Dimerization is required for transactivation by estrogen-receptor-related (ERR) orphan receptors: evidence from amphioxus ERR.

The estrogen-receptor-related (ERR) receptors are orphan members of the nuclear receptor superfamily that bind to their specific DNA target sites as homodimers. However, it has not been shown whether this mode of binding is required for the transcriptional activation they drive. We here show that heterodimerization can also occur between these receptors. Furthermore, we demonstrate that the unique amphioxus ortholog of ERR genes (AmphiERR) is expressed as two isoforms differing by an in-frame insertion. While the short isoform behaves like its mammalian counterparts, the long isoform (AmphiERR(L)) displays divergent transcriptional properties according to the target site to which it binds. Indeed, AmphiERR(L) binds as a monomer but does not activate transcription through the SF1 response element (SFRE). On the contrary, this isoform binds as a homodimer and activates transcription through the classical estrogen-response element. Our results strongly suggest that dimerization is required for transactivation exerted by the ERR receptors.

Characterization of oestrogen receptors in zebrafish (Danio rerio).

We cloned the cDNAs corresponding to three oestrogen receptors (ERs) in zebrafish (Danio rerio). Sequence analysis and phylogenetic studies demonstrated that two of these genes, ER beta.1 and ER beta.2, arose from duplication of the original ER beta in many species of the fish phylum, whereas ER alpha is unique. Zebrafish ERs behaved as oestrogen-dependent transcription factors in transactivation assays. However, their reactivity to various oestrogen modulators was different compared with that of mouse ERs. ER mRNA expression during zebrafish development is restricted to distinct time periods, as observed by RNase protection assays. ER beta.2 is initially expressed as maternally transmitted RNA, until 6 h after fertilization, when expression disappears. Between 6 and 48 h after fertilization, no ER expression could be observed. After 48 h after fertilization, all ERs, but predominantly ER alpha, began to be expressed. We conclude that oestrogen signal transduction can operate during zebrafish development only within discrete time windows.

Euteleost fish genomes are characterized by expansion of gene families.

The presence of additional hox clusters in the zebrafish has led to the hypothesis that there was a whole genome duplication at the origin of modern fish. To investigate the generality of this assumption, we analyzed all available actinopterygian fish gene families, and sequenced nuclear receptors from diverse teleost fish. The origin and timing of duplications was systematically determined by phylogenetic analysis. More genes are indeed found in zebrafish than in mouse. This abundance is shared by all major groups of euteleost fish, but not by eels. Phylogenetic analysis shows that it may result from frequent independent duplications, rather than from an ancestral genome duplication. We predict two zebrafish paralogs for most mouse or human genes, thus expressing a note of caution in functional comparison of fish and mammalian genomes. Redundancy appears to be the rule in fish developmental genetics. Finally, our results imply that the outcome of genome projects cannot be extrapolated easily between fish species.

Risk factors for diabetes mellitus in chronic pancreatitis.

BACKGROUND & AIMS: The influence of disease progression and pancreatic surgery on the appearance of diabetes mellitus in patients with chronic pancreatitis is unknown. METHODS: A prospective cohort study of 500 consecutive patients with chronic pancreatitis (alcoholics, 85%) followed up over a mean period of 7.0 +/- 6.8 years in a medical-surgical institution between 1973 and 1996 was performed. Multivariate analysis of risk factors for diabetes mellitus was performed after exclusion of 47 patients. Patients who underwent elective pancreatic surgery (n = 231, 51%) were compared with patients who never underwent surgery (n = 222, 49%). RESULTS: The cumulative rate of diabetes mellitus was 83% +/- 4% 25 years after the clinical onset of chronic pancreatitis (insulin requirement, 54% +/- 6%). The prevalence of diabetes mellitus did not increase in the surgical group overall but was higher 5 years after distal pancreatectomy (57% +/- 8%) than after pancreaticoduodenectomy (36% +/- 18%), pancreatic drainage (36% +/- 13%), or cystic, biliary, or digestive drainage (24% +/- 7%) (P = 0. 005), without difference in the latter ones. Pancreatic drainage did not prevent the onset of diabetes mellitus. Distal pancreatectomy (risk ratio, 2.4; 95% confidence interval [CI], 1.6-3.8; P < 0.0001) and early onset of pancreatic calcifications (risk ratio, 3.2; CI, 2. 2-4.7; P < 0.0001) were the only independent risk factors for diabetes mellitus. CONCLUSIONS: The risk of diabetes mellitus is not influenced by elective pancreatic surgical procedures other than distal pancreatectomy in patients with chronic pancreatitis. This risk seems to be largely caused by progression of the disease because it increased by more than 3-fold after the onset of pancreatic calcifications.

Clinical effects of root instrumentation using conventional steel or non-tooth substance removing plastic curettes during supportive periodontal therapy (SPT).

Although root instrumentation has been accepted as the most important cause-related treatment of periodontal diseases, repeated scaling and root planing may over time result in substantive loss of tooth substance and increased sensitivity of the teeth. In an effort to minimize these side effects of therapy, non-root substance removing curettes have been developed. However, the clinical effects of such plastic curettes with regard to the control of the periodontal infection has not yet been established. The aims of this study were, therefore, to compare the effects of root instrumentation using plastic curettes (Universal Perio Soft Scaler, Hawe-Neos Dental, Bioggio, TI, Switzerland) versus conventional steel curettes on the periodontal conditions during supportive periodontal therapy. 40 subjects participated in this parallel, randomized, double blind, prospective longitudinal clinical study following active peridontal therapy. 20 subjects served as a control group and were treated with conventional steel curettes during a supportive periodontal care visit (SPT). The other 20 subjects, the experimental group, were treated using plastic curettes during a similar SPT visit. Clinical parameters, such as bleeding on probing (BOP) and probing pocket depth (PPD), were assessed at baseline and 3-6 months later at the next regular SPT visit. In addition, the BOP percentage was determined 10 days following baseline. The results showed that there were no statistically significant differences between the 2 treatment modalities regarding BOP and PPD at any observation time. Both treatments were effective in reducing the BOP percentage which ranged from 17-42% at baseline by about 40% after 10 days (mean BOP baseline: 26%, mean BOP after 10 days: 16%). This clinical study suggests that non-root substance removing curettes may be valuable instruments for periodontally treated patients during maintenance care, thus minimizing trauma on the hard structures of the teeth.

Sustained hypothyroidism induced by recombinant alpha interferon in patients with chronic hepatitis C.

Thyroid dysfunction has been reported in patients with malignant disease treated with recombinant alpha interferon. Two cases of hypothyroidism in patients with chronic hepatitis C treated with recombinant alpha interferon are reported. In one patient, interferon induced hypothyroidism in the absence of pre-existing thyroid dysfunction and in the other it aggravated a pre-existing thyroid dysfunction. Both patients developed a severe, sustained hypothyroidism requiring thyroxine treatment for one year or more after stopping alpha interferon. Diagnosis of hypothyroidism during treatment can be difficult because of the common side effects of alpha interferon. Thyroid function should be assessed before and during alpha interferon therapy in patients with chronic hepatitis C.