to a slightly higher level than the C6 IV line. Northern and Western blot analysis also suggested that C6 0.5 cell preferentially over-expressed the mdrIa gene, whereas the C6 IV cells preferentially over-expressed the mdrIb gene. This differential over-expression was confirmed after polymerase-chain-reaction amplification of the cDNA sequences transcribed from total RNA extracted from the 2 lines. It can be concluded therefore that the mdrIa gene product is more efficient than the mdrIb gene product in extruding anti-cancer drugs from the cells; and that the mdrIb gene product might preferentially extrude vincristine rather than doxorubicin.     

The role of histones and their modifications in the informative content of chromatin

It is traditionally accepted that the DNA sequence cannot by itself explain all the mechanisms necessary for the development of living beings, especially in eukaryotes. Indeed part of the information used in these processes is stored in other ways, generally called 'epigenetic', whose molecular mechanisms are mostly unknown. The ultimate explanation for them might reside in the non-DNA moiety of chromatin which may play an active role in heredity ('chromatin information'). Histones are the universal structural component of chromatin. However, recent studies strongly suggest that histones, and their modifications--especially the reversible acetylation of lysines--may act as a recognition signal for regulatory proteins and they may participate, for this reason, in gene regulation. This type of information could be maintained through its replication and, ultimately, it could form the molecular basis of certain processes related to the development of the eukaryotic organisms.     

Risk of cancer in Finnish children living close to power lines

OBJECTIVE: To investigate the risk of cancer in children living close to overhead power lines with magnetic fields of > or = 0.01 microteslas (microT). DESIGN: Cohort study. SETTING: The whole of Finland. SUBJECTS: 68,300 boys and 66,500 girls aged 0-19 years living during 1970-89 within 500 m of overhead power lines of 110-400 kV in magnetic fields calculated to be > or = 0.01 microT. Subjects were identified by record linkages of nationwide registers. MAIN OUTCOME MEASURES: Numbers of observed cases in follow up for cancer and standardised incidence ratios for all cancers and particularly for nervous system tumours, leukaemia, and lymphoma. RESULTS: In the whole cohort 140 cases of cancer were observed (145 expected; standardised incidence ratio 0.97, 95% confidence interval 0.81 to 1.1). No statistically significant increases in all cancers and in leukaemia and lymphoma were found in children at any exposure level. A statistically significant excess of nervous system tumours was found in boys (but not in girls) who were exposed to magnetic fields of > or = 0.20 microT or cumulative exposure of > or = 0.40 microT years. CONCLUSIONS: Residentia magnetic fields of transmission power lines do not constitute a major public health problem regarding childhood cancer. The small numbers do not allow further conclusions about the risk of cancer in stronger magnetic fields.     

Geometric and mechanical properties of the coracoacromial ligament and their relationship to rotator cuff disease

One of the most common causes of pain and disability in the upper limb is inflammation of the rotator cuff tendons. When no significant bony abnormality exists in the surrounding structures, the coracoacromial ligament has been implicated as a possible cause of impingement on the cuff tendons. Geometric and mechanical properties of 20 coracoacromial ligaments, 10 from shoulders with rotator cuff tears and 10 from normal shoulders, were accurately determined. In comparing rotator cuff tear and normal specimens, statistically significant changes in geometric properties were measured in the lateral band, but not in the medial band, of the ligament. The lateral band, which is the region most likely to impinge on the rotator cuff, was shorter and had a larger cross-sectional area in specimens with rotator cuff tears. Although there were no statistical differences in structural properties of the ligament between normal and rotator cuff tear groups, significant changes were evident in material properties. Previously reported histologic differences in the ligament in shoulders with rotator cuff tears are supported by the decreased material properties measured in the current study. Whether the differences in the coracoacromial ligament cause impingement or are due to impingement is still unknown at this time.     

Determination of DNA damage in F344 rats induced by geometric isomers of tamoxifen and analogues

The transformation of Trypanosoma cruzi epimastigotes to mammal-infective metacyclic trypomastigotes (metacyclogenesis) can be performed in vitro under chemically defined conditions (TAU 3AAG medium). During this process, changes in the nature of cell surface sugar composition and sugar distribution was evaluated using FITC and gold-labeled lectins and observed by flow cytometry and transmission electron microscopy. The pattern of labeling with the lectins from Triticum vulgaris (WGA), Arachis hypogaea (PNA), Limax flavus (LFA), Canavalia ensiformis (Con-A), and Ricinus communis (RCA-I) significantly changed during the metacyclogenic process. The results obtained are discussed in relation to the role played by T. cruzi cell surface carbohydrate residues on the process of parasite-host cell interaction.     

The academic health center and the healthy community

US medical care reflects the priorities and influence of academic health centers. This paper describes the leadership role assumed by one academic health center, the State University at Buffalo's School of Medicine and Biomedical Sciences and its eight affiliated hospitals, to serve its region by promoting shared governance in educating graduate physicians and in influencing the cost and quality of patient care. Cooperation among hospitals, health insurance payers, the business community, state government, and physicians helped establish priorities to meet community needs and reduce duplication of resources and services; to train more primary care physicians; to introduce shared governance into rural health care delivery; to develop a regional management information system; and to implement health policy. This approach, spearheaded by an academic health center without walls, may serve as a model for other academic health centers as they adapt to health care reform.