Diagnostic dilemmas in oncology. Case 2. Umbilical metastasis as the presenting symptom of non-cell lung cancer.
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Abdominal Neoplasms↗
Biomedical subjects
B Brenner
Publications and source records attributed to B Brenner.
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↗
Placement of hemodialysis catheters through dilated external jugular and collateral veins in patients with internal jugular vein occlusions.
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Adult↗
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↗
Hereditary deficiency of vitamin K-dependent coagulation factors.
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Blood Coagulation Factors↗
A medical mission to Swaziland, Part 1.
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Eswatini↗
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↗
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↗
[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↗
Budd-Chiari syndrome associated with factor V leiden mutation: a report of 6 patients.
Budd-Chiari syndrome is characterized by hepatic venous outflow obstruction. Although myeloproliferative disorders are usually responsible for this severe thrombotic disorder, deficiency or dysfunction of the natural anticoagulants can be involved. Resistance to activated protein C caused by factor V Leiden mutation has been recently identified as a major cause of thrombophilia. We report 6 patients with Budd-Chiari syndrome associated with factor V Leiden mutation combined with another acquired thrombophilic state (myeloproliferative disorder and lupus anticoagulant in 3 cases) and without another thrombophilic disorder in the other 3 cases. We conclude that factor V Leiden mutation should be evaluated in any case of hepatic vein occlusion because the prevalence of this mutation in the general population is high.
Adolescent↗
Thin filament activation probed by fluorescence of N-((2-(iodoacetoxy)ethyl)-N-methyl)amino-7-nitrobenz-2-oxa-1,3-diazole-labeled troponin I incorporated into skinned fibers of rabbit psoas muscle.
A method is described for the exchange of native troponin of single rabbit psoas muscle fibers for externally applied troponin complexes without detectable impairment of functional properties of the skinned fibers. This approach is used to exchange native troponin for rabbit skeletal troponin with a fluorescent label (N-((2-(iodoacetoxy)ethyl)-N-methyl)amino-7-nitrobenz-2-oxa-1, 3-diazole, IANBD) on Cys(133) of the troponin I subunit. IANBD-labeled troponin I has previously been used in solution studies as an indicator for the state of activation of reconstituted actin filaments (. Proc. Natl. Acad. Sci. USA. 77:7209-7213). In the skinned fibers, the fluorescence of this probe is unaffected when cross-bridges in their weak binding states attach to actin filaments but decreases either upon the addition of Ca(2+) or when cross-bridges in their strong binding states attach to actin. Maximum reduction is observed when Ca(2+) is raised to saturating concentrations. Additional attachment of cross-bridges in strong binding states gives no further reduction of fluorescence. Attachment of cross-bridges in strong binding states alone (low Ca(2+) concentration) gives only about half of the maximum reduction seen with the addition of calcium. This illustrates that fluorescence of IANBD-labeled troponin I can be used to evaluate thin filament activation, as previously introduced for solution studies. In addition, at nonsaturating Ca(2+) concentrations IANBD fluorescence can be used for straightforward classification of states of the myosin head as weak binding (nonactivating) and strong binding (activating), irrespective of ionic strength or other experimental conditions. Furthermore, the approach presented here not only can be used as a means of exchanging native skeletal troponin and its subunits for a variety of fluorescently labeled or mutant troponin subunits, but also allows the exchange of native skeletal troponin for cardiac troponin.
Actin Cytoskeleton↗
Kinetics of thin filament activation probed by fluorescence of N-((2-(iodoacetoxy)ethyl)-N-methyl)amino-7-nitrobenz-2-oxa-1,3-diazole-labeled troponin I incorporated into skinned fibers of rabbit psoas muscle: implications for regulation of muscle contraction.
Making use of troponin with fluorescently labeled troponin I subunit (N-((2-(iodoacetoxy)ethyl)-N-methyl)amino-7-nitrobenz-2-oxa-1, 3-diazole-troponin I, IANBD-TnI) that had previously been described in solution studies as a probe for thin filament activation (. Proc. Natl. Acad. Sci. 77:7209-7213), we present a new approach that allows the kinetics of thin filament activation to be studied in skinned muscle fibers. After the exchange of native troponin for fluorescently labeled troponin, the fluorescence intensity is sensitive to both changes in calcium concentration and actin attachment of cross-bridges in their strong binding states (. Biophys. J. 77:000-000). Imposing rapid changes in the fraction of strongly attached cross-bridges, e.g., by switching from isometric contraction to high-speed shortening, causes changes in thin filament activation at fixed Ca(2+) concentrations that can be followed by recording fluorescence intensity. Upon changing to high-speed shortening we observed small (<20%) changes in fluorescence that became faster at higher Ca(2+) concentrations. At all Ca(2+) concentrations, these changes are more than 10-fold faster than force redevelopment subsequent to the period of unloaded shortening. We interpret this as an indication that equilibration among different states of the thin filament is rapid and becomes faster as Ca(2+) is raised. Fast equilibration suggests that the rate constant of force redevelopment is not limited by changes in the activation level of thin filaments induced by the isotonic contraction before force redevelopment. Instead, our modeling shows that, in agreement with our previous proposal for the regulation of muscle contraction, a rapid and Ca(2+)-dependent equilibration among different states of the thin filament can fully account for the Ca(2+) dependence of force redevelopment and the fluorescence changes described in this study.
Actin Cytoskeleton↗
The effect of thin filament activation on the attachment of weak binding cross-bridges: A two-dimensional x-ray diffraction study on single muscle fibers.
To study possible structural changes in weak cross-bridge attachment to actin upon activation of the thin filament, two-dimensional (2D) x-ray diffraction patterns of skinned fibers from rabbit psoas muscle were recorded at low and high calcium concentration in the presence of saturating concentrations of MgATPgammaS, a nucleotide analog for weak binding states. We also studied 2D x-ray diffraction patterns recorded under relaxing conditions at an ionic strength above and below 50 mM, because it had been proposed from solution studies that reducing ionic strength below 50 mM also induces activation of the thin filament. For this project a novel preparation had to be established that allows recording of 2D x-ray diffraction patterns from single muscle fibers instead of natural fiber bundles. This was required to minimize substrate depletion or product accumulation within the fibers. When the calcium concentration was raised, the diffraction patterns recorded with MgATPgammaS revealed small changes in meridional reflections and layer line intensities that could be attributed in part to the effects of calcium binding to the thin filament (increase in I380, decrease in first actin layer line intensity, increase in I59) and in part to small structural changes of weakly attached cross-bridges (e.g., increase in I143 and I72). Calcium-induced small-scale structural rearrangements of cross-bridges weakly attached to actin in the presence of MgATPgammaS are consistent with our previous observation of reduced rate constants for attachment and detachment of cross-bridges with MgATPgammaS at high calcium. Yet, no evidence was found that weakly attached cross-bridges change their mode of attachment toward a stereospecific conformation when the actin filament is activated by adding calcium. Similarly, reducing ionic strength to less than 50 mM does not induce a transition from nonstereospecific to stereospecific attachment.
Actins↗
Thrombophilia-associated pregnancy wastage.
OBJECTIVE: To critically review the literature regarding inherited thrombophilia and recurrent fetal loss. DESIGN: English-language literature review. PATIENT(S): Women who experienced repeated pregnancy wastage. INTERVENTION(S): Aspirin, glucocorticoids, heparin, and IV immunoglobulin for the prevention of miscarriage. MAIN OUTCOME MEASURE(S): Live birth, miscarriage, preeclampsia, and pregnancy loss. RESULT(S): Recurrent fetal loss and other placental vascular pathologies of pregnancy have long been associated with antiphospholipid syndrome, an acquired autoimmune thrombophilic state. The number of known heritable thrombophilic disorders has grown rapidly in recent years with the identification of activated protein C resistance, factor V Leiden mutation, and hyperhomocysteinemia as major causes of thrombosis. Data accumulated over the past 2 years suggest that heritable thrombophilia is associated with an increased risk of fetal loss and preeclampsia. The present review discusses potential pathogenetic mechanisms for this association and evaluates reported therapeutic regimens for the prevention of fetal loss in women with thrombophilia. CONCLUSION(S): Placental thrombosis may be the final common pathophysiologic pathway in most women with habitual abortions and repeated pregnancy wastage. Prophylactic antithrombotic therapy is indicated in women with heritable thrombophilia and antiphospholipid syndrome and probably is more effective than the previously used modalities of prednisone, aspirin, and IV immunoglobulin.
Abortion, Habitual↗
Expression of the apoptosis-related oncogenes bcl-2, bax, and p53 in Merkel cell carcinoma: can they predict treatment response and clinical outcome?
Chemotherapy and radiation therapy act predominantly through the induction of apoptosis in malignancies. Merkel cell carcinoma, an aggressive malignancy with prominent apoptosis, has proved to be sensitive to both modes to a certain degree. We used immunohistochemical methods to examine 25 Merkel cell carcinomas and 8 of their lymph node metastases to assess the status of the antiapoptotic gene bcl-2 and 2 proapoptotic genes, wild-type p53 and bax. All tumors showed prominent bax immunopositivity; 76% were positive for bcl-2, and only 28% were positive for p53, the latter presumably reflecting mutated p53. No statistically significant relationship was found between tumor immunopositivity and therapy response or survival. The widespread bax immunopositivity and the apparently low rate of p53 mutations, as suggested by the low rate of p53 immunopositivity, may be related to the presence of prominent apoptosis in Merkel cell carcinoma. The finding of bcl-2 immunopositivity in 76% of the tumors suggests that some of the tumor cells may be resistant to apoptosis-inducing agents.
Adult↗
Visual disturbances and pathologic ocular findings in primary antiphospholipid syndrome.
OBJECTIVE: To delineate the features and prevalence of the systemic and ophthalmic involvement of primary antiphospholipid syndrome (PAS). DESIGN: Prospective case series. PARTICIPANTS: A total of 39 consecutive patients with PAS. METHODS: During an 18-month period, the medical records of all patients with PAS who attended a clinic for thrombosis and hemostasis were reviewed on arrival. The patients were then referred to a retinal clinic and examined prospectively. The first 20 consecutive patients underwent retinal fluoroangiography. MAIN OUTCOME MEASURES: The prevalence of the various organs affected by the disease was noted in the group, as well as the prevalence and type of ophthalmic involvement. RESULTS: The most common forms of systemic involvement were fetal loss in 11 female patients (46%), central nervous system involvement in 17 patients (44%), and venous thrombosis in 16 patients (41%). Ophthalmic findings were as follows: 13 patients (33%) were symptomatic, and 12 of them complained of visual disturbances. In 10 (83%) of these 12 patients, the visual symptoms were transient, and 7 of them were nonocular in nature. Pathologic signs on ophthalmic examination were found in 5 of the 39 patients (13%), two of whom had intraocular pathologic findings related to PAS, and these were in the form of mild retinopathy. Of the 36 patients who were either asymptomatic or had transient visual disturbances, pathologic ocular findings were detected in only 2 (6%). Routine retinal fluoroangiography did not reveal any additional information that could not otherwise have been detected by funduscopy. CONCLUSIONS: Ocular involvement in PAS is uncommon. Transient visual disturbances are common, although most of them are related to central nervous system rather than ocular ischemia. Pathologic ophthalmic findings are unlikely to be found in asymptomatic patients or in patients with transient visual disturbances. Routine retinal fluoroangiography performed on patients with PAS is unproductive.
Adult↗
Relationship between birthweight and blood pressure in childhood.
Studies have shown an inverse relationship between birthweight and blood pressure in later life. The objective of this study is to analyze the relationship between birthweight and blood pressure in childhood in a North American-based population. Data on 2,958 births with follow-up at 7 years of age from the Providence, RI, cohort of the Collaborative Perinatal Project of the National Institute of Neurological Diseases and Stroke were retrospectively analyzed using univariate and multivariate analytic methods. Bivariate analysis of the total cohort showed a direct relationship between follow-up weight at age 7 years and birthweight (r = 0.24; P < 0.001) and follow-up weight with systolic (SBP) and diastolic blood pressure (DBP; r = 0.33; P < 0.001 and r = 0.22; P < 0.001, respectively). On multivariate analysis, follow-up weight and height were the strongest predictors of SBP and DBP. There was also a significant inverse relationship between birthweight and SBP. A cohort of term infants (n = 2,561) was subdivided into birthweight-for-gestational-age groupings to further evaluate the effects of birthweight on blood pressure. Small-for-gestational-age (SGA) infants were markedly smaller at age 7 years than those large-for-gestational-age (LGA; 21 +/- 4 kg v 26 +/- 4 kg; P < 0.01). Despite the direct association between follow-up weight and blood pressure, the mean blood pressure did not differ between SGA (103/58 mm Hg) and LGA patients (103/59 mm Hg). To assess whether birthweight was an independent predictor of blood pressure, blood pressures were predicted using linear regression equations. For every 1-kg decrease in birthweight in term infants, SBP at 7 years increased by 1.3 mm Hg and DBP by 0.6 mm Hg. In conclusion, controlling for weight and height in term infants at 7 years of age has an inverse linear effect on blood pressure. This suggests that birthweight in relation to gestation may be a contributor to the multifactorial cause of essential hypertension.
Birth Weight↗
Intracellular mechanisms of L-selectin induced capping.
Leucocyte adhesion to endothelial cells is a tightly regulated process involving selectins, integrins and immunoglobulin-like proteins. Cell adhesion and communication are controlled by membrane dynamics like receptor capping. Capping of surface receptors is an ubiquitous mechanism but still not well understood. Employing immunofluorescence techniques, we demonstrate that L-selectin triggering results in receptor capping of the L-selectin molecules in lymphocytes. Using pharmacological inhibitors and genetic deficient cell lines we show that this process involves intracellular signalling molecules. L-Selectin capping seems to be independent on activation of p56lck-kinase, but requires the neutral sphingomyelinase, small G proteins and the cytoskeleton. Therefore, capping of L-selectin upon stimulation might play an important role in the very early phase of lymphocyte trafficking.
B-Lymphocytes↗