The identification of short linear motif-mediated interfaces within the human interactome.

MOTIVATION: Eukaryotic proteins are highly modular, containing multiple interaction interfaces that mediate binding to a network of regulators and effectors. Recent advances in high-throughput proteomics have rapidly expanded the number of known protein-protein interactions (PPIs); however, the molecular basis for the majority of these interactions remains to be elucidated. There has been a growing appreciation of the importance of a subset of these PPIs, namely those mediated by short linear motifs (SLiMs), particularly the canonical and ubiquitous SH2, SH3 and PDZ domain-binding motifs. However, these motif classes represent only a small fraction of known SLiMs and outside these examples little effort has been made, either bioinformatically or experimentally, to discover the full complement of motif instances. RESULTS: In this article, interaction data are analysed to identify and characterize an important subset of PPIs, those involving SLiMs binding to globular domains. To do this, we introduce iELM, a method to identify interactions mediated by SLiMs and add molecular details of the interaction interfaces to both interacting proteins. The method identifies SLiM-mediated interfaces from PPI data by searching for known SLiM-domain pairs. This approach was applied to the human interactome to identify a set of high-confidence putative SLiM-mediated PPIs. AVAILABILITY: iELM is freely available at http://elmint.embl.de CONTACT: toby.gibson@embl.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

[The influence of age on the outcome of anterior cruciate ligament reconstruction]. / Der Einfluss des Lebensalters auf den Behandlungserfolg nach vorderer Kreuzbandplastik.

AIM: There is an increasing demand for a high loading capacity of the knee during exercise in the elderly patient with knee instability following rupture of the anterior cruciate ligament (ACL). The question is, if the results of an ACL reconstruction in patients over 40 years of age are as good as those in younger patients. METHOD: From 1989 to 1994 we replaced the ACL with a mid-third BPTB autograft in 397 patients following ACL rupture. A total of 309 patients (78%, 110 female, 199 male, the average age was 27 years) were followed for an average of 43 months. The results were compared relating to four groups of age (group 1: < 20 years, n = 41; group 2: 20 - 29 years, n = 175; group 3: 30 - 40 years, n = 77; group 4: > 40 years, n = 16). RESULTS: We did not find any significant differences between the groups in the different score ratings, the subjective and objective knee function and stability, the pain and the level of activity. The average Cincinnati score of the whole group was 91 points (HSS score: 78/16 % excellent/good, Lysholm score: 90 points, IKDC score: 22/31 % A/B). CONCLUSION: ACL replacement is a sufficient therapy for patients over 40 years of age with symptomatic knee instability following ACL rupture. The subjective and objective clinical outcome is comparable to the good results of ACL replacement in younger patients without any significant differences.

Programmed ventricular stimulation for arrhythmia risk prediction in patients with idiopathic dilated cardiomyopathy and nonsustained ventricular tachycardia.

OBJECTIVES: This study investigated the role of programmed ventricular stimulation (PVS) for arrhythmia risk prediction in patients with idiopathic dilated cardiomyopathy (IDC) and spontaneous nonsustained ventricular tachycardia (VT). BACKGROUND: Nonsustained VT in patients with IDC has been associated with a high incidence of sudden cardiac death. METHODS: Over the course of 4 years, 34 patients with IDC, a left ventricular (LV) ejection fraction < or = 35%, and spontaneous nonsustained VT underwent PVS. All patients were prospectively followed for 24+/-13 months. RESULTS: Sustained ventricular arrhythmias were induced in 13 patients (38%). Sustained monomorphic VT was induced in three patients (9%), and polymorphic VT or ventricular fibrillation (VF) in another 10 patients (29%). No sustained ventricular arrhythmia could be induced in 21 study patients (62%). Prophylactic implantation of third-generation defibrillators (ICDs) with electrogram storage capability was performed in all 13 patients with inducible sustained VT or VF, and in nine of 21 patients (43%) without inducible sustained VT or VF. There were no significant differences between the additional use of amiodarone, d,I-sotalol, and beta-blocker therapy during follow-up in patients with and without inducible VT or VF. During 24+/-13 months of follow-up, arrhythmic events were observed in nine patients (26%) including sudden cardiac deaths in two patients and ICD shocks for rapid VT or VF in seven patients. Arrhythmic events during follow-up occurred in four of 13 patients with inducible ventricular arrhythmias compared with five of 21 patients without inducible ventricular arrhythmias at PVS (31% vs. 24%, p=NS). CONCLUSION: PVS does not appear to be helpful for arrhythmia risk stratification in patients with IDC, a left ventricular ejection fraction < or =35%, and spontaneous nonsustained VT. Due to the limited number of patients, however, the power of this study is too small to exclude moderately large differences in outcome between patients with IDC with and without inducible VT or VF.

Effects of the oxytocin fragment prolyl-leucyl-glycinamide on sexual behavior in the rat.

Prolyl-leucyl-glycinamide (PLG), a natural brain peptide, is identical in structure to the C-terminal of oxytocin. Moreover, PLG and oxytocin can act as opiate antagonists. Evidence that opiates and oxytocin have significant influences on reproductive behavior suggests that PLG may also be effective. Morphine and/or PLG were administered intraperitoneally to male and female rats and sexual behavior was observed. PLG (0.1-10 mg/kg) was found to facilitate female sexual behavior in Experiment 1. In Experiment 2, the ability of PLG to facilitate female receptivity was found to be progesterone dependent. In Experiment 3, tyrosine-prolyl-leucyl-glycinamide, a putative precursor to PLG, failed to facilitate lordosis. In Experiment 4, PLG failed to facilitate male sexual behavior. In Experiments 5 and 6, PLG did not affect morphine-induced inhibition of either male or female sexual behavior. These data suggest that PLG differentially affects female receptivity and male sexual behavior. The current results support the hypothesis that PLG is an active metabolite of oxytocin in the female, but do not provide evidence that PLG functions as an opiate antagonist of sexual behavior.

The effect of intralesional interferon gamma on basal cell carcinomas.

This open label study evaluated the effect of nine intralesional injections of two different doses of interferon gamma on basal cell carcinomas in 29 patients. One group of 15 patients received interferon gamma, 0.01 mg (20,000 IU), intralesionally three times a week for 3 weeks. Fourteen patients received interferon gamma, 0.05 mg (100,000 IU), intralesionally in the same dosage schedule. Excisional biopsy specimens 12 weeks after therapy showed no evidence of tumor remaining in 7 of 14 patients (50%) treated with the higher dose of interferon gamma, whereas only 1 of 15 patients (7%) treated with low-dose interferon gamma was cured according to histologic criteria (p = 0.025). Seventy-six percent of patients reported at least one adverse reaction, but most were considered mild by the patient and the investigator.

Long-term effect of mackerel diet on blood pressure, serum lipids and thromboxane formation in patients with mild essential hypertension.

Twelve male patients with mild essential hypertension were put on a diet supplemented with 2 cans of mackerel/day (= 2.2 g daily of eicosapentaenoic acid, EPA, C20:5 n-3 and 2.8 g daily of docosahexaenoic acid, DHA, C22:6 n-3) for 2 weeks within an isocaloric regimen and then with 3 cans/week (= 3.3 g/week, equivalent to 0.47 g daily of EPA and 4.2 g/week, equivalent to 0.69 g daily of DHA) for 8 months with a subsequent period of 2 months on normal diet. Eleven male hypertensives matched for age, body weight index, blood pressure and serum lipids with no change in their nutritional habits served as controls. After the first dietary period (2 weeks) a significant decrease of serum triglycerides (TG), total and LDL-cholesterol, blood pressure and thromboxane B2 (TxB2) was found, whereas HDL cholesterol and potassium in erythrocytes were significantly increased. During the second dietary period (8 months) providing the lower dose of EPA, serum lipids and the other biochemical parameters returned to the initial values. Blood pressure, however, remained significantly lower and rose to the basal levels only after the third period (2 months) on normal diet. In the control group no alterations could be seen. The data suggest a dose-related differential effect of dietary EPA on serum lipids, lipoproteins, TxB2 and blood pressure in subjects with mild hypertension.