PubMed Health⌕ Search

Biomedical subjects

S Falk

Publications and source records attributed to S Falk.

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

Endotoxin desensitization of human mononuclear cells after cardiopulmonary bypass: role of humoral factors.

BACKGROUND: The ability of leukocytes to release proinflammatory cytokines on lipopolysaccharide stimulation in vitro is impaired after cardiopulmonary bypass (CPB). This study tested contribution and interaction of humoral factors in altered leukocyte responsiveness to lipopolysaccharide. METHODS: Whole blood and isolated peripheral-blood mononuclear cells (PBMCs) from 10 patients obtained after induction of anesthesia (T1) and 20 min (T2) and 24 h (T3) after CPB were cultured in the absence or presence of lipopolysaccharide and assessed for release of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-1beta and their functional antagonists, IL-1 receptor antagonist (IL-1ra) and IL-10. In addition, dose-response characteristics and interaction of IL-10 and norepinephrine as modulators of TNF-alpha release were studied. RESULTS: Cardiopulmonary bypass induced release of antiinflammatory (T2: IL-10: median 25 pg/ml, 25th-75th percentile 9-42; IL-1ra: median 1,528 pg/ml, 25th-75th percentile 1,075-17,047; P < 0.05 compared with T1) but failed to induce proinflammatory cytokines (T2: TNF-alpha: median 0 pg/ml, 25th-75th percentile 0-6; IL-1beta: median 1 pg/ml, 25th-75th percentile 0-81; nonsignificant). Removal of plasma at T2 increased TNF-alpha response to lipopolysaccharide (+83.8%; P < 0.05), whereas it suppressed IL-10 (-36.8%; P < 0.05). Similarly, incubation of PBMCs (T1) with plasma obtained after CPB (T2) as well as addition of IL-10 or norepinephrine in concentrations present in plasma after CPB led to a reduced lipopolysaccharide-stimulated TNF-alpha and an increased IL-10 response. Coadministration of norepinephrine and IL-10 had synergistic effects. Although pretreatment with an anti-IL-10 antibody and labetalol before addition of plasma obtained at T2 largely restored the TNF-alpha response in vitro, their addition post-treatment failed to restore the monocytic TNF-alpha response. CONCLUSIONS: Plasma contains interacting factors that inhibit the release of TNF-alpha and increase the release of IL-10, presumably attenuating the inflammatory response to CPB. Although norepinephrine fails to induce a cytokine response in the absence of other stimuli, its administration seems to augment the antiinflammatory IL-10 response while attenuating the TNF-alpha response.

Adult↗
PubMed1999

Real-time fluorimetric analysis of gramicidin D- and alamethicin-induced K+ efflux from Sf9 and Cf1 insect cells.

Gramicidin D and alamethicin are pore-forming peptides which exhibit lethal properties against a large spectrum of cells. Despite a wealth of experimental data from artificial membranes, the time course and quantitative analysis of the activity of these ionophores are not well described in living cells. In the present study, the newly described fluorescent dye CD-222 was used to monitor extracellular potassium ion concentration and report the effects of these antibiotics on the K+ permeability of the plasma membrane of Spodoptera frugiperda (Sf9) and Choristoneura fumiferana (Cf1) insect cells. Both peptides induced a rapid efflux of intracellular K+ as a consequence of ion channel formation in the cell membrane. K+ efflux began without any measurable delay. While the final extracellular K+ concentration was unaffected by ionophore concentration, the rate of K+ efflux was dose dependent. Using a model describing the partition of the peptides in lipid membranes, the K+ efflux kinetic parameters were determined for both cell types and both pore formers. The proposed stoichiometry for the channel formed by gramicidin in living cells is in good agreement with the two-monomers model based on data from artificial membrane systems. The K+-permeable channel formed by alamethicin in insect cells appears to involve three monomers.

Alamethicin↗
PubMed1999

Kinetic mechanisms of inhibitor binding: relevance to the fast-acting slow-binding paradigm.

Although phlorizin inhibition of Na+-glucose cotransport occurs within a few seconds, 3H-phlorizin binding to the sodium-coupled glucose transport protein(s) requires several minutes to reach equilibrium (the fast-acting slow-binding paradigm). Using kinetic models of arbitrary dimension that can be reduced to a two-state diagram according to Cha's formalism, we show that three basic mechanisms of inhibitor binding can be identified whereby the inhibitor binding step either (A) represents, (B) precedes, or (C) follows the rate-limiting step in a binding reaction. We demonstrate that each of mechanisms A-C is associated with a set of unique kinetic properties, and that the time scale over which one may expect to observe mechanism C is conditioned by the turnover number of the catalytic cycle. In contrast, mechanisms A and B may be relevant to either fast-acting or slow-binding inhibitors. However, slow-binding inhibition according to mechanism A may not be compatible with a fast-acting behavior on the steady-state time scale of a few seconds. We conclude that the recruitment hypothesis (mechanism C) cannot account for slow phlorizin binding to the sodium-coupled glucose transport protein(s), and that mechanism B is the only alternative that may explain the fast-acting slow-binding paradigm.

Animals↗
PubMed1999

Quinolines attenuate PAF-induced pulmonary pressor responses and edema formation.

In the present study we have investigated the mechanisms of pulmonary edema caused by platelet-activating factor (PAF) in isolated rat lungs as well as in mice in vivo. In blood-free perfused and ventilated rat lungs, PAF increased lung weight by 0.59 +/- 0.18 g. The cyclooxygenase inhibitor aspirin (500 microM) blocked this response by one-third, and the quinolines quinine (330 microM), quinidine (100 microM), and chloroquine (100 microM) by two-thirds. Lipoxygenase inhibition (10 microM AA861) alone or in combination with thromboxane receptor antagonism (10 microM SQ29548) had no effect on PAF-induced weight gain. In combination with aspirin, quinine or quinidine completely prevented PAF-induced weight gain and the concomitant increase of the capillary filtration coefficient (K(f,c)). Pretreatment with quinine in vivo prevented not only PAF-, but also endotoxin-induced edema formation as assessed by Evans Blue extravasation. In addition, in vivo quinine prevented the endotoxin-induced release of tumor neurosis factor (TNF). Furthermore, in perfused lungs quinine reduced the PAF-induced increases in airway and vascular resistance, as well as thromboxane release. These findings demonstrate the following anti-inflammatory properties of quinolines: reduction of thromboxane and TNF formation; reduction of PAF-induced vasoconstriction and bronchoconstriction; and attenuation of PAF- and lipopolysaccharide (LPS)-induced edema formation. We conclude that the PAF- induced edema consists of two separate mechanisms, one dependent on an unknown cyclooxygenase metabolite, the other one sensitive to quinolines.

Airway Resistance↗
PubMed1999

Hemolysate-mediated renal vasoconstriction and hypersensitization.

The present studies measured vessel diameter, before and after addition of hemolysate, in isolated afferent arterioles (AA) and efferent arterioles (EA) obtained from the rat kidney. Human red blood cells (RBC) were hemolyzed in distilled water and membranes were discarded after centrifugation. Hemolysate added to the bath solution caused vigorous AA and EA contraction and, after washout, hypersensitized the AA and EA to doses of angiotensin II (AII) which would normally only elicit 50% contraction (EC50). Neither the contraction nor the hypersensitization were mimicked by pure human hemoglobin. The vasoconstrictive responses in the AA and EA were accompanied by increased cytosolic-free calcium concentration. Further purification (desalting) of the hemolysate to remove substance of < or = 1000 Da (which include ATP) did not eliminate the vasoconstrictive component from the hemolysate. Finally, cultured rat aortic vascular smooth muscle cells also demonstrated a rapid increase in (Ca2+i) when exposed to hemolysate. This increase in (Ca2+i) was, in part, dependent on Ca2+ influx since it could be attenuated with diltiazem (10(-5) M). In conclusion, hemolysate contains a factor which induces contractions of the isolated rat kidney AA and EA and rapid elevations in (Ca2+i). This factor, from hemolyzed RBC, is not hemoglobin itself.

Animals↗
PubMed1998

Reduction of an eight-state mechanism of cotransport to a six-state model using a new computer program.

A computer program was developed to allow easy derivation of steady-state velocity and binding equations for multireactant mechanisms including or without rapid equilibrium segments. Its usefulness is illustrated by deriving the rate equation of the most general sequential iso ordered ter ter mechanism of cotransport in which two Na+ ions bind first to the carrier and mirror symmetry is assumed. It is demonstrated that this mechanism cannot be easily reduced to a previously proposed six-state model of Na+-D-glucose cotransport, which also includes a number of implicit assumptions. In fact, the latter model may only be valid over a restricted range of Na+ concentrations or when assuming very strong positive cooperativity for Na+ binding to the glucose symporter within a rapid equilibrium segment. We thus propose an equivalent eight-state model in which the concept of positive cooperativity is best explained within the framework of a polymeric structure of the transport protein involving a minimum number of two transport-competent and identical subunits. This model also includes an obligatory slow isomerization step between the Na+ and glucose-binding sequences, the nature of which might reflect the presence of functionally asymmetrical subunits.

Biological Transport↗
PubMed1998

Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial.

OBJECTIVE: To test if supplemental dietary selenium is associated with changes in the incidence of prostate cancer. PATIENTS AND METHOD: A total of 974 men with a history of either a basal cell or squamous cell carcinoma were randomized to either a daily supplement of 200 microg of selenium or a placebo. Patients were treated for a mean of 4.5 years and followed for a mean of 6.5 years. RESULTS: Selenium treatment was associated with a significant (63%) reduction in the secondary endpoint of prostate cancer incidence during 1983-93. There were 13 prostate cancer cases in the selenium-treated group and 35 cases in the placebo group (relative risk, RR=0.37, P=0.002). Restricting the analysis to the 843 patients with initially normal levels of prostate-specific antigen (< or = 4 ng/mL), only four cases were diagnosed in the selenium-treated group and 16 cases were diagnosed in the placebo group after a 2 year treatment lag, (RR=0.26 P=0.009). There were significant health benefits also for the other secondary endpoints of total cancer mortality, and the incidence of total, lung and colorectal cancer. There was no significant change in incidence for the primary endpoints of basal and squamous cell carcinoma of the skin. In light of these results, the 'blinded' phase of this trial was stopped early. CONCLUSIONS: Although selenium shows no protective effects against the primary endpoint of squamous and basal cell carcinomas of the skin, the selenium-treated group had substantial reductions in the incidence of prostate cancer, and total cancer incidence and mortality that demand further evaluation in well-controlled prevention trials.

Basal Cell Carcinoma↗
PubMed1998

Deciding about hormone therapy: validation of a model.

OBJECTIVE: The purposes of this study were to (1) validate components of a decision process regarding adoption of hormone therapy and (2) compare the decision processes women used with respect to their evaluation of decision quality. DESIGN: A sample of women participating in a population-based study of midlife women's health participated in individual in-depth interviews. RESULTS: Content analysis of 30 recorded interviews provided evidence that each component of the decision process (precontemplation, contemplation, commitment, critical evaluation, and continuance) was replicated. Few additional codes were identified, and these could be subsumed under the phases of the original decision model. CONCLUSIONS: Women's self-reported statuses on a screening questionnaire corresponded to the stages of the decision model coded from their interviews. What women actually decided to do (use hormone therapy or something else) was not associated with their decision process. Satisfaction with the decision, uncertainty about the decision, and other factors related to the decision were independent of the decision phases.

Adult↗
PubMed1996

[Metastatic malignant melanoma in treated non-Hodgkin's lymphoma].

Secondary cutaneous neoplasia, e.g. basal cell malignant carcinomas or squamous cell carcinomas, is frequently observed in patients with malignant lymphomas. The association between malignant lymphoma and secondary malignant melanoma has only been rarely reported. We describe a patient with a low-grade nodal B-cell lymphoma who, while on treatment with steroids and an alkylating agent, developed a malignant melanoma level IV which rapidly metastasized to lymph nodes involved by the malignant lymphoma.

Adult↗
PubMed1996

[Axillary silicon lymphadenopathy after breast augmentation].

We report on a case of axillary lymphadenopathy in a 40-year-old woman secondary to a bilateral silicone augmentation mammoplasty which occurred 10 years after surgery. Microscopic silicone leakage ("bleeding") from an intact prothesis lead to sizeable lymph node enlargement. The suspected malignant tumour (metastasis/malignant lymphoma) could be ruled out by histological examination of the lymph node.

Adult↗
PubMed1994

Characterization of the beta 2-microglobulin endocytic pathway in rat proximal tubule cells.

The uptake mechanism(s) of low-molecular-weight proteins by proximal tubule cells remains incompletely characterized. We utilized a biochemical and semiquantitative morphological approach to better characterize the endocytic pathway of an anionic protein, beta 2-microglobulin (beta 2M), in the rat proximal tubule. Indirect immunogold techniques revealed beta 2M was taken up via a classic receptor-mediated endocytic pathway. In vitro biochemical and morphological characterization of iodinated beta 2M and gold-conjugated beta 2M (gold-beta 2M) binding to isolated brush-border membrane vesicles (BBMV) documented specific and quantitatively similar binding interactions of the modified beta 2M with BBMV. Kinetic characterization of the in vivo endocytic pathway of gold-beta 2M was undertaken using microinfusion of individual tubules. beta 2M initially bound at the apical surface, was internalized into subapical coated vesicles and delivered to endosomal-like structures within 5 min, and, finally, was concentrated in lysosomal-like structures within 15 min. This uptake was inhibited by excess unconjugated beta 2M. In addition, we directly showed that uptake did not occur across the basolateral surface. Finally, by passing solubilized BBMV over beta 2M affinity columns we were able to isolate binding activity.

Animals↗
PubMed1993

Splenic haematopoiesis in primary (idiopathic) osteomyelofibrosis: immunohistochemical and morphometric evaluation of proliferative activity of erytro- and endoreduplicative capacity of megakaryopoiesis (PCNA- and Ki-67 staining).

Using monoclonal antibodies against proliferating cell nuclear antigen or PCNA (PC10) and the Ki-67 antigen (MIB1), an immunohistochemical and morphometric study was performed on routinely processed splenic tissue from ten patients with primary (idiopathic) osteomyelofibrosis (OMF). To determine the proliferation capacity of erythroid precursors and the endoreduplicative activity of megakaryocytes, corresponding antibodies (Ret40f and CD61) were applied in combination with the cell-cycle markers (sequential double-immunostaining). Morphometric analysis revealed no significant differences in PCNA or Ki-67 reactivity in either cell lineages. In comparison with previous studies on normal bone marrow, in splenic tissue showing myeloid metaplasia, the numbers of PCNA-labelled proerythroblasts, erythroblasts and megakaryocytes were conspicuously increased. Considering the ineffective erythropoiesis in OMF, there seemed to be a disproportional enhancement in PCNA and Ki-67 immunostaining of the red cell lineage. Similarly, the small size of megakaryocytes in advanced, OMF-associated myeloid metaplasia was in keeping with an impairment of endoreduplicative activity. In addition to various other contributory factors, anaemia in OMF may be partially caused by secondary folate (haematinic) deficiency. From experimental studies this defect is known to cause an abnormal arrest in the S-phase of the cell-cycle, comparable to that characterising pernicious anaemia. As a sequel of this pathomechanism, an undue overexpression of PCNA and Ki-67 has to be assumed, that is not necessarily associated with DNA synthesis or cell cycling.

Aged↗
PubMed1993

Primary angiosarcoma of the spleen. A clinicopathologic study of 40 cases.

Forty primary splenic angiosarcomas occurring in 21 men and 19 women, 19-84 years old (median 59 years) are reported. Patients presented with splenomegaly (35 of 38, 92%), abdominal pain (33 of 40, 83%), and systemic symptoms such as fatigue (2 of 40, 5%), fever (4 of 40, 10%), and/or weight loss (16 of 40, 40%). Five (13%) experienced splenic rupture associated with hemoperitoneum. Abnormal laboratory findings included cytopenia (31 of 34, 91%), leukocytosis (8 of 21, 38%), and thrombocytosis (1/39, 3%). Most spleens weighed 500-1,000 g (mean, 1,180 g). The cut splenic surfaces showed multiple hemorrhagic nodules that were frequently associated with infarction, although some had a diffuse pattern of involvement. Microscopically, there were a variety of histologic patterns displayed by the vasoformative component. A honeycomb or sponge-like pattern was common in some, whereas others simulated a cavernous hemangioma or normal splenic sinuses (pseudosinusoidal pattern). Papillary endothelial tufts and solid proliferations of spindled to round to epithelioid cells were also seen. Factor VIII-related antigen was detected in 19 of 23 cases, BMA-120 in 18 of 23, UEA-1 receptor in 18 of 23, and vimentin in 23 of 23 as well as CD68 antigen in 1 of 23 cases. S-100 protein and cytokeratin were not found in any of the 23 cases studied. Metastases in 22 of 32 patients (69%) were to the liver (13 patients), bone or bone marrow (7 patients), lymph nodes (1 patient), and brain (1 patient). Three patients had concomitant malignancies and one had a prior history of a mixed B-cell lymphoma 5 years previously that had been treated with chemotherapy. Follow-up in 38 patients revealed that 30 (79%) are dead at a median interval of 6 months (range 0-48 months) and 8 are alive 5-21 months after diagnosis. These findings indicate that splenic angiosarcoma is an aggressive neoplasm with a high metastatic rate and an abysmal prognosis. Recognition of the wide range of histologic patterns is of diagnostic value but no apparent prognostic significance.

Adult↗
PubMed1992

In vitro culture of common acute lymphoblastic leukemia blasts: effects of interleukin-3, interleukin-7, and accessory cells.

We investigated the effects of interleukin-3 (IL-3), IL-7, IL-1, and IL-6, of irradiated bone marrow-derived fibroblasts (Fb) and of in vitro matured peripheral blood macrophages (M phi), on the survival, proliferation, and maturation of purified blasts from nine common acute lymphoblastic leukemias (cALLs) in 7-day suspension culture. Exposure to IL-3, IL-7, IL-1, and IL-6 resulted in a mean 2.8-, 1.5-, 1.4-, and 1.6-fold stimulation of 3H-thymidine (3H-TdR) incorporation, respectively. Cocultures of cALL blasts with irradiated M phi, either allowing direct cell-cell contact or preventing it by membrane filters, or with irradiated Fb, resulted in a mean 31.7-, 4.1-, and 11.2-fold increase of 3H-TdR incorporation, respectively. Southern blot analysis of immunoglobulin and T-cell receptor (TCR) gene rearrangements before and after culture indicated exclusive proliferation of the leukemic clone in three of eight samples, whereas additional generation of nonleukemic cells was found in five samples. Polyclonal growth pattern corresponded to the detection of heterogeneous cell populations using FACS analysis. Survival of cALL blasts as defined by the detection of cells coexpressing both CD10 and CD19 after culture was supported by accessory cells in five of eight samples. No evidence of induced lymphoid maturation was found under any culture condition. Our data demonstrate supportive effects of stromal cells on cALL growth, which cannot be replaced by IL-3 or IL-7.

Blotting, Southern↗