Mammalian base excision repair and DNA polymerase beta

OBJECTIVE: To describe six dogs with congenital abnormalities involving the portal vein, caudal vena cava, or both. ANIMALS: Six client-owned dogs with congenital interruption of the portal vein or the caudal vena cava, or both. METHODS: Portal vein and caudal vena cava anatomy was evaluated by contrast radiography and visualization at surgery. Vascular casts or plastinated specimens were obtained in three animals. RESULTS: Portal blood shunted into the caudal vena cava in four dogs and the left hepatic vein in one. Two of these five dogs also had interruption of the caudal vena cava with continuation as azygous vein, as did an additional dog, in which the portal vein was normally formed. Portal vein interruption was present in 5 of 74 (6.8%) dogs with congenital portosystemic shunts evaluated at the Veterinary Teaching Hospital during the study period. CONCLUSIONS: Serious malformations of the abdominal veins were present in more than 1 in 20 dogs with single congenital portosystemic shunts. CLINICAL RELEVANCE: Veterinarians involved in diagnosis and surgery for portosystemic shunts should be aware of these potential malformations, and portal vein continuity should be evaluated in all dogs before attempting shunt attenuation.     

The human homologue for the Caenorhabditis elegans cul-4 gene is amplified and overexpressed in primary breast cancers

Amplification is a key mechanism whereby a cancer cell increases the message level of genes that confer a selective advantage when they are overexpressed. In breast cancer, there are many chromosome regions present in multiple copies relative to overall DNA copy number (amplicons), and their target genes are unknown. Using differential display, we have cloned and sequenced the full coding region of a candidate amplicon target gene located on chromosome 13. This candidate is the human homologue of the Caenorhabditis elegans cul-4 gene, cul-4A, a member of the novel cullin gene family, which is involved in cell cycle control of C. elegans. cul-4A was amplified and overexpressed in 3 of 14 breast cancer cell lines analyzed, and it was overexpressed in 8 additional cell lines in which it was not amplified. The latter observation, indicating that its overexpression can occur by mechanisms other than gene amplification, suggests that cul-4A plays a key role in carcinogenesis. Moreover, cul-4A was found to be amplified in 17 of 105 (16%) cases of untreated primary breast cancers, and 14 of 30 cases analyzed (47%) were shown by RNA in situ hybridization to overexpress cul-4A. These results suggest that up-regulation of cul-4A may play an important role in tumor progression.     

The role of ifosfamide in paediatric cancer

Postmortem studies have associated Alzheimer's disease (AD) with regionally increased oxidative damage to brain. Lacking, however, is a specific marker of oxidative damage to brain that may be measured during life. We tested the hypothesis that cerebrospinal fluid (CSF) concentrations of F2-isoprostanes (F2-IsoPs), stable products of arachidonate peroxidation, are increased in CSF of AD patients. CSF from lateral ventricles (VF) was analyzed from 11 AD patients and 11 control subjects who participated in a rapid autopsy program. VF F2-IsoP concentrations were significantly elevated in AD patients compared with control subjects (72 +/- 7 vs 46 +/- 4 pg/ml) and were significantly linearly correlated with brain weight (-0.3 pg/ml/g, r2 = 0.32). These results suggest that quantification of CSF F2-IsoP concentrations may provide a useful biomarker of central nervous system oxidative damage in AD.     

Peptides that mimic the group B streptococcal type III capsular polysaccharide antigen

In some but not all arterial beds, smooth muscle cell calcium-activated K+ channels (KCa channels) play a central role in the mediation of the vasodilator response to nitric oxide (NO) and other nitrates. We investigated the effect of nitrates on KCa channels in the relaxation of human coronary arteries by means of isometric contraction experiments in arterial rings. We also measured whole-cell currents in freshly isolated human coronary artery vascular smooth muscle cells via the patch-clamp technique. Sodium nitroprusside, diethylamine-nitric oxide complex sodium salt and isosorbide mononitratre completely relaxed rings preconstricted with 5 microM serotonin and produced dose-dependent relaxations of 5 microM serotonin-preconstricted human rings. The relaxations were inhibited by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-oxyl 3-oxide (10 microM), which neutralizes nitric oxide. The KCa channel blockers iberiotoxin (100 nM) and tetraethylammonium ions (1 mM) significantly inhibited SNP-induced relaxations of human coronary arteries. Moreover, in the patch-clamp experiments, SNP (1 microM) stimulated KCa currents and spontaneous transient outward K+ currents carried by Ca spark activated KCa channels. The SNP-induced (1 microM) KCa current was strongly inhibited by iberiotoxin (100 nM). These data show that activation of KCa channels in smooth muscle cells contributes to the vasodilating actions of nitrates and nitric oxide in human coronary arteries. This finding may have unique clinical significance for the development of antianginal and antihypertensive drugs that selectively target K+ channels and Ca sparks.     

Laminin and alpha-dystroglycan mediate acetylcholine receptor aggregation via a MuSK-independent pathway

Specific isoforms of laminin (LN) are concentrated at neuromuscular junctions (NMJs) where they may participate in synaptic organization or function. In myotubes from C2 cells, LN is concentrated within the majority of spontaneous acetylcholine receptor (AChR) aggregates. Neural agrin substantially increases this colocalization, suggesting that agrin can recruit LN into AChR aggregates. Addition of LN to C2 myotubes induces a more than twofold increase in the number of AChR aggregates. These aggregates have a larger size and are more dense than are those induced by agrin, suggesting that LN is involved in the growth and/or stabilization of AChR aggregates. Consistent with this hypothesis, an antiserum to LN reduces the size of individual AChR aggregates but increases their number. In C2 myotubes, extracellular matrix receptors containing the integrin beta1 subunit are poorly colocalized with AChR aggregates, suggesting that integrins may not be involved in LN-induced aggregation. In contrast, almost all AChR aggregates are associated with dystroglycan immunoreactivity, and monoclonal antibody (mAb) IIH6 against alpha-dystroglycan (alpha-DG), a LN and agrin receptor, causes a concentration-dependent inhibition of LN-induced aggregation. Moreover, S27 cells, which lack a functional alpha-DG, and two C2-derived cell lines expressing antisense DG mRNA fail to aggregate AChRs in response to LN. Finally, LN-induced AChR aggregation does not involve the phosphorylation of the muscle-specific tyrosine kinase receptor (MuSK) or the AChR beta subunit. We hypothesize that the interaction of LN with alpha-DG contributes to the growth and/or stabilization of AChR microaggregates into macroaggregates at the developing NMJ via a MuSK-independent mechanism.     

The prevalence of Addison's disease in Coventry, UK

The prevalence of Addison's disease (chronic adrenal failure) has not been widely investigated and is usually given as 39 in a million. We conducted a prevalence study using a postal survey of general practitioners in Coventry. Three quarters (139/188) replied, representing 79/85 (93%) of the practices. Thirty cases of Addision's disease were found from a total patient list of 323852, of which a third were tuberculous in origin and two-thirds non-tuberculous (12/30 autoimmune, 8/30 unclassified). We conclude that Addison's disease is 2.4 times more common than previously reported. The tuberculous group was older, 65 vs 52 years (p < 0.05), and had had the disease for longer than the non-tuberculous group, 20 vs 12 years (p < 0.05). There was no significant difference in the age at diagnosis.     

Microbicidal activity of eosinophils is associated with activation of the arginine-NO pathway

The burden, the coping strategies and the social network of a sample of 236 relatives of patients with schizophrenia, living in five European countries, were explored by well-validated assessment instruments. In all centres, relatives experienced higher levels of burden when they had poor coping resources and reduced social support. Relatives in Mediterranean centres, who reported lower levels of social support, were more resigned, and more often used spiritual help as a coping strategy. These data indicate that family burden and coping strategies can be influenced by cultural factors and suggest that family interventions should have also a social focus, aiming to increase the family social network and to reduce stigma.