The P2Y1 receptor responds to adenine nucleotides and is present in platelets, heart, smooth muscles prostate, ovary, and brain. A selective antagonist may be useful as an antithrombotic agent. We have analyzed the binding site of this G protein-coupled receptor using ligand design, site-directed mutagenesis, and homology modeling based on rhodopsin. We have designed and synthesized a series of deoxyadenosine 3',5'-bisphosphate derivatives that act as antagonists, or, in some cases with small structural changes, as agonists or partial agonists. The 2-position accommodates Cl or thioethers, whereas the N6-position is limited to Me or Et. 2'-Substitution with OH or OMe increases agonist efficacy over 2'-H. Using molecular modeling of the binding site, the oxygen atoms of the ribose moiety were predicted to be non-essential, i.e. no specific H-bonds with the receptor protein appear in the model. We have, therefore, substituted this moiety with carbocylics, smaller and larger rings, conformationally constrained rings, and acyclics, with retention of affinity for the receptor. With simplified pharmacophores we are exploring the steric and electronic requirements of the receptor binding site, and the structural basis of receptor activation.

Binding Sites↗

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[Ablative and extremity salvage tumor surgery of the lower extremity--a 10 year comparison].

AIM: The treatment of choice for local tumor control was amputation in the 1970's. Nowadays, limb salvage procedures have become the new standard, implicating that limb salvage surgery results in a better quality of life. This study attempts to prove this hypothesis. METHOD: In total, 102 patients who survived longer than ten years after tumor treatment of the lower extremities were investigated, of these, 71 patients underwent ablative procedures compared to 31 patients with limb salvage surgery. Operative revisions, education level, and occupational situation were evaluated in both groups. To analyze the outcome of every patient regarding functional results, quality of life, life contentment, and social parameters, the functional evaluation system of the Muskulo-Skeletal-Tumor Society (MSTS), the Freiburger Life-Contentment-Questionnaire (FLZ) and the Quality of Life Questionnaire (QLQ-C-30) of the European Organization of Research and treatment of Cancer (EORTC) were used. RESULTS: Patients treated with a limb salvage procedure underwent more surgical revisions (p < 0.000). Educational level and occupational situation showed no difference in both groups. Functional results reached similar levels in both groups (74.6% vs. 73.8%). Life contentment and Quality of Life measurements showed good results in both groups. The FLZ-questionnaire showed significantly better results for the ablative group in some items. CONCLUSION: The type of surgical local therapy of lower extremity tumors has no measurable effect on quality of life according to long-term follow-up in lower extremity tumors. In cases with a risk of inadequate margins when performing limb salvage surgery, an ablative procedure should be preferred.

Activities of Daily Living↗

PubMedDate not supplied

[Prognosis in Ewing sarcoma patients with initial pathological fractures of the primary tumor site].

In this retrospective analysis, data of 52 patients with Ewing's sarcoma or PNET with a pathological fracture in the area of the primary tumor were evaluated. All patients were treated according to the trials CESS 81, CESS 86 P, CESS 86, CESS 91 P and EICESS 92 of the German Society of Pediatric Oncology and Haematology (GPOH). At the date of evaluation (15. September 1994) all patients had completed treatment and had been under observation for at least one year following diagnosis. The median follow-up time was 28 months. 22 patients were female, 30 male. The median age was 12 years. 75% of primary tumors had a volume of > or = 100 ml. 30 patients presented with fractures in proximal, 12 in central and 10 in distal parts of the skeleton. 10 patients had primary metastases. The histological definition was Ewing's sarcoma (including atypical Ewing's sarcoma) in 43 patients, PNET in 8 and small-cell osteosarcoma in 1 patient. For local therapy the patients underwent surgery, definitive radiotherapy or a combination of both. The percentage of primary metastases in the group of the patients with pathological fractures is comparable to the whole reference group. The present analysis focuses on those patients with pathological fractures who had no metastases at diagnosis. The relapse-free survival of patients with a pathological fracture and no primary metastases is 58%, the overall survival 65%. These rates are similar to those of the reference group of protocol patients without pathological fractures at diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMedDate not supplied

A common 936 C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels.

BACKGROUND: Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis. Strong interindividual variations of VEGF plasma levels have been reported previously. Aim of the present study was to search for mutations in the 3' untranslated region (3'-UTR) of the VEGF gene and to analyze their relation to VEGF plasma levels. METHODS: The complete 3'-UTR (nucleotide 700-2622) of the VEGF gene was screened for sequence variations by single-strand conformation polymorphism (SSCP) analysis. Frequencies of mutated alleles were determined in 119 healthy subjects; VEGF plasma levels were analyzed in a subgroup of 23 healthy men aged 18-36 years. RESULTS: Three novel mutations (702 C/T, 936 C/T, 1612 G/A) were found, allele frequencies of 702T, 936T and 1612A were of 0.017, 0.160 and 0.471, respectively. VEGF plasma levels were significantly lower in carriers of the 936T allele (9.1 +/- 2.7 pg/ml, mean +/- SEM) than in noncarriers (28.0 +/- 5.5 pg/ml, p = 0.033), whereas the 702 C/T and the 1612 G/A mutations showed no association with VEGF plasma levels. The 936 C/T exchange led to the loss of a potential binding site for transcription factor AP-4, although the functionality of this binding site remains unclear. CONCLUSION: We have found three common mutations in the VEGF gene; one of them, a 936 C/T exchange, may be an important determinant of VEGF plasma levels.

3' Untranslated Regions↗

PubMedDate not supplied

[On the significance of the paper quality of testing filters].

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Anti-Bacterial Agents↗

PubMedDate not supplied

[A pilot plant for whirl layer coating].

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Air↗

PubMedDate not supplied

Intraoperative clotting factor dilution and activated hemostasis in children with Ewing's sarcoma or osteosarcoma: a prospective longitudinal study.

BACKGROUND: The study was designed to evaluate prospectively intraoperative changes in coagulation and fibrinolysis in young patients with Ewing's sarcoma (n = 12) or osteosarcoma (n = 12) who underwent major surgery, and to relate them to hematocrit (HCT) readings. MATERIALS AND METHODS: Blood samples (von Willebrand factor, fibrinogen, antithrombin III, protein C, plasminogen, t-PA ag, PAI 1 activity, F1+2, D-dimer, PAP) were obtained immediately prior to starting anesthesia, two and four hours later, immediately after surgery and on the first postoperative day. Intra- and postoperative hemostatic parameters were adjusted to preoperative HCT readings. RESULTS: Major surgery induced dilution coagulopathy due to blood product transfusion to support the patient's vascular volume. Postoperatively, VWF (0.01) and fibrinogen (0.007) were found to be significantly enhanced, whereas antithrombin III levels were significantly (0.007) decreased. D-dimer formation showed a clear, significant (0.0019) rise two hours after skin incision and remained elevated through the first postoperative day. F1+2 and PAP showed only minor deviations. T-PA (0.012) and PAI 1 (0.001) rose during the operation and normalized on the first postoperative day. Within 36 hours of the initial operation, six of the 24 patients (25%) returned to surgery to stop severe hemorrhage. CONCLUSIONS: These findings indicate that hemostatic parameters may be useful when monitoring surgery- and transfusion-induced hemostatic imbalance. Furthermore, the significant differences between the HCT-uncorrected concentration of the various plasma proteins clearly demonstrated the need to use HCT correction factors which may influence the necessity for and/or the frequency of substitution therapy with protein concentrates.

Adolescent↗

PubMedDate not supplied

Results of early surgery in poor-grade aneurysm patients.

METHODS: During a 4-year-period (1991-1994) a total of 85 poor-grade [Hunt and Hess (H&H) IV and V] patients were treated for aneurysmal subarachnoid hemorrhage. Patients who were admitted in poor grades but improved after initial treatment were excluded from this study. RESULTS: Overall mortality was 46% (N = 39). In particular, 29% (18 out of 63) of surgically treated patients had died as opposed to 95% (21 out of 22) of conservatively treated patients. Early surgery provided favourable (Glasgow-Outcome-Scores (GOS) 4-5) results in 52% of H&H grade IV patients but only in 22% of grade V patients. In particular, approximately one fourth of grade IV patients had a good outcome and 30% were only moderately disabled. Intracranial pressure (ICP) below 20 mmHg proved to be a favourable prognostic sign. CONCLUSIONS: It is concluded that, in consideration of the management mortality encountered with delayed surgery, H&H grade IV patients benefit from early surgical treatment while the prognosis of grade V patients still remains unfavourable.

Adult↗