Role of the modular domains of SR proteins in subnuclear localization and alternative splicing specificity

SR proteins are required for constitutive pre-mRNA splicing and also regulate alternative splice site selection in a concentration-dependent manner. They have a modular structure that consists of one or two RNA-recognition motifs (RRMs) and a COOH-terminal arginine/serine-rich domain (RS domain). We have analyzed the role of the individual domains of these closely related proteins in cellular distribution, subnuclear localization, and regulation of alternative splicing in vivo. We observed striking differences in the localization signals present in several human SR proteins. In contrast to earlier studies of RS domains in the Drosophila suppressor-of-white-apricot (SWAP) and Transformer (Tra) alternative splicing factors, we found that the RS domain of SF2/ASF is neither necessary nor sufficient for targeting to the nuclear speckles. Although this RS domain is a nuclear localization signal, subnuclear targeting to the speckles requires at least two of the three constituent domains of SF2/ASF, which contain additive and redundant signals. In contrast, in two SR proteins that have a single RRM (SC35 and SRp20), the RS domain is both necessary and sufficient as a targeting signal to the speckles. We also show that RRM2 of SF2/ASF plays an important role in alternative splicing specificity: deletion of this domain results in a protein that, although active in alternative splicing, has altered specificity in 5' splice site selection. These results demonstrate the modularity of SR proteins and the importance of individual domains for their cellular localization and alternative splicing function in vivo.     

News Media Use and Adolescents' Attitudes about Nuclear Issues: An American-Soviet Comparison

Both Soviet and American youth show a great concern about the possible effects of nuclear war, with heavy media users in both countries more optimistic, but the relation was stronger among Soviet students.     

Intramuscular ceftriaxone compared with oral amoxicillin-clavulanate for treatment of acute otitis media in children

Two hundred and fifteen children aged 4 months 6 years with acute otitis media (AOM) were randomized to be treated either by a single i.m. injection of ceftriaxone, 50 mg/kg, with a second dose in the event of unsatisfactory response after 48 h or a history of recurrent AOM (109 patients) or amoxicillin clavulanate 12.5 mg tid (106 patients). The failure rate was similar in children treated by ceftriaxone and amoxicillin clavulanate, 4.6% and 4.7%, respectively (standard error for intergroup difference -2.87%, 95% confidence interval -5.62% to 5.87%). No significant differences between the groups were found in the dynamics of the resolution of the acute symptomatology, otoscopy findings, relapse rate at 30 days or tympanographic evidence of middle ear effusion at the scheduled visits on days 30, 60 and 90. Recurrence of AOM between days 31 and 90 was observed significantly in more children treated with amoxicillin clavulanate than with ceftriaxone--25 out of 84 (29.4%) versus 11 out of 81 (13.6%) (P = 0.012). Conclusion: Ceftriaxone injection(s) is as efficient at least as 10-day oral amoxicillin clavulanate for treatment of acute otitis media in children. Although not recommended as routine, ceftriaxone can be considered in the management of acute otitis media under special circumstances, particularly in cases when the ability to tolerate or absorb oral drugs is compromised, in children refusing or unable to take oral therapy or when the compliance is questionable.     

Estimation of foetal brain dose from I-131 in the foetal thyroid

The ingestion of I-131 by pregnant women can have consequences for the developing foetus, in particular brain function. As the foetal thyroid accumulates iodine from the twelfth week of gestation onwards, the determination of foetal brain dose resulting from such I-131 accumulation is essential. Normal dosimetric methods fail to treat the case of foetus. Using an approximation method based on the MIRD approach, a foetal dose estimation scheme is developed to allow the determination of foetal brain dose from foetal thyroid irradiation. Dose values are obtained for the foetus based on the maternal intake of I-131. It was found that the choice of biokinetic model for the mother/foetus has a large impact on the determined dose estimate.     

Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes

We analyzed the management of regional lymph nodes in 110 patients with squamous cell carcinoma of the penis treated at the Netherlands Cancer Institute between 1956 and 1989 with curative intent. Of 66 patients who presented with unsuspected nodes 57 were placed on a surveillance program, while lymph node dissection was performed in 5 (with adjuvant external radiation therapy in 1) and 4 were treated with external radiation therapy only. The management of 40 patients with clinically suspected nodes included surveillance in 5, lymph node dissection in 27 (with adjuvant radiotherapy in 11), biopsy in 4 and external radiation therapy in 4. Postoperative radiotherapy had been given if more than 2 nodes were involved or when extracapsular growth was observed. Overall, 25 patients had a regional recurrence, 5 of whom could be cured subsequently. All regional recurrences developed within 2 years after primary treatment. Analysis showed 100% survival in histologically proved node negative patients (stage pN0). The success of lymph node dissection was related to the extent of the metastatic spread and to the number of involved nodes. Patients with 1 positive node and unilateral inguinal involvement showed a statistically significant survival advantage compared to patients with more extensive spread. Considering the indications for node dissection we found a clear relationship among T category, grade and the probability of lymph node invasion. Patients with stage T1 tumors and stage T2, grades 1 and 2 tumors presented significantly less often with lymphatic invasion than those with other categories of disease and were less likely to have a regional recurrence after treatment of the primary tumor only. In these categories we recommend surveillance of the regional lymph nodes in patients who present with unsuspected nodes. However, patients with stage T2 grade 3, stage T3 and operable stage T4 tumors should undergo an immediate inguinal node dissection because of the high probability of clinically occult lymph node invasion (in our material more than 50%). With respect to the extent of the node dissection, we found that the likelihood of spread to the contralateral and/or pelvic regions was related to the number of invaded nodes in the inguinal region. We recommend contralateral node dissection and unilateral pelvic node dissection when 2 or more positive nodes are found in the dissected groin specimen. Primary pelvic node dissection should be performed in patients who present initially with cytologically or biopsy proved positive inguinal nodes.(ABSTRACT TRUNCATED AT 400 WORDS)     

Acute Weston Hurst necrotizing hemorrhagic leukoencephalitis

The clinical and pathological findings of a 43-year-old woman, diagnosed as having acute hemorrhagic leukoencephalitis at postmortem examination, are presented. The acute hemorrhagic leukoencephalitis affects mainly young adults and is the most fulminant from of demyelinating disease. It is frequently preceded by a respiratory infection. Diagnosis is facilitated by CT scanning and MRI, which reveal the massive lesion in the cerebral white matter. Many cases terminate fatally in 2 or 4 days, but in others survival is longer. The pathological findings are distinctive.