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Biomedical subjects

B Brenner

Publications and source records attributed to B Brenner.

At least 163 records · Page 9Linked to original sources
PubMed1996

HELLP syndrome associated with factor V R506Q mutation.

The pathogenesis of HELLP (haemolysis, elevated liver enzyme and low platelet count) syndrome, a severe presentation of pre-eclampsia, is still an enigma. Activated protein C resistance resulting from a mutation in coagulation factor V has recently emerged as the leading cause of thrombosis in pregnancy. We report on two patients with HELLP syndrome who were found to be heterozygous for factor V R506Q mutation, leading to activated protein C resistance. These findings suggest that the pathogenesis of HELLP syndrome is associated with a thrombotic process, and point to the potential benefit of anti-thrombotic therapy in this condition.

Adult↗
PubMed1996

Fas-induced programmed cell death is mediated by a Ras-regulated O2- synthesis.

Fas induces apoptosis in lymphocytes via a poorly defined intracellular signalling cascade. Previously, we have demonstrated the involvement and significance of a signalling cascade from the Fas receptor via sphingomyelinases and ceramide to Ras in Fas-induced apoptosis. Here we demonstrate rapid and transient synthesis of reactive oxygen intermediates (ROI) via activation of Ras after Fas. Genetic inhibition of Ras by transfection of transdominant inhibitory N17Ras blocked Fas-mediated ROI synthesis and programmed cell death. Likewise, the antioxidants N-acetyl-cysteine and N-t-butyl-phenylnitrone abolished Fas-induced cell death, pointing to an important role for Ras-triggered ROI synthesis in Fas-mediated programmed cell death.

Acetylcysteine↗
PubMed1996

Ala244Val is a common, probably ancient mutation causing factor VII deficiency in Moroccan and Iranian Jews.

We investigated the molecular basis for factor VII (FVII) deficiency in Israel and found that 13 patients were homozygous and 10 heterozygous for a C to T substitution at nucleotide 10648 of the FVII gene. This predicted an Ala244Val change and was associated with decreased FVII activity and antigen level. Of the 36 Ala244Val positive alleles, 20 were observed in patients of Moroccan origin, 10 in Iranian-Jewish patients and 6 in patients of other origins. A computer model of the serine protease domain of FVII suggested that the Ala244Val substitution may cause distortion of the entire protein structure. Intragenic polymorphic sites analyses disclosed a founder effect for the Moroccan and Iranian-Jewish patients. A survey of the Ala244Val mutation revealed an allele frequency of 1:42.5 in Moroccan Jews and 1:40 in Iranian Jews. As Moroccan Jews have been separated from Iranian Jews for more than two millennia, the data suggest that the Ala244Val mutation occurred in ancient times.

Alanine↗
PubMed1996

Merkel cell carcinoma in Israel.

Merkel cell carcinoma is a rare and highly malignant skin tumor. We present the first report on the clinical and epidemiologic characteristics of Merkel cell carcinoma in Israel. Our findings, including average age of 69 years at diagnosis, equal sex distribution, disease location on sun-exposed skin, and an overall 3 year survival of 58%, are consistent with the data reported in the literature. Unique findings in our study were the predominance of Ashkenazic Jews and the excessive rate of second malignancies. This initial report on Merkel cell carcinoma in Israel emphasizes the need for increased awareness of this aggressive and potentially lethal skin malignancy.

Adult↗
PubMed1995

Molecular analysis of Ras activation by tyrosine phosphorylated Vav.

Vav has been shown to activate Ras (1-3) and is regulated by tyrosine phosphorylation (1) or binding of diglycerides (3) to the cysteine rich domain. In the present study employing different Ras activation assay techniques using [3H]GDP release or [32P]alpha GTP-binding from membrane-bound or soluble recombinant Ras, we demonstrate that Ras activity can be increased by tyrosine phosphorylated Vav upon cellular stimulation via the IL-2 receptor or the TCR/CD3-complex. Increase of [32P]alpha GTP-binding to Ras catalyzed by phosphorylated Vav is similar to the activity of immunoprecipitated Sos. The activity of Vav measured by binding of [32P]alpha GTP to Ras was linear with respect to the concentration of Vav protein used. To study molecular characteristics of this Vav-Ras interaction, we used several Ras mutants and demonstrate that Vav activity towards Ras depends on the integrity of the same or similar domains as Ras activation by SDC 25 or CDC 25.

CD3 Complex↗
PubMed1995

Court ordered obstetric intervention: a commentary.

A case is presented where the Courts have authorised an obstetric intervention deemed necessary for the well-being of both mother and child. Although the case is one of maternal psychosis, there are legal and ethical concerns whenever court-ordered intervention is deemed necessary. Approaches to this difficult medical decision making problem in the form of utilitarian "burdens v benefit" ratio analysis or the recognised traditional ethical principles of beneficence, nonmaleficence, justice and acting in the patient's best interest are considered. The Royal College of Obstetricians and Gynaecologists guidelines suggesting "that it is inappropriate ... to invoke judicial intervention to overrule an informed and competent woman's refusal of a proposed medical treatment, even though her refusal might place her life and that of her fetus at risk" are questioned.

Adult↗
PubMed1995

[Symptomatic antiphospholipid antibody after neuroleptic drugs].

Symptomatic antiphospholipid antibody has rarely been described in patients treated with neuroleptic drugs. We report the appearance of this antibody in association with retinal artery occlusion, in a 40-year-old man treated by neuroleptic drugs who later developed acute agranulocytosis following clozapine.

Adult↗
PubMed1995

Equilibration and exchange of fluorescently labeled molecules in skinned skeletal muscle fibers visualized by confocal microscopy.

Confocal laser fluorescence microscopy was used to study in real time under nearly physiological conditions the equilibration and exchange characteristics of several different fluorescently labeled molecules into chemically skinned, unfixed skeletal muscle fibers of rabbit psoas. The time required for equilibration was found to vary widely from a few minutes up to several days. Specific interactions of molecules with myofibrillar structures seem to slow down equilibration significantly. Time for equilibration, therefore, cannot simply be predicted from diffusion parameters in solution. Specific interactions resulted in characteristic labeling patterns for molecules like creatine kinase (muscle type), pyruvate kinase, actin-binding IgG, and others. For the very slowly equilibrating Rh-NEM-S1, changes in affinity upon binding to actin in the absence of calcium and subsequent slow cooperative activation, beginning at the free end of the filament at the H-zone, were observed. In the presence of calcium, however, binding of Rh-NEM-S1 was homogeneous along the whole actin filament from the very beginning of equilibration. The dissociation properties of the dynamic interactions were analyzed using a chase protocol. Even molecules that bind with rather high affinity and that can be removed only by applying extreme experimental conditions like Rh-phalloidine or Rh-troponin could be displaced easily by unlabeled homologous molecules.

Actins↗
PubMed1995

Parallel inhibition of active force and relaxed fiber stiffness by caldesmon fragments at physiological ionic strength and temperature conditions: additional evidence that weak cross-bridge binding to actin is an essential intermediate for force generation.

Previously we showed that stiffness of relaxed fibers and active force generated in single skinned fibers of rabbit psoas muscle are inhibited in parallel by actin-binding fragments of caldesmon, an actin-associated protein of smooth muscle, under conditions in which a large fraction of cross-bridges is weakly attached to actin (ionic strength of 50 mM and temperature of 5 degrees C). These results suggested that weak cross-bridge attachment to actin is essential for force generation. The present study provides evidence that this is also true for physiological ionic strength (170 mM) at temperatures up to 30 degrees C, suggesting that weak cross-bridge binding to actin is generally required for force generation. In addition, we show that the inhibition of active force is not a result of changes in cross-bridge cycling kinetics but apparently results from selective inhibition of weak cross-bridge binding to actin. Together with our previous biochemical, mechanical, and structural studies, these findings support the proposal that weak cross-bridge attachment to actin is an essential intermediate on the path to force generation and are consistent with the concept that isometric force mainly results from an increase in strain of the attached cross-bridge as a result of a structural change associated with the transition from a weakly bound to a strongly bound actomyosin complex. This mechanism is different from the processes responsible for quick tension recovery that were proposed by Huxley and Simmons (Proposed mechanism of force generation in striated muscle. Nature. 233:533-538.) to represent the elementary mechanism of force generation.

Actins↗
PubMed1995

Application of a bedside whole blood D-dimer assay in the diagnosis of deep vein thrombosis.

Cross-linked fibrin degradation products have been used to detect venous thrombosis. While the sensitivity of plasma D-dimer measured by ELISA in the diagnosis of deep vein thrombosis (DVT) is high, the utility of ELISA methods is limited in a clinical setting. This study analysed the diagnostic value of a rapid D-dimer assay performed on whole blood samples (SimpliRed D-dimer) compared with latex and ELISA in 86 patients suspected of having DVT. SimpliRed D-dimer was positive in 47/50 of patients with DVT established by Doppler ultrasound (DU; sensitivity 94%). SimpliRed D-dimer was positive in 35/37 of patients with proximal DVT, nine out of nine with popliteal DVT and three out of four with superficial thrombophlebitis. The specificity of SimpliRed D-dimer in the diagnosis of DVT was 61%. The sensitivity of the SimpliRed D-dimer assay was at least comparable with the ELISA (87%) and superior to the latex assay (80%). The positive predictive value (77%), the negative predictive value (88%) and the overall accuracy (80%) of the SimpliRed assay were better than the ELISA and latex methods. It is concluded that SimpliRed D-dimer is a rapid useful assay for screening of patients suspected of having deep vein thrombosis.

Adolescent↗
PubMed1995

Interferon-alpha-2b with VMCP for induction in multiple myeloma: the Israel Myeloma Cooperative Group experience.

In 1988, a prospective, randomized multicenter study was initiated to determine the efficacy of a combined induction regimen with recombinant interferon-alpha-2b (IFN-alpha) and maintenance with IFN-alpha on the response and survival rates in multiple myeloma (MM) patients. Induction therapy consisted of VMCP (vincristine, melphalan, cyclophosphamide, prednisone), randomized to combine IFN-alpha at a dose of 2 x 10(6) U, 5 days per week throughout the induction period of 12 months. Patients who achieved plateau phase were subsequently randomized again between IFN alpha maintenance (2 x 10(6) U, 3 days a week) for 12 months and no maintenance therapy. Of the previously untreated patients, 84 were initially randomized for induction therapy, and 31 for the maintenance phase with IFN-alpha. Results of the cohort median survival, based on the intention to treat, have shown that those on the VMCP/IFN-alpha arm had a median survival of 53 months, compared with patients on the VMCP induction arm who a median survival of 26 months (P = 0.052). The median survival of stage 3 evaluable patients who were on the VMCP/IFN induction arm was 43 months, and 13 months for patients treated by VMCP alone (P = 0.008). No significant difference in survival was detected among patients in partial remission (after induction) who had a second IFN-alpha randomization at the plateau phase. Hematologic toxicity, mild to moderate fever, and fatigue were more common in the VMCP/IFN induction arm. The results show that VMCP/IFN is a well-tolerated treatment regimen, and is superior to VMCP for patients with stage 3 myeloma.

Adult↗
PubMed1995

Distinct molecular processes associated with isometric force generation and rapid tension recovery after quick release.

It was proposed by Huxley and Simmons (Nature 1971, 233:533-538) that force-generating cross-bridges are attached to actin in several stable positions. In this concept, isometric force is generated by the same mechanism as the quick tension recovery after an abrupt release of length; i.e., when crossbridges proceed from the first postulated stable position to the second and/or subsequent positions, resulting in straining of the elastic elements within the cross-bridges. Therefore, isometric force is generated by cross-bridges in the second or even subsequent stable positions. However, through mechanical measurements of skinned rabbit psoas muscle fibers, we found that during isometric contraction only the first stable state is significantly occupied; i.e., isometric force is generated by cross-bridges in the first of the stable states. Thus, isometric force and the quick tension recovery appear to result from two distinctly different molecular processes. We propose that isometric force results from a structural change in the actomyosin complex associated with the transition from a weakly bound configuration to a strongly bound configuration before the reaction steps in the Huxley-Simmons model, whereas a major component of quick tension recovery originates from transitions among the subsequent strongly bound states. Mechanical, biochemical, and structural evidence for the two distinct processes is summarized and reviewed.

Actins↗
PubMed1994

Variant Bernard-Soulier syndrome associated with a homozygous mutation in the leucine-rich domain of glycoprotein IX.

We describe a new variant of Bernard-Soulier syndrome. The patient (W.K.) showed the classic bleeding symptoms together with absence of platelet agglutination to restocetin plus von Willebrand factor, whereas aggregation to ADP, collagen, and arachidonic acid was normal. Platelets were markedly larger than normal and the patient had life-long thrombocytopenia. Surface-labeling of the platelets and two-dimensional gel electrophoresis showed reduced but detectable amounts of glycoprotein (GP) Ib-IX-V present;however, there was markedly less GPIX (2% +/- 1% of normal) than GPIb alpha, Ib beta, or V (7% +/- 2% of normal). This disproportion was confirmed by Western blotting. Sequence analysis was performed after polymerase chain reaction amplification of the coding region of the GPIX and GPI b alpha genes from the patient. A point mutation (A-->G) was found in GPIX converting 45Asn to Ser within the leucine-rich domain. No mutations were found in GPIb alpha. Both alleles of GPIX contained the same defect, which was confirmed by the appearance of a new cleavage site for the restriction enzyme Fnu4HI. This substitution did not affect glycosylation at the neighboring 44Asn as judged by the distribution on two-dimensional gels but did appear to change the conformation of the leucine-rich domain, thus reducing surface expression of the complex. The relationship between GPIb and GPV was not affected, indicating that GPIX does not regulate this. This homozygous mutation in GPIX indicates that, among other possible functions, the leucine-rich domains present on all components of GPIb-IX-V may play a role in the assembly and surface expression of the complex.

Adult↗