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Biomedical subjects

B Brenner

Publications and source records attributed to B Brenner.

At least 253 records · Page 14Linked to original sources

Normal response of factor VIII and von Willebrand factor to 1-deamino-8D-arginine vasopressin in nephrogenic diabetes insipidus.

The effects of 1-deamino-8D-arginine vasopressin (DDAVP) on plasma factor VIII and von Willebrand factor (vWF) levels were studied in four patients with nephrogenic diabetes insipidus (NDI) from two unrelated families. While the urine osmolality remained low, the plasma levels of factor VIII and vWF rose 2- to 3-fold after infusion of 0.3 micrograms/kg DDAVP, compared to preinfusion levels. The degree of increase was similar in both NDI patients and normal subjects. We conclude that in NDI patients the end-organ resistance to DDAVP is confined to the kidneys and does not involve the sites from which factor VIII and vWF are released.

Adult↗

Spontaneous intracranial hemorrhage in immune thrombocytopenic purpura.

Spontaneous intracranial hemorrhage (ICH) is a rare but devastating complication in patients with chronic immune thrombocytopenic purpura (ITP). We report four patients with chronic ITP unresponsive to steroid treatment who developed ICH. One patient had systemic lupus erythematosus; in another patient, the ICH originated from an arteriovenous malformation. High dose steroids, platelet concentrates, emergency splenectomy, and subsequent evacuation of intracranial hematoma, if necessary, can lead to a reasonable outcome of ICH in patients with chronic ITP.

Adolescent↗

Splenectomy in agnogenic myeloid metaplasia and postpolycythemic myeloid metaplasia. A study of 34 cases.

A retrospective analysis of 34 successive splenectomies in 137 patients with myelofibrosis was carried out. Indications, complications, and response to splenectomy were compared between 22 patients with agnogenic myeloid metaplasia (AMM) and 12 patients with postpolycythemic myeloid metaplasia (PPMM). Painful splenomegaly, refractory hemolytic anemia, and refractory thrombocytopenia were the common indications for surgery. The best results were obtained for painful splenomegaly. For the other indications, half to three fourths of the patients improved with splenectomy. An increased incidence of excessive hemorrhage, infected hematoma, and early mortality was more common in the PPMM group and was found to be connected with large spleens, prolonged bleeding time, and prominent thrombocytopenia. Persistent thrombocytosis after surgery was more common in the AMM group. Leukemic transformation seemed to be related to thrombocytosis and to prior therapy with alkylating agents. Median survival following splenectomy was 43 months in the AMM group and 32 months in the PPMM group. We conclude that splenectomy has a role in improving the quality of life by ameliorating mechanical discomfort and decreasing transfusion requirement in the late phase of AMM. However, in patients with PPMM, because of the high complication rate, splenectomy should be carefully considered for specific indications on an individual basis.

Adult↗

The mechanism of muscle contraction. Biochemical, mechanical, and structural approaches to elucidate cross-bridge action in muscle.

Muscle contraction occurs when the thin actin and thick myosin filaments slide past each other. It is generally assumed that this process is driven by cross-bridges which extend from the myosin filaments and cyclically interact with the actin filaments as ATP is hydrolysed. Current biochemical studies suggest that the myosin cross-bridge exists in two main conformations. In one conformation, which occurs in the absence of MgATP, the cross-bridge binds very tightly to actin and detaches very slowly. When all the cross-bridges are bound in this way, the muscle is in rigor and extremely resistant to stretch. The second conformation is induced by the binding of MgATP. In this conformation the cross-bridge binds weakly to actin and attaches and detaches so rapidly that it can slip from actin site to actin site, offering very little resistance to stretch. During ATP hydrolysis by isolated actin and myosin in solution, the cross-bridge cycles back and forth between the weak-binding and strong-binding conformations. Assuming a close correlation between the behaviour of isolated proteins in solution and the cross-bridge action in muscle, Eisenberg and Greene have developed a model for cross-bridge action where, in the fixed filament lattice in muscle, the transition from the weak-binding to the strong-binding conformation causes the elastic cross-bridge to become deformed and exert a positive force, while the transition back to the weak-binding conformation upon binding of MgATP, causes deformation which, during fibre shortening, leads to rapid detachment of the cross-bridge and its re-attachment to a new actin site. From the results of in vitro experiments, it was furthermore suggested that relaxation occurs when the transition from the weak-binding to the strong-binding conformation is blocked. Results of recent mechanical and X-ray diffraction experiments on skinned fibre preparations are consistent with the assumed close correlation between the behaviour of isolated proteins in solution and the behaviour of cross-bridges in muscle. Furthermore, X-ray diffraction experiments allowed to provide experimental evidence for the postulated structural difference between attached weak-binding and attached strong-binding cross-bridges. Finally, recent studies have confirmed the prediction of Eisenberg and Greene that the rate limiting step in vitro determines the rate of force generation in muscle.

Actins↗

Hereditary protein C deficiency during pregnancy.

Hereditary protein C, a primary hypercoagulable state, has not been previously associated with preeclamptic toxemia. A woman with previous preeclamptic toxemia and fetal deaths presented with recurrent deep vein thrombosis during her third pregnancy. Hereditary protein C was diagnosed but full heparinization followed by low-dose heparin failed to prevent preeclamptic toxemia.

Adult↗

Influence of splenectomy on hemostasis in agnogenic myeloid metaplasia.

The effect of splenectomy on hemostatic tests was studied in 10 patients with agnogenic myeloid metaplasia. Prolonged partial thromboplastin time and abnormal prothrombin consumption were found before splenectomy and were normalized postoperatively in the majority of patients. Prolonged bleeding time and prothrombin time were normalized in some patients. While platelet counts and fibrinogen levels rose significantly following splenectomy, platelet aggregation remained impaired. Thrombocytosis and increased fibrinogen level after splenectomy in patients with agnogenic myeloid metaplasia can enhance a thromboembolic tendency.

Adult↗

Eosinophilic fibrohistiocytic lesion of bone marrow associated with monoclonal gammopathy and osteolytic lesions.

We describe a 63-year-old male patient with severe osteoporosis, multiple lytic bone lesions, and monoclonal gammopathy (IgG lambda). Whereas the tentative diagnosis in this case was multiple myeloma, bone marrow trephine biopsies of the iliac crest and from an osteolytic lesion of the tibia both showed a peculiar infiltrate consisting of numerous elongated mast cells, eosinophils, and some plasma cells and lymphocytes. The bone marrow lesions fit the diagnosis of eosinophilic fibrohistiocytic lesion of bone marrow (EFHBM). The patient had no abnormality that could be related to a known allergic disease, and no relationship to drug hypersensitivity could be established. The features of the bone marrow infiltrate and its association with monoclonal gammopathy may suggest a linkage between EFHBM and the monoclonal gammopathy.

Bone Marrow Diseases↗

The cross-bridge cycle in muscle. Mechanical, biochemical, and structural studies on single skinned rabbit psoas fibers to characterize cross-bridge kinetics in muscle for correlation with the actomyosin-ATPase in solution.

A characteristic and important feature of myocardium is the modulation of tension when stimulated or possibly even when unstimulated. In addition, resistance to stretch and its variation in unstimulated heart muscle is an important factor in myocardial function. These features may occur in some new light when viewed from some recent advances in understanding of cross-bridge action and regulation of muscle. For this reason we give a short review of such advances. Firstly, we summarize some of our earlier results obtained in experiments designed to see whether and to what extent actomyosin ATPase data obtained in solution might apply in muscle. Secondly, we present a recently developed experimental approach to estimate the rate constants that determine the cycling of cross-bridges between weak-binding, 'non-force-generating' states and strong-binding, 'force-generating' states. The estimated rate constants confirm the prediction of cross-bridge models derived from in vitro studies that the step which is rate-limiting in solution also determines the rate of force-generation in the cross-bridge cycle in muscle. Experiments at various Ca++ concentrations imply that a major mechanism of regulation is the control of the transition from the weak-binding, 'non-force-generating' states to the strong-binding, 'force-generating' states while the number of activated interaction sites appears unchanged and always at its maximum. This implies that changes in the force-pCa relation cannot be interpreted without detailed analysis of cross-bridge kinetics, and that factors other than Ca++ may have the potential to modulate muscle activity, both in stimulated and unstimulated muscle, by affecting cross-bridge kinetics.

Adenosine Triphosphatases↗

Stiffness of skinned rabbit psoas fibers in MgATP and MgPPi solution.

The stiffness of single skinned rabbit psoas fibers was measured during rapid length changes applied to one end of the fibers. Apparent fiber stiffness was taken as the initial slope when force was plotted vs. change in sarcomere length. In the presence of MgATP, apparent fiber stiffness increased with increasing speed of stretch. With the fastest possible stretches, the stiffness of relaxed fibers at an ionic strength of 20 mM reached more than 50% of the stiffness measured in rigor. However, it was not clear whether apparent fiber stiffness had reached a maximum, speed independent value. The same behavior was seen at several ionic strengths, with increasing ionic strength leading to a decrease in the apparent fiber stiffness measured at any speed of stretch. A speed dependence of apparent fiber stiffness was demonstrated even more clearly when stiffness was measured in the presence of 4 mM MgPPi. In this case, stiffness varied with speed of stretch over about four decades. This speed dependence of apparent fiber stiffness is likely due to cross-bridges detaching and reattaching during the stiffness measurement (Schoenberg, 1985. Biophys. J. 48:467). This means that obtaining an estimate of the maximum number of cross-bridges attached to actin in relaxed fibers at various ionic strengths is not straightforward. However, the data we have obtained are consistent with other estimates of cross-bridge affinity for actin in fibers (Brenner et al., 1986. Biophys. J. In press.) which suggest that ~60-90% of the cross-bridges attached in rigor are attached in relaxed fibers at an ionic strength of 20 mM and ~2-10% of this number of cross-bridges are attached in a relaxed fiber at an ionic strength of 170 mM.

Adenosine Triphosphate↗

Ca2+-sensitive cross-bridge dissociation in the presence of magnesium pyrophosphate in skinned rabbit psoas fibers.

We find that at 6 degrees C in the presence of 4 mM MgPPi, at low or moderate ionic strength, skinned rabbit psoas fibers exhibit a stiffness and an equatorial x-ray diffraction pattern similar to that of rigor fibers. As the ionic strength is increased in the absence of Ca2+, both the stiffness and the equatorial x-ray diffraction pattern approach those of the relaxed state. This suggests that, as in solution, increasing ionic strength weakens the affinity of myosin cross-bridges for actin, which results in a decrease in the number of cross-bridges attached. The effect is Ca2+-sensitive. Assuming that stiffness is a measure of the number of cross-bridge heads attached, in the absence of Ca2+, the fraction of attached cross-bridge heads varies from approximately 75% to approximately 25% over an ionic strength range where ionic strength in solution weakens the binding constant for myosin subfragment-1 binding to unregulated actin by less than a factor of 3. Therefore, this phenomenon appears similar to the cooperative Ca2+-sensitive binding of S1 to regulated actin in solution (Greene, L. E., and E. Eisenberg, 1980, Proc. Natl. Acad. Sci. USA, 77:2616). By comparing the binding constants in solution and in the fiber under similar conditions, we find that the "effective actin concentration," that is, the concentration that gives the same fraction of S1 molecules bound to actin in solution as cross-bridge heads are bound to actin in a fiber, is in the millimolar range. An effective actin concentration in the millimolar range suggests that the strength of actin binding to cross-bridges in fibers may be several orders of magnitude weaker than the strength of ATP binding. Previously, it has been assumed that these two quantities were equal, as this gives the minimum energy loss when ATP dissociates the cross-bridge from actin (Morales, 1980, J. Supramol. Struct., 3:105:1975; Eisenberg, E.,Hill, T. L. and Y. Chen, 1980, Biophys. J., 29:195).

Actins↗

Rate of force generation in muscle: correlation with actomyosin ATPase activity in solution.

Crossbridge models of muscle contraction based on biochemical studies predict that there may be a relationship between the rate-limiting step in the actomyosin ATPase cycle in vitro and the rate of force development in vivo. In the present study, we measured the rate of force redevelopment in skinned rabbit muscle fibers following unloaded isotonic shortening and a rapid restretch. For comparison, ATPase activity was measured under identical conditions, using myosin subfragment-1 chemically crosslinked to actin. We found that the time course of force redevelopment is well fitted by a single exponential function, implying that force redevelopment is a first-order process, described by a single rate constant. The magnitude of this rate constant is in close agreement with the rate constant necessary to simulate the experimental force-velocity relation on the basis of a crossbridge model of the type proposed by A. F. Huxley in 1957. In addition, the observed close correlation between the rate constant for force redevelopment and the maximal actin-activated actomyosin ATPase rate under a variety of conditions suggests that the step that determines the rate of force generation in the crossbridge cycle may be the physiological equivalent of the rate-limiting step in the actomyosin ATPase cycle in solution.

Actomyosin↗

Partial response of meningeal myeloma to craniospinal radiotherapy.

Concomitant occurrence of meningeal involvement and thoracic plasmacytoma was observed in a patient with IgA lambda myeloma. Cerebrospinal fluid analysis revealed IgA-lambda paraprotein and pathological plasma cells. CT scan of the chest and lumbar myelogram excluded spinal cord compression. The patient partially responded to craniospinal irradiation but succumbed to rapidly progressive myeloma 20 weeks following diagnosis of meningeal involvement.

Aged↗