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S Haas

Publications and source records attributed to S Haas.

At least 55 records · Page 3Linked to original sources
PubMed2001

A model for the detection of clonality in marked hematopoietic stem cells.

The semirandom location of retroviral integration in the target cell genome introduces a marker in the form of a fusion sequence composed of a genomic and a proviral part that is unique for each transduced cell and its clonal progeny. High-sensitivity detection of these fusion sequences would allow the tracking of clonal contributions of individual, marked hematopoietic progenitor, and stem cells in vivo. Clone detection by Southern blot has helped to analyze models of oligoclonal repopulation but is limited in sensitivity and specificity. Inverse PCR (Nolta et al., Proc. Natl. Acad. Sci. USA 93: 2414-2419) can demonstrate the clonal identity by sequencing but does not permit simultaneous detection of multiple clones. In an efficiently transduced rhesus macaque model (Tisdale et al., Blood 92: 2681-2687; Wu et al., Mol. Ther. 1: 285-293) Kim et al. (Blood 96: 1-8) have identified more than 40 insertion sequences from marrow CFU by inverse PCR. However, no previous study has been able to directly analyze the number of clones active in vivo. Here we demonstrate that the application of a recently developed PCR technology allows the simultaneous visualization of multiple integration sites from small clonal contributions to hematopoietic cells. By combining solid-phase primer extension with ligation-mediated PCR, direct genomic sequencing of retroviral integration sites was obtained in murine bone marrow samples. Further development of this technology will allow analysis of the clonal composition of marked hematopoiesis in small and large animals as well as in human gene transfer.

Animals↗
PubMed2001

Global analysis of the general stress response of Bacillus subtilis.

Gene arrays containing all currently known open reading frames of Bacillus subtilis were used to examine the general stress response of Bacillus. By proteomics, transcriptional analysis, transposon mutagenesis, and consensus promoter-based screening, 75 genes had previously been described as sigma(B)-dependent general stress genes. The present gene array-based analysis confirmed 62 of these already known general stress genes and detected 63 additional genes subject to control by the stress sigma factor sigma(B). At least 24 of these 125 sigma(B)-dependent genes seemed to be subject to a second, sigma(B)-independent stress induction mechanism. Therefore, this transcriptional profiling revealed almost four times as many regulon members as the proteomic approach, but failure of confirmation of all known members of the sigma(B) regulon indicates that even this approach has not yet elucidated the entire regulon. Most of the sigma(B)-dependent general stress proteins are probably located in the cytoplasm, but 25 contain at least one membrane-spanning domain, and at least 6 proteins appear to be secreted. The functions of most of the newly described genes are still unknown. However, their classification as sigma(B)-dependent stress genes argues that their products most likely perform functions in stress management and help to provide the nongrowing cell with multiple stress resistance. A comprehensive screening program analyzing the multiple stress resistance of mutants with mutations in single stress genes is in progress. The first results of this program, showing the diminished salt resistance of yjbC and yjbD mutants compared to that of the wild type, are presented. Only a few new sigma(B)-dependent proteins with already known functions were found, among them SodA, encoding a superoxide dismutase. In addition to analysis of the sigma(B)-dependent general stress regulon, a comprehensive list of genes induced by heat, salt, or ethanol stress in a sigma(B)-independent manner is presented. Perhaps the most interesting of the sigma(B)-independent stress phenomena was the induction of the extracytoplasmic function sigma factor sigma(W) and its entire regulon by salt shock.

Bacillus subtilis↗
PubMed2001

Prevention of venous thromboembolism: recommendations based on the International Consensus and the American College of Chest Physicians Sixth Consensus Conference on Antithrombotic Therapy.

The primary purpose of a Consensus Conference is to provide informed guidance on treatment decisions, assisting clinicians to make the optimal therapeutic choice for the patient, and providing protection against unjustified malpractice actions. The First American College of Chest Physicians (ACCP) Consensus Conference took place in 1985 and, using a systematic approach, provided recommendations for anti-thrombotic therapy based on published studies, and graded those recommendations on the level of clinical evidence. The European Consensus Conference was convened in 1991 to build on this process. During this period, the main developments included the introduction and widespread use of new thromboprophylactic agents such as low-molecular-weight heparins, and improved risk assessment, including an awareness that outpatients and general medical patients may also be at risk. Subsequently, the recommendations have been carefully reviewed and updated by experts who represent the extensive range of opinions in the field. The latest International Consensus Statement was published in 1997, and the most recent ACCP Consensus in 2001 and they provide extensive practice guidelines in the management of venous thromboembolism.

Anticoagulants↗
PubMed2001

Anticoagulation: the present and future.

Thrombin is a central bioregulator of coagulation and is therefore a key target in the therapeutic prevention and treatment of thromboembolic disorders, including deep vein thrombosis and pulmonary embolism. The current mainstays of anticoagulation treatment are heparins, which are indirect thrombin inhibitors, and coumarins, such as warfarin, which modulate the synthesis of vitamin K-dependent proteins. Although efficacious and widely used, heparins and coumarins have limitations because their pharmacokinetics and anticoagulant effects are unpredictable, with the risk of bleeding and other complications resulting in the need for close monitoring with their use. Low-molecular-weight heparins (LMWHs) provide a more predictable anticoagulant response, but their use is limited by the need for subcutaneous administration. In addition, discontinuation of heparin treatment can result in a thrombotic rebound due to the inability of these compounds to inhibit clot-bound thrombin. Direct thrombin inhibitors (DTI) are able to target both free and clot-bound thrombin. The first to be used was hirudin, but DTIs with lower molecular weights, such as DuP 714, PPACK, and efegatran, have subsequently been developed, and these agents are better able to inhibit clot-bound thrombin and the thrombotic processes that take place at sites of arterial damage. Such compounds inhibit thrombin by covalently binding to it, but this can result in toxicity and nonspecific binding. The development of reversible noncovalent DTIs, such as inogatran and melagatran, has resulted in safer, more specific and predictable anticoagulant treatment. Oral DTIs, such as ximelagatran, are set to provide a further breakthrough in the prophylaxis and treatment of thrombosis.

Administration, Oral↗
PubMed2001

Total knee arthroplasty after open reduction and internal fixation of fractures of the tibial plateau: a minimum five-year follow-up study.

BACKGROUND: There is little information in the literature regarding the outcome of total knee arthroplasty following open reduction and internal fixation of fractures of the tibial plateau. The goal of this study was to evaluate the results of such procedures after a minimum of five years of follow-up. METHODS: We retrospectively analyzed the outcomes of fifteen total knee arthroplasties performed at an average of 38.6 months (range, eight months to eleven years) after open reduction and internal fixation of a fracture of the tibial plateau in fifteen consecutive patients. The average duration of follow-up after the total knee arthroplasty procedures was 6.2 years (range, 5.4 to 11.1 years). The average age of the patients was fifty-six years (range, thirty-seven to sixty-eight years) at the time of the arthroplasty. We evaluated the outcomes on the basis of the Hospital for Special Surgery knee score, the Short Form-36 score, and radiographs of the knees. RESULTS: The average Hospital for Special Surgery knee score was 51 points (range, 20 to 74 points) before the arthroplasty, and it increased to 80 points (range, 44 to 91 points) postoperatively. Four knees were scored as excellent, eight had a good result, one was rated as fair, and two had a poor result. The average Short Form-36 scores were 58.0 points for general health, 72.4 points for bodily pain, 72.1 points for mental health, 58.3 points for physical functioning, 84.6 points for physical role functioning, 81.0 points for social functioning, and 57.7 points for vitality. The average active postoperative arc of motion was 105 degrees (range, 70 degrees to 135 degrees ) compared with 87 degrees (range, 20 degrees to 125 degrees ) preoperatively. Incomplete radiolucencies were noted on all of the postoperative radiographs made after the total knee arthroplasties. There was a high rate of infection (three patients), patellar tendon disruption (two patients), and postoperative secondary procedures (three patients required closed manipulation). The patients with infection were considered to have a failure of treatment: two required arthrodesis, and one required a two-stage exchange. CONCLUSION: On the basis of our results, we concluded that total knee arthroplasty after open reduction and internal fixation of a fracture of the tibial plateau decreases pain and improves knee function, but the procedure is technically demanding and is associated with a high failure rate (five of fifteen).

Adult↗
PubMed2000

Quasiparticle bound states around impurities in d(x(2)-y(2))-wave superconductors

Zn and Ni impurities in the hole-doped high-temperature superconductors are known to have strong effects on thermodynamic and transport properties. A recent scanning tunneling microscope study of Zn-doped Bi2212 [S. H. Pan et al., Nature (London) 403, 746 (2000)] has provided high-resolution images of the local density of states around nonmagnetic impurities in d(x(2)-y(2))-wave superconductors. These pictures contain detailed information about the spinor wave functions u(r) and v(r) of bound states with energy E0 approximately Delta/30, centered at the Zn sites. We show that this type of wave function follows from the solutions of the Bogoliubov-de Gennes equations for d(x(2)-y(2))-wave superconductors.

Journal Article↗
PubMed2000

Clinical consequences of molecular diagnosis in families with mismatch repair gene germline mutations.

Hereditary nonpolyposis colorectal cancer (HNPCC), clinically defined by the Amsterdam criteria, is associated with mismatch repair gene germline mutations. This study was performed to evaluate the efficiency of combined clinical and molecular diagnostics in identifying carriers of a mutated gene in families meeting criteria of the Bethesda guidelines and to examine the influence of molecular diagnosis on clinical decision-making in carriers and noncarriers. Seventy-two patients meeting criteria of the Bethesda guidelines were tested for microsatellite instabilities (MSI). MSI-H tumors were found in 38 (52.8%) index patients. Complete sequencing of hMLH1 and hMSH2 in 38 MSI-H patients and of hMSH6 in one of these patients revealed 15 pathogenic germline mutations, including three novel mutations, and three novel unclassified germline variants. Twelve of the 15 pathogenic mutations were found in patients fulfilling the Amsterdam I/II criteria. Surgical and genetic counseling was offered to the affected families; as a result of molecular diagnosis in the 15 families, 26 index patients and affected carriers and 8 asymptomatic carriers of a mutated mismatch repair gene were included in the surveillance program, and 26 noncarriers were excluded from this program. Although germline mutations are detected in only 20.8% of patients fulfilling criteria of the Bethesda guidelines, family history and MSI-H tumor classification are both strong indicators for germline mutations in hMSH2, hMLH1, and hMSH6 genes, resulting in a 51.9% mutation detection rate. Identification of individual mutation status allows clear-cut decisions on whether or not inclusion in surveillance programs is indicated.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Effects of recombinant human growth hormone in catabolic adults with chronic renal failure.

Growth hormone (GH) has been used for the treatment of catabolism in a few pilot studies and in two placebo-controlled studies of 6 months duration. Treatment with GH in doses of 2-4 IU/m2/day (0.67-1.33 mg/m2/day) resulted in clear anabolic effects and a significant change in body composition. Lean body mass increased by more than 3 kg within 6 months, whereas fat mass was decreased by the same amount, resulting in a constant total body weight. As there were no major side-effects, controlled long-term studies are justified.

Adult↗
PubMed2000

[Therapy of venous thromboembolism with low-molecular-weight heparins].

Low-molecular-weight heparins, nowadays already widely used for the prevention of thromboembolism, have now also become available for the treatment of deep-vein thrombosis. This article should serve to explain the rationale for this development and to demonstrate the clinically relevant advantages of the use of low-molecular-weight heparins. After briefly describing the characteristic properties of heparins the most relevant studies comparing the use of low-molecular-weight heparin versus unfractionated heparin for the treatment of thromboembolism are discussed. In conclusion, clinical trials suggest that low-molecular-weight heparins given subcutaneously can replace the hitherto standard intravenous application of unfractionated heparin in the initial treatment of deep-vein thrombosis, granting equal or even better efficacy and potentially lower rates of adverse side effects. Furthermore, the simplicity of this therapeutic regime allows for treatment of patients at home, thus offering patients mobility and also reducing the cost of treatment.

Anticoagulants↗
PubMed2000

Interaction between the LMWH reviparin and aspirin in healthy volunteers.

AIMS: To investigate potential interactions between reviparin and acetylsalicylic acid (ASA 300 mg o.d. from day 1-5). METHODS: In an open, randomized, three-way-cross over study nine healthy volunteers received reviparin (s.c. injection of 6300 anti-Xa units) or placebo from days 3 to 5 and acetylsalicylic acid (ASA 300 mg) or placebo from days 1 to 5. Assessments included bleeding time (BT), collagen (1 microg ml-1) induced platelet aggregation (CAG), heptest, plasma antifactor Xa-activity and activated partial thromboplastin time (aPTT). RESULTS: Median bleeding time at day 5 was 5.5 min after reverparin alone and after ASA alone and was 9.6 min after the combination of reviparin and ASA. ASA treatment reduced CAG from 84% to 40 to 50% of Amax; values after combined treatment of reviparin with ASA were not different from those after ASA alone. aPTT was prolonged to 32 s after reviparin; this effect was not modified if subjects received ASA. Combined treatment with ASA and reviparin had no effect on plasma anti-Xa-activity and heptest compared with reviparin alone. CONCLUSIONS: We could not entirely exclude a small interaction between reviparin and ASA on bleeding time, but the effect is probably without clinical significance.

Adult↗
PubMed2000

Recommendations for prophylaxis of venous thromboembolism: International Consensus and the American College of Chest Physicians Fifth Consensus Conference on antithrombotic therapy.

The primary purpose of a Consensus Conference is to provide informed guidance on treatment decisions, assisting clinicians to make the optimal therapeutic choice for the patient, and providing protection against unjustified malpractice actions. The First American College of Chest Physicians (ACCP) Consensus Conference took place in 1985 and, using a systematic approach, provided recommendations for antithrombotic therapy based on published studies, and graded those recommendations on the level of clinical evidence. The European Consensus Conference was convened in 1991 to build on this process. During this period, the main developments included the introduction and widespread use of new thromboprophylactic agents such as low-molecular-weight heparins, and improved risk assessment, including an awareness that out-patients and general medical patients may also be at risk. Subsequently, the recommendations have been carefully reviewed and updated by experts who represent the extensive range of opinions in the field. The latest International Consensus Statement was published in 1997, and the most recent ACCP Consensus in 1998 and they provide extensive practice guidelines in the management of venous thromboembolism.

Arthroplasty, Replacement, Hip↗
PubMed2000

Deep vein thrombosis: beyond the operating table.

Deep vein thrombosis (DVT) is of clinical importance and carries the short-term risk of pulmonary embolism. Patients undergoing orthopedic surgery are at particular risk of DVT. Pharmacological prophylaxis to prevent thromboembolic events has become standard practice in this patient group. However, DVT may also lead to long-term venous insufficiency, causing disabling symptoms of swelling, chronic pain, and skin ulceration, imposing substantial health-care costs. Prevention of these long-term sequelae of DVT, termed post-thrombotic syndrome (PTS), may be of equal or even greater clinical, economic, and medicolegal significance than avoidance of the short-term effects. Surveys suggest that PTS is present in 30%-70% of patients, 5 years after an initial symptomatic or asymptomatic, proximal or distal DVT. Post-thrombotic syndrome is not reliably prevented by treatment of the initial DVT with anticoagulant therapy or thrombolysis. Therefore, prevention of DVT is the only effective approach to PTS prevention. Pharmacological thromboprophylaxis prevents venographically proven DVT in patients following orthopedic surgery, and is now recommended by North American and European consensus statements. Uncertainties remain, however, regarding the optimal duration of postsurgical prophylaxis.

Anticoagulants↗
PubMed2000

The inhibitory potency and selectivity of arginine substrate site nitric-oxide synthase inhibitors is solely determined by their affinity toward the different isoenzymes.

We have investigated various nitric oxide (NO) synthase inhibitors for their affinity and selectivity toward the three human isoenzymes in radioligand binding experiments. Therefore, we developed the new radioligand [(3)H]2-amino-4-picoline to measure binding of these compounds to the three human NO synthase (NOS) isoenzymes. Aminopicoline is a potent and nonselective inhibitor of all three isoforms. [(3)H]2-amino-4-picoline bound saturably and with high affinity to human NOSs. Affinity constants (K(D) values) of 59, 111, and 136 nM were obtained for the inducible, neuronal, and endothelial NOS isoforms (iNOS, nNOS, eNOS). Binding of [(3)H]2-amino-4-picoline was competitive with the substrate arginine. From all the inhibitors tested, AMT (2-amino-5, 6-dihydro-6-methyl-4H-1,3-thiazine hydrochloride) showed the highest affinity and no selectivity. L-NIL [L-N(6)-(1-Iminoethyl)lysine hydrochloride] and aminoguanidine were moderately iNOS-selective while L-NA (N(G)-nitro-L-arginine) and L-NAME (N(G)-nitro-L-arginine methyl ester hydrochloride) showed selectivity toward the constitutive isoforms. High iNOS versus eNOS selectivity was found for 1400W, whereas several isothiourea derivatives and 1400W displayed moderate n- versus eNOS selectivity. To relate the affinity of these compounds to their inhibitory potency, we measured the inhibitory potency under almost identical conditions using a new microtiter plate assay. The inhibitory potency of selective and nonselective NOS inhibitors was almost exactly mirrored by their affinity toward the different isoenzymes. Highly significant correlations were obtained between the potency of enzyme inhibition and the inhibition of [(3)H]2-amino-4-picoline binding for all three isoenzymes. These data show that the potency and selectivity of NOS inhibitors are solely determined by their affinity toward the different isoforms. Furthermore, these data identify the new radioligand [(3)H]2-amino-4-picoline as a very useful radiolabel for the investigation of the substrate binding site of all three isoforms.

Arginine↗
PubMed1999

[Prognostic significance of cell-cycle regulatory proteins for outcome after primary radiochemotherapy in patients with advanced head and neck cancer].

BACKGROUND: Primary radiochemotherapy is gaining increasing importance for the treatment of advanced head and neck squamous cell carcinomas. However, there is a lack of clinical factors concerning prognostic information in relation to treatment. In this pilot study, we examined whether molecular factors can provide such information. PATIENTS AND METHODS: The expression patterns and their possible prognostic relevance of the cell cycle regulatory proteins p53, p21(WAF/CIP1), Rb, p16(INK4A), CDK4 and Cyclin D1, MIB1 (Ki-67) and BCL-2 were analysed in pretreatment tumor biopsies from 43 patients with advanced carcinomas of the oropharynx (n = 26), hypopharynx (n = 10) and larynx (n = 7) by applying immunohistochemistry to paraffin sections of tumor specimens. All patients were treated by the same method of an accelerated "concomitant boost" radiochemotherapy with carboplatin in a phase II study. Median followup time was 56 months. RESULTS: No correlation was found between any of the markers and the remission rate, T-stage, N-stage, rate of loco-regional recurrences and distant metastases. However, independent of the tumor stage, patients with CDK4/cyclin-D1 overexpressing tumors had a significantly shortened overall survival (P = 0.014 and 0.026, respectively). CONCLUSION: The results of this pilot study indicate that CDK4 and cyclin D1 over-expression provide useful prognostic information about clinical outcome after primary radiochemotherapy of head and neck cancer patients.

Adult↗
PubMed1999

Heparin-induced thrombocytopenia: clinical considerations of alternative anticoagulation with various glycosaminoglycans and thrombin inhibitors.

Heparin-induced thrombocytopenia (HIT), the most common complication of heparin therapy, is also the most common form of the drug-induced thrombocytopenias. HIT is classified as type I and type II, the first being benign and the latter severe. HIT type II is attributed to an immune response characterized by complexes of heparin and platelet factor (PF) 4. Enzyme-linked immunosorbent assays allow easy and simple determination of these antibody titers; however, because specificity and sensitivity is not optimal, there is concern that the clinical relevance may be low. In clinical trials many patients were shown to form HIT-IgG in response to heparin without developing manifestations of HIT type II. Therefore, routine screening of clinically asymptomatic patients for antiheparin/PF 4 antibodies is not recommended. HIT type II is a clinico-pathologic syndrome that ideally should be confirmed by laboratory testing. If any clinical suspicion arises, however, heparin and low molecular weight heparin therapy should be discontinued and an alternative anticoagulant therapy started. Alternative drugs have been evaluated in significant numbers of patients including danaparoid and thrombin inhibitors. In the case of danaparoid, it is highly recommended that an in vitro test for cross-reactivity be performed before the onset of therapy. If testing cannot be performed, immediate administration of a thrombin inhibitor is preferred.

Anticoagulants↗
PubMed1999

Soluble adhesion molecules in the HIT syndrome: pathophysiologic role and therapeutic modulation.

Heparin-induced thrombocytopenia pathophysiology is now known to be a complex process that involves platelets, vascular endothelium, and leukocytes/lymphocytes. The activation products from these sites also contribute to the activation of coagulation and fibrinolytic deficit. While many of the markers of hemostatic activation processes have been found to be increased during the acute phase of heparin-induced thrombocytopenia syndromes, the circulating levels of soluble adhesion molecules such as the P, E, and L selectins, and intracellular and vascular cell adhesion molecules have not been reported. Since the pathophysiology of heparin-induced thrombocytopenia involves the activation of platelets, endothelium, and leukocytes, it is expected that the activation products related to these hemostatic systems including soluble selectins and cellular adhesion molecules will also be increased in circulating blood. These alterations may also provide an index of the pathophysiologic process. With the availability of highly sensitive enzyme-linked immunosorbent assays for soluble P, E, and L selectins, intracellular and vascular cell adhesion molecules, it is now possible to measure these adhesion molecules in biological fluids. This study reports on the circulating levels of various adhesion molecules in patients with heparin-induced thrombocytopenia and their modulation after therapeutic interventions by the use of direct thrombin inhibitors. With the availability of recombinant hirudin, it is now possible to treat these patients with alternate antithrombin agents. However, the immunoactivation of platelets and other cells as shown here indicates the possible need for additional adjunct therapeutic approaches to suppress their participation in the thrombotic process. The reported increase in the circulating levels of the soluble adhesion molecules during the heparin-induced thrombocytopenia and heparin-induced thrombocytopenia with thrombosis syndrome suggests that the antiheparin platelet factor 4 antibody is capable of modulating their regulation. The prognostic role of these mediators in the management of heparin-induced thrombocytopenia syndrome warrants further investigation.

Antithrombins↗