Non-additivity in protein-DNA binding.

MOTIVATION: Localizing protein binding sites within genomic DNA is of considerable importance, but remains difficult for protein families, such as transcription factors, which have loosely defined target sequences. It is generally assumed that protein affinity for DNA involves additive contributions from successive nucleotide pairs within the target sequence. This is not necessarily true, and non-additive effects have already been experimentally demonstrated in a small number of cases. The principal origin of non-additivity involves the so-called indirect component of protein-DNA recognition which is related to the sequence dependence of DNA deformation induced during complex formation. Non-additive effects are difficult to study because they require the identification of many more binding sequences than are normally necessary for describing additive specificity (typically via the construction of weight matrices). RESULTS: In the present work we will use theoretically estimated binding energies as a basis for overcoming this problem. Our approach enables us to study the full combinatorial set of sequences for a variety of DNA-binding proteins, make a detailed analysis of non-additive effects and exploit this information to improve binding site predictions using either weight matrices or support vector machines. The results underline the fact that, even in the presence of significant deformation, non-additive effects may involve only a limited number of dinucleotide steps. This information helps to reduce the number of binding sites which need to be identified for successful predictions and to avoid problems of over-fitting. AVAILABILITY: The SVM software is available upon request from the authors.

Annular pancreas and intermittent duodenal obstruction in an alcoholic adult.

Annular pancreas is a congenital anomaly which, though present at birth, may cause few symptoms until adulthood. A case of annular pancreas with intermittent duodenal obstruction is described in a 49-year-old alcoholic man. Few other entities cause such obstruction. In similar cases, clinical suspicion of annular pancreas may lead to prompt diagnosis and treatment.

Evaluation of dye penetrations around two resin-based materials used as fissure sealants.

Two materials, based on Bis GMA resin, which may be used as fissure sealants were evaluated for dye penetration between sealant and enamel. The conventional fissure sealant (Durafil Flow) showed the greatest degree of dye penetration in the largest number of specimens. The penetration of the dye was less extensive when a filled resin (P30) was used. The use of a dentine adhesive together with the filled resin further reduced the penetration of the dye. The number of teeth exhibiting leakage with this treatment was the smallest noted.

Abnormal crypts of Morgagni: the cause of perianal abscess and fistula-in-ano.

Fistula-in-ano in infants is thought to begin with a cryptitis that proceeds to a perianal abscess. Of 52 patients in 15 years, 51 were male, 45 were under 12 months, 7 had multiple tracts, and 2 recurred in 6 years; all of which points to a developmental anomaly. We believe the anomaly to be a markedly irregular thickened dentate line that harbors from 3 to 13 deep (3 to 10 mm) abnormal crypts (AC), which foster cryptitis. There have been no recurrences since we started doing cryptotomies on these AC in addition to the fistulotomy. The cause may be a defect in the dorsal portion of the cloacal membrane which fuses with the hindgut during the seventh week.

Surgical versus nonoperative treatment of symptomatic carotid stenosis. 211 patients documented by intravenous angiography.

From 1980 through 1982, intravenous extracranial digital subtraction angiography (DSA) was performed in 6684 patients at the Cleveland Clinic. Of these, 211 previously unoperated patients had prior transient ischemic attacks (TIA) or strokes in conjunction with greater than 50% carotid stenosis on unequivocal DSA studies. Nonoperative management was employed in 126 patients, including 120 (84%) who received antiplatelet therapy or formal anticoagulation. The remaining 85 patients underwent carotid endarterectomy. During a mean follow-up interval of 36 months, there was no overall difference in survival, late TIA, or stroke between the nonoperated and surgical cohorts. However, parity was maintained in these groups only because of the prevalence of intermediate (50-69%) stenotic lesions and stable internal carotid occlusions in the nonoperated group. Carotid endarterectomy provided superior stroke prevention for patients with greater than 70% unilateral stenosis (p = 0.04), for those with greater than 50% bilateral stenosis (p = 0.004), and for those with internal carotid occlusions associated with greater than 50% contralateral stenosis (p = 0.03). The special risk of such discrete subsets should be recognized in order to plan appropriate treatment at the present time, as well as to conduct safe clinical trials in the future.

Surgical versus nonoperative treatment of asymptomatic carotid stenosis. 290 patients documented by intravenous angiography.

From 1980 through 1982, intravenous extracranial digital subtraction angiography (DSA) was performed in 6684 patients at the Cleveland Clinic. Of these, 290 previously unoperated patients had asymptomatic carotid stenosis exceeding 50% of lumen diameter on unequivocal DSA studies. Either the presence or the absence of carotid bruits substantially misrepresented the severity of angiographic stenosis on approximately 30% of sides. Nonoperative management was employed in 195 patients, including 104 (53%) who received antiplatelet therapy, while another group of 95 patients underwent prophylactic carotid endarterectomy. During mean follow-up intervals of 33-38 months, surgical treatment significantly reduced the cumulative incidence of subsequent neurologic events in men (p = 0.05). Statistically unconfirmed trends also suggested that carotid endarterectomy tended to prevent late strokes in subsets of patients with greater than 70% stenosis or bilateral carotid lesions. The overall stroke rate for women was higher in the surgical group (p = 0.03), in part because of their unusual risk for perioperative complications (9%) in this particular series.