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Biomedical subjects

B Brenner

Publications and source records attributed to B Brenner.

At least 37 records · Page 2Linked to original sources
PubMed2000

Cross-bridge attachment during high-speed active shortening of skinned fibers of the rabbit psoas muscle: implications for cross-bridge action during maximum velocity of filament sliding.

To characterize the kinetics of cross-bridge attachment to actin during unloaded contraction (maximum velocity of filament sliding), ramp-shaped stretches with different stretch-velocities (2-40,000 nm per half-sarcomere per s) were applied to actively contracting skinned fibers of the rabbit psoas muscle. Apparent fiber stiffness observed during such stretches was plotted versus the speed of the imposed stretch (stiffness-speed relation) to derive the rate constants for cross-bridge dissociation from actin. The stiffness-speed relation obtained for unloaded shortening conditions was shifted by about two orders of magnitude to faster stretch velocities compared to isometric conditions and was almost identical to the stiffness-speed relation observed in the presence of MgATPgammaS at high Ca(2+) concentrations, i.e., under conditions where cross-bridges are weakly attached to the fully Ca(2+) activated thin filaments. These data together with several control experiments suggest that, in contrast to previous assumptions, most of the fiber stiffness observed during high-speed shortening results from weak cross-bridge attachment to actin. The fraction of strongly attached cross-bridges during unloaded shortening appears to be as low as some 1-5% of the fraction present during isometric contraction. This is about an order of magnitude less than previous estimates in which contribution of weak cross-bridge attachment to observed fiber stiffness was not considered. Our findings imply that 1) the interaction distance of strongly attached cross-bridges during high-speed shortening is well within the range consistent with conventional cross-bridge models, i.e., that no repetitive power strokes need to be assumed, and 2) that a significant part of the negative forces that limit the maximum speed of filament sliding might originate from weak cross-bridge interactions with actin.

Actins↗
PubMed2000

Resistance to antiretroviral drugs in patients with primary HIV-1 infection. Investigators of the Quebec Primary Infection Study.

The widespread use of antiretroviral agents (ARVs) and the growing occurrence of HIV strains resistant to these drugs have given rise to serious concerns regarding the transmission of resistant viruses to newly infected persons. Plasma viral RNA from 80 individuals newly infected between 1997 and 1999 was genotyped by automated sequencing to analyze the profile of viruses resistant to nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs) and to protease inhibitors (PIs). The prevalence of mutations that conferred primary resistance to PIs (L10I, D30Y, V82A, L90M) was 15% of the cohort. RT genotypic variants, associated with high-level resistance to ARVs, were observed in 21% of individuals, including NRTI, NNRTI and multidrug (MDR) resistance in 6, 5, and 10% of cases, respectively. The phenotypic susceptibility of viral isolates to ARVs was also assayed and showed transmission of high-level resistance to ZDV, 3TC, and PIs in those individuals with MDR. The transmission of drug-resistant HIV genotypic variants is a serious problem that merits further attention by public health officials, virologists, and clinicians.

Anti-HIV Agents↗
PubMed2000

Comparison of clinical performance, histology and single-fiber contractility in free neurovascular muscle flaps.

The aim of this study was to obtain further insights about muscle regeneration processes in free neurovascular flaps. In cases of insufficient functional return of muscle strength, several factors, such as diminished axonal ingrowth, fatty degeneration, or connective tissue proliferation are discussed. In the study, free neurovascular latissimus dorsi (LD) flaps were examined after a regeneration period of 2 to 6 years. Clinical function (M1 to M4) and histopathologic characteristics of the muscle grafts were correlated. The rare instances of secondary procedures, such as tenolysis or scar correction, were used for biopsies of the muscle graft. Free neurovascular LD flaps were examined after a regeneration period between 2 and 6 years. The grafted LD was compared to normal, healthy LD muscle. Normal LD muscle showed a typical homogeneous pattern of types 1 and 2 fibers in a ratio of almost 1:1. No significant differences concerning fiber distribution and fiber diameters in three anatomic areas of the LD (proximal, medial, caudal) could be detected. After regeneration, the authors found the following: type grouping of muscle fiber types, fiber splitting, and groups of hypertrophic and atrophic fibers. Most of the muscle fibers were not reinnervated by axons and were atrophic or degenerated. The essential proliferation of connective and fatty tissue was absent. Normal and hypertrophic fibers were found mainly in the muscle grafts with good clinical results. In muscle grafts with good contraction force (M4), 46 percent of reinnervated muscle fibers were found; M3 contractility was correlated with 31 percent of reinnervated muscle fibers; M2 with 24 percent; and M1 with 21 percent of reinnervated fibers. The force of a free muscle graft seems to depend mainly on the quality of nerve regeneration. Characteristics of the muscle fiber itself were not examined extensively, because the single-fiber contractility of the regenerated fibers was similar to the contractility of normal, healthy fibers.

Adult↗
PubMed2000

Echocardiography in nonbacterial thrombotic endocarditis: from autopsy to clinical entity.

Bacteria-free verrucae, frequently termed "non-bacterial thrombotic endocarditis," have been recognized in autoimmune disorders as well as in neo-plastic diseases. The antemortem diagnosis of non-bacterial thrombotic endocarditis is rare, and most existing data result from postmortem examinations. In 3 prospective echocardiographic studies we found typical cardiac valvular lesions in patients with primary antiphospholipid syndrome, myelo-proliferative disorders, and solid malignant tumors. Cardiac lesions associated with these 3 different entities had common echocardiographic appearance and correlated positively with thromboembolic events. The possibility of common pathogenesis is suggested, and clinical significance is discussed.

Antiphospholipid Syndrome↗
PubMed2000

Oral etoposide for Merkel cell carcinoma in patients previously treated with intravenous etoposide.

We describe three patients with advanced Merkel cell carcinoma who were treated with etoposide given orally for recurrent regional lymph node involvement 18 to 30 months after exposure to etoposide given intravenously. Etoposide given orally (100 mg/day) was given for 10 to 14 consecutive days and repeated every 21 to 28 days for a median of three courses (range: two to four). Toxicity was minimal and mainly hematologic. Two patients showed a complete response and one a partial response, all of very rapid onset. All three patients are alive 6, 9, and 42 months from the start of oral treatment. Two remain progression free, and one had a recurrence 1 month after completion of chemotherapy. We suggest that orally administered etoposide, a topoisomerase II inhibitor, has a strong antitumor effect in advanced Merkel cell carcinoma, even in patients previously treated parenterally with the same drug. This action may be explained by the greater dependence of the drug's efficacy on the duration of administration rather than the dose intensity.

Administration, Oral↗
PubMed2000

Inherited thrombophilia and fetal loss.

Acquired thrombophilia is a well-established cause of pregnancy loss. Increasing numbers of recent observations suggest that inherited thrombophilia is not only associated with gestational thromboembolism but is also a major cause of fetal loss. This review focuses on association of fetal loss with inherited thrombophilias, including dysfibrinogenemia and protein C, protein S, and antithrombin III deficiencies. Activated protein C resistance and factor V Leiden mutation are frequent causes of pregnancy loss. Thrombophilic states such as factor V Leiden and hyperhomocysteinemia may also play a role in other gestational vascular complications, including intrauterine growth restriction, preeclampsia, and placental abruption. Preliminary reports suggest that antithrombotic therapy may be of value in this setting. The potential application of antithrombotic modalities to prevent fetal loss in women with thrombophilia is discussed.

Abortion, Habitual↗
PubMed2000

The effect of thrombophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation.

OBJECTIVE: To observe the effect of thrombophylaxis on pregnancy in women with a history of unexplained recurrent pregnancy loss also carrying the factor V Leiden mutation. METHODS: Between 1 January and 31 December 1996, activated protein C (APC) resistance and factor V Leiden mutation were prospectively measured in 56 nonpregnant women, with a history of two or more unexplained recurrent pregnancy losses. During the same study period, seven women carrying the factor V Leiden mutation conceived, and were subsequently followed throughout their pregnancy. Subcutaneous low molecular weight heparin (LMWH, enoxaparin, 40 mg/day) and oral low dose aspirin (100 mg/day) were administered throughout the pregnancies, starting at early first trimester. Ultrasound and Doppler umbilical and fetal middle cerebral arterial flow studies were performed in the second and third trimesters, and the course and outcome of the pregnancies were documented. RESULTS: Activated protein C resistance and factor V Leiden were found in 20 (36%) and 12 (21%) women of the study, respectively. Five of the seven pregnancies occuring progressed uneventfully to term with normal fetal growth, normal Doppler flow studies and uneventful neonatal outcome. Two of the seven women had early missed abortions. CONCLUSIONS: Thrombophylaxis, beginning in early pregnancy, in women with unexplained recurrent pregnancy loss associated with factor V Leiden mutation, seems to be safe and allow normal fetal development and good neonatal outcome. To prove the efficacy of thrombophylaxis by LMWH and low dose aspirin in this setting prospective controlled studies seem to be justified.

Abortion, Habitual↗
PubMed2000

Activated protein C resistance and factor V Leiden mutation can be associated with first-as well as second-trimester recurrent pregnancy loss.

PROBLEM: To examine whether the occurrence of activated protein C resistance (APCR) and factor V Leiden mutation differs in women with first- compared to women with second-trimester unexplained recurrent pregnancy loss. METHOD OF STUDY: Seventy eight consecutive women with two or more unexplained post-embryonic recurrent pregnancy losses and 139 fertile women with at least one successful pregnancy and no abortions were prospectively investigated for APCR and the factor V Leiden mutation. No women were pregnant at the time of investigation. APCR was defined as APC sensitivity ratio (APC SR) of < or = 2.0. All patients with an APC SR < or = 2.4 were investigated for the factor V Leiden mutation. Women in this study were divided into three groups. Group A included only women with a history of recurrent first-trimester embryonic loss (37 women) and Group B included women with second-trimester abortions with or without additional first-trimester abortions (41 women). Group C included the controls (139 women). RESULTS: APCR and factor V Leiden mutations were significantly more prevalent in all recurrent pregnancy loss patients in this study as compared to controls. 38%(30/78) and 19%(15/78) in contrast to 8% (11/139) and 6% (8/139), respectively. All three groups in the study were comparable regarding age, parity, and number of living children, whereas Groups A and B were also comparable regarding gravidity. Mean APC SRs were significantly higher in Group C as compared to Groups A and B. The incidence of APCR was significantly higher in Groups A and B, as compared to controls, 27 and 49% in contrast to 8%, respectively. Moreover, the incidence of the factor V Leiden mutation was significantly higher in Groups A and B as compared to Group C, 16 and 22% as distinct from 6%, respectively. The incidence of APCR was higher in Group B as compared to Group A, 49% in contrast to 27%, with borderline significance: however, the factor V Leiden mutation did not significantly differ between the two groups. CONCLUSIONS: APCR and factor V Leiden are associated with unexplained recurrent pregnancy loss. The occurrence of APCR and factor V Leiden seems to be linked to post-embryonic first-trimester as well as second-trimester recurrent pregnancy loss. The significance of acquired, non-heritable APCR in recurrent fetal loss patients, especially in the second-trimester aborters, is still to be determined.

Abortion, Habitual↗
PubMed2000

Surfactant modulates intracellular signaling of the adhesion receptor L-selectin.

Intraalveolar leukocyte accumulation is one of the hallmarks during respiratory distress. In the intraalveolar space, leukocyte activation is mediated by pathogens, cytokines, and different ligands binding to adhesion molecules. Leukocyte stimulation via the adhesion molecule L-selectin is specifically induced by ligands expressed on leukocytes, platelets, endothelial cells, or lipopolysaccharide. Recently, we have demonstrated that leukocyte activation by L-selectin transmits several intracellular signaling cascades resulting in capping and cytoskeletal changes, the activation of kinases and neutral sphingomyelinase, the recruitment of adaptor proteins to the cell membrane, the activation of the small G-proteins Ras and Rac, and the release of oxygen. In the present study, we examined the effects of surfactant on L-selectin-induced signal transduction in leukocytes. Using fluorescence microscopy, we provide evidence that preincubation of leukocytes with surfactant significantly inhibits receptor capping; 28+/-7% of cells show capping after L-selectin stimulation versus 8+/-5% and 3+/-1% of cells after preincubation with Exosurf and Curosurf, respectively (p < 0.05). The activity of the neutral sphingomyelinase in cell lysates is also modulated by surfactant. In addition, we show that the activation of the tyrosine kinase p56lck is diminished by approximately 50% after surfactant treatment. This results in inhibition in tyrosine phosphorylation of certain intracellular proteins. The interaction of the L-selectin molecule with its antibody was not influenced by surfactant as shown by flow cytometry. Surfactant inhibits intracellular signaling events of the L-selectin receptor in leukocytes and might therefore contribute to the modulatory effects of surfactant on immune function.

Humans↗
PubMed2000

Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.

Inherited and acquired thrombophilia are associated with recurrent pregnancy loss (RPL). We have evaluated the efficacy and safety of the low molecular weight heparin enoxaparin in 50 women, (mean age 26 +/- 3 years) with RPL (> or =3 losses in 1st, > or =2 losses in 2nd and > or =1 loss in 3rd trimester) who were found to harbor thrombophilia. Twenty-seven had a solitary thrombophilic defect, and twenty-three women had combined thrombophilic defects: 17--two defects and 6--three defects. Following diagnosis of thrombophilia, sixty-one subsequent pregnancies were treated with the low molecular weight heparin enoxaparin throughout gestation until 4 weeks after delivery. Dosage was 40 mg/day in women with solitary defect and 80 mg/day in combined defects. Aspirin, 75 mg daily was given in addition to enoxaparin to women with antiphospholipid syndrome. Forty-six out of 61 (75%) gestations treated by enoxaparin resulted in live birth compared to only 38/193 (20%) of the untreated pregnancies in these 50 women prior to diagnosis of thrombophilia (p <0.00001). In 23 women without a single living child following 82 untreated gestations, antithrombotic therapy resulted in 26/31 (84%) successful deliveries (p <0.0001). In 20 women with a prior living child, antithrombotic therapy improved successful delivery from 33/86 (38%) to 20/21 (95%) (p <0.0001). Enoxaparin dose of 40 mg/day resulted in live birth in 24/35 (69%) of gestations, compared to 19/23 (83%) gestations in women treated with 80 mg/day (p = 0.37). Only one thrombotic episode and one mild-bleeding episode were noticed during enoxaparin therapy. Enoxaparin is safe and effective in prevention of pregnancy loss in women with inherited and acquired thrombophilia.

3' Untranslated Regions↗
PubMed1999

Variability in the ratio of mutant to wildtype myosin heavy chain present in the soleus muscle of patients with familial hypertrophic cardiomyopathy. A new approach for the quantification of mutant to wildtype protein.

The ratio of mutant to wildtype myosin heavy chain (beta-isoform, beta-MHC) in the soleus muscle of patients with familial hypertrophic cardiomyopathy was determined by a combination of HPLC, mass spectrometry and capillary zone electrophoresis. In two patients, one with a Val 606 Met mutation and another with a Gly 584 Arg mutation, the fraction of mutant beta-MHC was only 12+/-6% and 23+/-0.7% of total beta-MHC, respectively. These results demonstrate the necessity to determine the ratio of mutant to wildtype protein for the interpretation of functional studies on biopsy material from heterozygous patients with an inherited disease.

Amino Acid Substitution↗
PubMed1999

Prognostic factors for local control of early glottic cancer: the Rabin Medical Center retrospective study on 207 patients.

PURPOSE: Different radiation therapy schedules and devices have been used over the last 20 years at Rabin Medical Center in patients with early glottic cancer. The aim of the present retrospective analysis was to identify the subgroup of patients at high risk of failure of radiation treatment. MATERIALS AND METHODS: Between 1974 and 1994, 207 patients with squamous cell carcinoma of the glottis, 182 Stage T1 and 25 Stage T2, underwent definitive radiation therapy. During this period, treatment was administered with different radiation devices (60Co or 6-MV X ray), using different dose/fraction protocols (1.8 or 2 Gy per day, 5 or 6 fractions per week), total doses (42-77.4 Gy), overall radiation times, and delays. These treatment variables, in addition to certain patient and tumor characteristics, were correlated with local control at a median follow-up of 57 months (range 18-265 months). RESULTS: The 5-year local control rates for T1 and T2 tumors were 88% and 73%, respectively. Univariate analysis showed that smoking, diabetes mellitus, anterior commissure involvement, T stage, and extension of tumor to one third or more of the vocal cord were highly significantly correlated with decreased local control. None of the treatment variables, including dosage at which complete tumor regression was noted, were found to be predictive. By multivariate analysis, only anterior commissure involvement was found to be highly significant (risk ratio 1.9, 95% CI 1.2-3.0, p = 0.027), and T stage was borderline significant (risk ratio 1.6, 95% CI 1.0-2.5, p = 0.054). CONCLUSION: This study suggests that only two tumor characteristics are predictive of local failure of early glottic cancer: anterior commissure involvement and T stage. Treatment variables apparently do not influence local control.

Adult↗
PubMed1999

[Ambulatory oral procedures in patients on low-dose aspirin].

Discontinuation of long-term, low-dose aspirin prior to ambulatory oral surgical procedures was assessed in a blind, controlled prospective study. 50 patients on low-dose aspirin who needed dental extractions, periodontal surgery, or other ambulatory oral surgery were randomly divided into test and control groups. The control patients stopped taking aspirin a week before operation, but in the test group aspirin was continued. Before, during and after surgery bleeding time was tested. Although bleeding time was significantly longer when aspirin was continued, in both groups it was within normal limits. Intraoperative hemorrhage was more frequent in those taking aspirin. Hemostasis control posed no problem and there were no postoperative complications in either group. It is concluded that discontinuing low-dose aspirin prior to elective oral surgery is not justified.

Adult↗