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Biomedical subjects

B Brenner

Publications and source records attributed to B Brenner.

At least 217 records · Page 12Linked to original sources
PubMed1991

Immunization by gamma-IFN-treated B16-F10.9 melanoma cells protects against metastatic spread of the parental tumor.

B16-F10.9 is a highly metastatic clone of the B16-F10 melanoma line, that expresses low levels of MHC class-I antigens. F10.9 cells transfected with H-2Kb are highly immunogenic and consequently exhibit a low metastatic phenotype. Treatment with gamma-IFN elevated H-2Kb and H-2Db cell surface expression of F10.9 cells to levels much higher than did transfection of these genes. Yet, following intravenous injection, the gamma-IFN treated cells generated high loads of lung metastases. However, when tested for their immunogenic effect, they elicited CTL and were sensitive to CTL. Immunization with both the positive transfectant KI and the gamma-IFN-treated F10.9 cells protected in vivo against metastatic spread of a subsequent transplant of parental F10.9 cells. The protection elicited by KI transfectants was more effective than the protection by gamma-IFN-treated cells.

Animals↗
PubMed1991

A new concept for the mechanism of Ca+(+)-regulation of muscle contraction. Implications for physiological and pharmacological approaches to modulate contractile function of myocardium.

Recent development of an experimental protocol to determine kinetics of active cross-bridge turnover is muscle allows analysis of possible Ca+(+)-effects on cross-bridge turnover kinetics. This analysis enabled us to distinguish the two main hypotheses about the mechanism of regulation of muscle contraction. In the first hypothesis, the number of actively turning over cross-bridges is changed, while cross-bridge turnover kinetics are unaffected by Ca++ (regulation by "cross-bridge recruitment"). In the other hypotheses, cross-bridge turnover kinetics are controlled by Ca++, while the number of actively turning over cross-bridges is essentially unaffected (regulation by "rate modulation"). It is found that the major mechanism of regulation of muscle contraction is by a change in the rate constant (fapp) that determines the transition of a cross-bridge from the weak-binding (non-force generating) configuration to its strong-binding (force generating) configuration. It is demonstrated that the concept of "rate modulation" requires reinterpretation of force-pCa relations and of the mechanisms of physiological and pharmacological modulation of force-pCa relations. On this basis, an additional mechanism for positive inotropic interventions is demonstrated which may have advantages over the previously established mechanisms.

Animals↗
PubMed1991

Dynamic actin interaction of crossbridges: a general principle and its implications for crossbridge action in muscle.

The oar-like crossbridge cycle, developed up to the mid-1970's, was shown to be inconsistent with more recent biochemical results. In crossbridge theories developed on the basis of the more recent kinetic schemes of the actomyosin ATPase in solution (Eisenberg and coworkers), however, the key elements proposed by Huxley (1957) were retained, one of which is the assumption that detachment of a force-generating crossbridge can only occur via completion of the ATPase cycle (release of ADP and rebinding of ATP). Furthermore, in these theories regulation is assumed to act by blocking/unblocking of a step subsequent to crossbridge attachment (e.g., Pi-release step). Both concepts, however, were recently shown to be in conflict with studies on skinned muscle fibers (still low ATPase activity at high-speed isotonic shortening, regulation acts via turnover kinetics and not recruitment (39]. By incorporation of the observed reversible actin interaction of crossbridges in all states, including the force-generating states, a working hypothesis can be developed (Fig. 5) which can account for the isotonic data. A mechanism by which such a scheme can also account for regulation via turnover kinetics was previously discussed (39).

Actins↗
PubMed1991

Cardiac involvement in patients with primary antiphospholipid syndrome.

To evaluate cardiac involvement in primary antiphospholipid syndrome, two-dimensional and Doppler echocardiographic studies were performed in 34 consecutive patients with this syndrome. All patients had an increased level of serum anticardiolipin antibodies with no evidence of malignancy or systemic lupus erythematosus. The clinical manifestations of primary antiphospholipid syndrome were arterial thrombosis in 14 patients, venous thrombosis in 6 and recurrent fetal loss in 14. Valvular lesions were observed on two-dimensional echocardiography in 11 patients (32%) (9 women and 2 men), aged 24 to 57 years (mean +/- 1 SD 36 +/- 10). Abnormal echocardiographic findings were observed in 9 (64%) of 14 patients with arterial thrombosis versus 1 (17%) of 6 patients with venous thrombosis and 1 (7%) of 14 patients with recurrent fetal loss. The most common echocardiographic abnormality was mitral leaflet thickening, found in five patients; this was associated with mitral regurgitation in three and with combined mild mitral stenosis and regurgitation in one patient. Localized subvalvular mitral thickening was observed in one patient and calcification of the anulus in another. Aortic valve thickening was observed in two patients, one of whom also had a moderate degree of aortic regurgitation. Vegetation-like lesions on the mitral or aortic valve were found in two patients. It is concluded that valvular lesions are commonly found in primary antiphospholipid syndrome, particularly when the syndrome is manifested by peripheral arterial thrombosis. The location and appearance of valvular lesions in this syndrome are heterogeneous. Most patients have no clinically significant valvular disease. Two-dimensional and Doppler echocardiographic studies are often informative in these patients.

Adult↗
PubMed1991

X-ray diffraction testing for weak-binding crossbridges in relaxed bony fish muscle fibres at low ionic strength.

Equatorial X-ray diffraction patterns from single skinned fibres from bony fish muscle (turbot) were obtained with the fibres at 6 degrees C bathed in relaxing solutions of 170 down to 26 mM ionic strength. Diffraction patterns from rigor fibres were also obtained as controls. Unlike fibres from rabbit muscle, which show very clear evidence of substantial crossbridge formation at low ionic strength in what is mechanically a rapid equilibrium ("weak-binding") state (Brenner et al., 1982), diffraction patterns from bony fish fibres showed only a small change in relative peak intensities at low ionic strength (26 mM) compared with normal (170 mM) ionic strength. However, there was a slight ordering of the filament lattice at low ionic strength. The specimen temperature used (about 6 degrees C) was not far from the normal physiological temperature of the fish. Likewise, only a small change was seen by Xu et al. (1987) in patterns from frog fibres at low ionic strength at 2 to 6 degrees C. (Rabbit fibres previously studied, where large changes were seen at temperatures of 5 to 20 degrees C, were about 17 to 32 degrees C below physiological.) The I11/I10 ratio for fish fibres at 26 mM ionic strength was actually lower than that for rabbit even at normal ionic strength. This may be associated with an intrinsic structural difference between these muscles or alternatively with the disordering of the crossbridge helix in rabbit muscle found at low temperature by Wray (1987), and could support the view that rabbit fibres at 5 degrees C and normal ionic strength may already have a significant population of weak-binding crossbridges.

Animals↗
PubMed1991

Characterization of radial force and radial stiffness in Ca(2+)-activated skinned fibres of the rabbit psoas muscle.

1. When chemically skinned muscle fibres are activated by Ca2+ at an ionic strength of 170 mM, the spacing between the filaments has been shown to decrease with increasing force, suggesting that the cross-bridges can generate force not only in the axial but also in the radial direction. In the present study, radial force and radial stiffness of activated single skinned rabbit psoas fibres were studied by X-ray diffraction. The responses of the lattice spacing to changes in osmotic pressure by application of dextran T500, which is equivalent to force applied in the radial direction, was examined. The radial force generated by the attached cross-bridges was calculated, with the approximation that a negligible fraction of cross-bridges was attached in the relaxed muscle at the same ionic strength of 170 mM. 2. The active radial force was found to be a slightly non-linear function of lattice spacing, reaching zero at 34 nm. The radial force was compressive at lattice spacing greater than 34 nm and expansive at less than 34 nm. 3. The active axial force, on the other hand, was found to be much less affected by the application of dextran T500. Active axial force increased by 4% to a plateau at 4% dextran T500 and then decreased by 10% at 8% dextran T500. 4. While not under osmotic pressure, the radial force of the activated fibre was determined to be 400 pN (single thick filament)-1. This is of the same order of magnitude as the axial force. The radial stiffness was also comparable to the axial stiffness at 7 pN (thick filament)-1 (0.1 nm)-1. 5. The radial elasticity of the fully activated fibre differs significantly from that of the fibre in rigor. The radial stiffness exhibited by fibres in rigor was approximately five times higher, at 30 pN (thick filament)-1 (0.1 nm)-1 and the point where the radial force reached zero was 38 nm. 6. In the activated state, the point at which radial force reaches zero is independent of the level of Ca2+ activation, i.e. independent of the number of cross-bridges attached to actin in the force-generating state. We suggest that the zero-force point is equivalent to the equilibrium point of a spring and is an intrinsic property of the radial elasticity of the cross-bridge. 7. It is concluded that activated and rigor cross-bridges exhibit a spring-like property in the radial direction.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Renal extramedullary hematopoiesis simulating hypernephroma.

We report a 63-year-old woman who presented with anemia and a left kidney mass. Guided fine-needle aspiration of the mass revealed extramedullary hematopoiesis and enabled avoiding an unnecessary operation. Subsequent bone marrow biopsy demonstrated myelofibrosis. Twenty-four months later the mass remained stable.

Carcinoma, Renal Cell↗
PubMed1991

The prevalence and interaction of human immunodeficiency virus and hepatitis B virus infections in Israeli hemophiliacs.

The prevalence, clinical manifestations and serological markers of hepatitis B virus (HBV) and human immunodeficiency (HIV) infections were studied in 117 Israeli hemophiliacs. Positive serological markers for HBV infection (HB surface antigen, antibody to HB surface antigen or antibody to HB core antigen) were more common in patients treated with non heat-treated F-VIII concentrates (NHTC) than with cryoprecipitate (48/49 vs. 23/29, P less than 0.05), and in patients treated with greater than 10,000 factor units/year (90% vs. 62%, P less than 0.05). Of the 117 patients, 55% were HIV negative, 29% had asymptomatic HIV seropositivity and 16% had symptomatic HIV infection (lymphadenopathy syndrome, AIDS-related complex or AIDS). HIVB seropositivity was more common in patients treated with NHTC than in those treated with cryoprecipitate (83% vs. 11%, P less than 0.001), and in patients treated with greater than 100,000 compared to less than 10,000 F-VIII units/year (70% vs. 15%, P less than 0.001). Hypergammaglobulinemia correlated with HIV seropositivity, alanine aminotransferase levels and type and amount of concentrate therapy. Of 50 HIV-seropositive patients, 40 (98%) had serological markers of HBV infection compared with only 40 of 52 HIV-negative patients (77%) (P less than 0.01). Symptomatic HIV infection was more common in patients with a positive history of jaundice, 7 of 18 (38%) compared with 12 of 99 (12%) (P less than 0.005). These findings suggest that HBV and HIV infections are less prevalent in cryoprecipitate-treated patients, and that HBV seropositivity is a predictor of HIV seropositivity in hemophiliacs.

Factor VIII↗
PubMed1990

The effect of combined factor XI deficiency with von Willebrand factor abnormalities on haemorrhagic diathesis.

To account for the lack of correlation between the level of factor XI (FXI) in deficient patients and haemorrhagic manifestations, we correlated the prevalence of combined FXI and von Willebrand's factor (vWF) deficiency in 212 FXI-deficient patients. Fifty-four patients had a combined FXI and vWF deficiency: 16 patients had severe and 38 patients had mild FXI deficiency. In a group of 28 patients with comparably mild FXI deficiency, 14 bleeders had significantly lower mean vWF, Ag, ristocetin cofactor and ristocetin induced platelet aggregation than 14 non-bleeders selected on the basis of comparable FXI levels. These findings suggest that the combination of FXI and vWF deficiency is common and may affect the bleeding tendency in mild FXI deficiency.

Adolescent↗
PubMed1990

Effect of ritanserin, a 5-hydroxytryptamine2-receptor antagonist, on platelet function and thrombin generation at the site of plug formation in vivo.

To investigate the role of serotonin in platelet plug formation we studied, in eight healthy volunteers, the effect of ritanserin (a 5-hydroxytryptamine2-receptor antagonist) on the platelet release reaction (represented by beta-thromboglobulin release) platelet prostaglandin metabolism (represented by thromboxane B2 formation), and thrombin generation (represented by fibrinopeptide A formation) in the microvasculature. After administration of ritanserin lower amounts of thromboxane B1 were generated in the initial stages of plug formation, suggesting an inhibitory effect on the platelet prostaglandin metabolism. Similar amounts of beta-thromboglobulin were released after the administration of ritanserin compared with placebo, indicating a minor effect of ritanserin on the release reaction. Reduction of thrombin formation by ritanserin in the later stages of hemostasis suggested an inhibitory effect of this substance on the procoagulatory activity of platelets or endothelial cells. This could be attributable to interference with the formation or function of coagulation factor complexes on cell surfaces, or it could be the consequence of a reduction of the platelet activity.

Adult↗
PubMed1990

Effect of conjugated estrogens on platelet function and prostacyclin generation in CRF.

In a double-blind, randomized, placebo-controlled cross-over study, we investigated in seven patients with chronic renal failure the effect of conjugated estrogens (0.6 mg/kg/day for 5 days) on template bleeding time and on thromboxane A2 (TxA2), beta-thromboglobulin (beta-TG) and prostacyclin (PGI2) concentrations in blood emerging from the template bleeding time incisions. Administration of conjugated estrogens resulted in a significant shortening of the bleeding time in six out of seven patients with a maximum effect 7 and/or 14 days following treatment. Both TxA2 (measured as thromboxane B2, TxB2) and beta-TG release in bleeding time blood were significantly higher following administration of conjugated estrogens as compared to placebo administration. No difference was seen in endothelial PGI2 (measured as 6-keto-prostaglandin F1 alpha) formation when patients were treated with conjugated estrogens as compared to placebo administration over the 28 day observation period. We conclude that in patients with chronic renal failure, infusion of conjugated estrogens results in a significant shortening of the bleeding time together with an increase in platelet reactivity, as indicated by an increase of TxA2 and beta-TG concentration in the microvasculature. No effect was seen on PGI2 production, thereby excluding a major effect on vascular prostaglandin metabolism.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Diminution of inducible lymphokine-activated killer cell activity in individuals with AIDS-related disorders.

We have compared the relative ability of lymphokine-activated killer (LAK) cells derived from peripheral blood of HIV-seropositive people, AIDS subjects, and healthy controls, to lyse a panel of natural killer (NK)-sensitive and NK-resistant tumor and virally-infected targets. We have found that LAK cells derived from HIV-seropositive populations show a significant, albeit reduced, capacity to lyse U937, K562, and RAJI target cell lines, in comparison with similarly derived cells from healthy controls. The reductions in LAK activity in both HIV-seropositive asymptomatic and AIDS populations reflect a significant reduction in cytotoxic potential of individual LAK cells. The maximal LAK cytotoxic potentials of control, asymptomatic seropositive, and AIDS populations are comparable. LAK cells derived from HIV-seropositive populations show an enhanced capacity to lyse HIV-infected U937 targets relative to their uninfected counterparts. These enhancements in HIV-infected U937 versus U937 cytolysis arise from increases in the maximal cell-mediated cytolytic plateau. Depletion of NK (CD56+) lymphocytes from peripheral blood prior to LAK cell generation markedly diminishes subsequent specific and total inducible LAK activity. In some subjects, peripheral blood T-cell depletion prior to LAK cell generation results in LAK cells that are subsequently enriched for cytolytic activity, whereas in other subjects similar T-cell depletion impairs inducible LAK cell responses.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Magnetic resonance imaging of blood and clots in vitro.

The effects of variations in blood clot composition on magnetic relaxation rates and magnetic resonance (MR) image have been characterized in vitro. Both 1/T1 and 1/T2 were found to be linear functions of hematocrit for blood and clot, with increases in hematocrit resulting in progressive decreases in image signal intensity. Clot formation in fully oxygenated samples produced no change in relaxation rates or MR images compared with unclotted blood, but clot retraction was associated with a significant increase in 1/T2 that resulted in a decreased signal. Retraction resulted in a heterogenous image with appearance of a hypointense peripheral rim; differences in the method of clot preparation resulted in significant image inhomogeneity. The pattern of fibrinolysis was found to depend on the type of plasminogen activator used and its site of initial application. Injection of tissue plasminogen activator into the clot resulted in lysis, primarily in the clot interior, whereas placing the enzyme in the surrounding serum caused degradation from the outside of the clot. Both observations are consistent with the high binding affinity of tissue plasminogen activator for fibrin. By comparison, streptokinase, with low fibrin binding affinity, dissolved thrombi in a peripheral pattern whether injected into the thrombus or introduced in the serum. These findings identify several variables of clot composition and structure that influence MR images of thrombi and should be considered in their interpretation.

Blood↗
PubMed1990

Hereditary deficiency of all vitamin K-dependent procoagulants and anticoagulants.

Hereditary combined deficiency of vitamin K-dependent factors is a rare entity. We report a 7-year-old girl of Arab origin with hereditary deficiency of the procoagulants factors II, VII, IX and X and the natural anticoagulants proteins C and S. The patient is the tenth offspring of a consanguinous marriage and presented at 6 weeks with spontaneous intracerebral haemorrhage. Symptoms improved following plasma infusion. A sibling died at 5 d from uncontrollable umbilical bleeding. Blood coagulation work-up at 6 years showed: factor II:C (activity) 12 U/dl, factor II:Ag (antigen) 40 U/dl; factor VII:C 12 U/dl; factor IX:C 36 U/dl, factor IX:Ag 57 U/dl; factor X:C 17 U/dl, factor X:Ag 54 U/dl; protein C activity 43 U/dl; protein C:Ag 45 U/dl; protein S:Ag 34 U/dl; levels of factors V:C and VIII:C were normal. Assays of coagulation factors in the parents and five of the siblings were within the normal range. Following acute infection and dilantin therapy procoagulant activity levels were reduced further and were partially increased after vitamin K infusion. Crossed immunoelectrophoresis of prothrombin in the presence of calcium lactate revealed a population of des-carboxyprothrombin. Serum vitamin K epoxide levels were undetectable. The data suggest that the defect in our patient stems from abnormal carboxylation of the vitamin K-dependent proteins and that the mode of inheritance is autosomal recessive.

Blood Coagulation Disorders↗
PubMed1990

Quantitation of venous clot lysis with the D-dimer immunoassay during fibrinolytic therapy requires correction for soluble fibrin degradation.

Plasma cross-linked fibrin-degradation products were analyzed using a D-dimer (DD) immunoassay in patients with deep vein thrombosis (DVT) or acute myocardial infarction (MI) treated with fibrinolytic therapy, and the results were correlated with clot lysis documented angiographically. In 13 patients with DVT, the mean DD concentration increased 10-fold (1,074 +/- 252 to 10,333 +/- 1,004 ng/ml) during therapy, but neither the peak level nor the DD concentration integrated over the course of therapy correlated with clot lysis. Since plasma DD can derive from degradation of soluble plasma fibrin as well as from thrombi, the contribution of the former was estimated by in vitro incubation of the pretreatment plasma with plasminogen activator. Subtraction of this value from the measured posttreatment DD concentration provided a "corrected" level that represented DD originating from lysis of thrombi. This modification resulted in improved correlation of DD levels with clot lysis. The mean corrected peak DD was higher in patients with successful thrombolysis (8,780 +/- 1,352 ng/ml) compared with patients without lysis (3,075 +/- 589 ng/ml, p less than 0.001). There was a moderate correlation between the volume of clot lysed and the corrected peak DD (r = 0.62) and a higher correlation with the corrected DD integrated over the course of treatment (r = 0.97). By contrast, the corrected DD concentrations were near zero in patients treated for MI with or without thrombolytic reperfusion, suggesting that fibrin in small coronary thrombi did not contribute significantly to total plasma DD during therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Diagnosis of femoropopliteal venous thrombosis with MR imaging: a comparison of four MR pulse sequences.

In a prospective study, MR images were evaluated in seven patients with femoropopliteal venous thrombosis with symptoms of less than 5 days duration. T1-weighted (600/25 [TR/TE]), intermediate (2000/30), and T2-weighted (2000/100) spin-echo series and a gradient-recalled acquisition in the steady state (GRASS) series were compared. Using venography as the standard for diagnosis, we found GRASS to be the most sensitive of the MR techniques, showing thrombi in all patients. It provided good contrast between the low-intensity thrombus and high-intensity flowing blood and also between thrombus and intermediate- or high-intensity perivascular tissues. The T1-weighted series was the least sensitive technique. All thrombi showed heterogeneity in the transaxial image with differences in signal between the peripheral and central regions. A higher intensity signal in the center than in the periphery at some level of the thrombus was found in six of seven T2-weighted or GRASS images. Heterogeneity in the signal intensity was more frequent in distal portions of thrombi, whereas the most proximal extent was homogeneous in appearance in six of seven cases. The heterogeneous appearance may be related to the greater age of the distal thrombus, because deep venous thrombi are known to begin in the calf and extend proximally over time. We conclude, on the basis of our experience with a small number of patients, that the GRASS MR technique is more sensitive for detecting acute deep venous thrombosis than T1-weighted, intermediate, and T2-weighted MR images.

Adult↗