The relation between rhinitis and allergic asthma. The action of antihistaminics on bronchial hyperreactivity

The intermediate filament nestin is highly expressed in multipotential stem cells of the developing central nervous system (CNS). During neuro- and gliogenesis, nestin is replaced by cell type-specific intermediate filaments, e.g. neurofilaments and glial fibrillary acidic protein (GFAP). In this study, we demonstrate that nestin expression is re-induced in reactive astrocytes in the lesioned adult brain. Following ischaemic and mechanical lesioning, a strong and sustained expression of nestin was noted in GFAP-positive cells surrounding the lesion site. Lesion experiments in transgenic mice carrying the lacZ gene under control of regulatory sequences from the nestin gene suggested that the upregulation of nestin in reactive astrocytes is mediated via the same sequences that control nestin expression during CNS development. These observations and recent data on the co-expression of glial and neuronal marker antigens in reactive astrocytes point to a close relationship between proliferating astrocytes and neuroepithelial precursor cells.     

A longitudinal study of markers of bone turnover in Graves'' disease and their value in predicting bone mineral density

Alterations of chromosome 8, including deletions of 8p, occur frequently in many tumors. In this study, fluorescence in situ hybridization was used to study the relationship between 8p deletions, 8q gains, and phenotype in bladder cancer. Cells from 87 tumors were examined by dual-labeling fluorescence in situ hybridization with a centromere 8 probe (pJM12) and P1 probes for 8p22, 8p12, 8q12, and 8q24. Both 8p22 deletions and 8q24 gains were strongly associated with tumor phenotype. There was a marked difference in 8p22 deletions between noninvasive (pTa) tumors (3/33) and minimally invasive (pT1) tumors (8/19; P = 0.005) whereas there was no significant difference between pT1 and muscle-invasive (pT2-4) tumors (19/35; P = 0.3926). Six tumors with 8p22 deletion were examined at 8p12. Three of these tumors showed no 8p12 deletion, narrowing down the site of a putative tumor suppressor gene distal to 8p12. In one other case, there was a marked increase in 8p12 copy number (> 40 per cell; amplification), suggesting the presence of an oncogene involved in bladder cancer at 8p12. The marked difference in 8p22 deletions between noninvasive (pTa) and minimally invasive (pT1) tumors is consistent with a role of a putative tumor suppressor gene on 8p for development of invasive tumor phenotype.     

Pulmonary embolism: prospective comparison of spiral CT with ventilation-perfusion scintigraphy

PURPOSE: To compare prospectively the accuracy of spiral computed tomography (CT) with that of ventilation-perfusion scintigraphy for diagnosing pulmonary embolism. MATERIALS AND METHODS: Within 48 hours of presentation, 142 patients suspected of having pulmonary embolism underwent spiral CT, scintigraphy, and (when indicated) pulmonary angiography. Pulmonary angiography was attempted if interpretations of spiral CT scans and of scintigrams were discordant or indeterminate and intermediate-probability, respectively. RESULTS: In the 139 patients who completed the study, interpretations of spiral CT scans and of scintigrams were concordant in 103 patients (29 with embolism, 74 without). In 20 patients, intermediate-probability scintigrams were interpreted (six with embolism at angiography, 14 without); diagnosis with spiral CT was correct in 16. Interpretations of spiral CT scans and those of scintigrams were discordant in 12 cases; diagnosis with spiral CT was correct in 11 cases and that with scintigraphy was correct in one. Spiral CT and scintigraphic scans of four patients with embolism did not show embolism. Sensitivities, specificities, and kappa values with spiral CT and scintigraphy were 87%, 95%, and 0.85 and 65%, 94%, and 0.61, respectively. CONCLUSION: In cases of pulmonary embolism, sensitivity of spiral CT is greater than that of scintigraphy. Interobserver agreement is better with spiral CT.     

Clinical determinants of mortality in patients with angiographically diagnosed ischemic or nonischemic cardiomyopathy

OBJECTIVES: We sought to characterize the clinical determinants of mortality in patients with angiographically diagnosed ischemic or nonischemic cardiomyopathy. BACKGROUND: Patients with ischemic cardiomyopathy may have a worse prognosis than patients with nonischemic cardiomyopathy. Few studies have assessed the effect of ischemic versus nonischemic etiology on outcomes. METHODS: We analyzed prospectively collected data on 3,787 patients with a left ventricular ejection fraction < or = 40% who underwent coronary angiography. Patients were considered to have ischemic cardiomyopathy (n = 3,112) if they had a history of myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery or at least one major epicardial coronary artery with > or = 75% stenosis; all others were considered to have nonischemic cardiomyopathy (n = 675). RESULTS: The median age, ejection fraction and proportion of patients with New York Heart Association functional class III or IV symptoms for the nonischemic and ischemic groups were 55 years versus 63 years, 27% versus 32% and 57% versus 25%, respectively. After adjustment for baseline clinical risk factors and presenting characteristics, ischemic etiology remained an important independent predictor of 5-year mortality (p < 0.0001). The extent of coronary artery disease was a better predictor of survival than ischemic or nonischemic etiology (log likelihood chi-square 700 vs. 675, respectively). CONCLUSIONS: Ischemic etiology is a significant independent predictor of mortality in patients with cardiomyopathy. However, the extent of coronary artery disease contributes more prognostic information than the clinical diagnosis of ischemic or nonischemic cardiomyopathy. Further research is needed to refine the clinical definition of ischemic cardiomyopathy so that physicians can appropriately prescribe treatment and accurately predict outcome.     

Effects of vasodilators and perfusion pressure on coronary flow and simultaneous release of nitric oxide from guinea pig isolated hearts

OBJECTIVE: The aims were to validate the use of a direct reading NO electrode, to compare the effects of diverse acting drugs on altering coronary flow (CF) and NO release, and to examine the effects of altered perfusion pressure on flow-induced changes in NO concentration [NO] in the hemoglobin free effluent of guinea pig isolated hearts. METHODS: Hearts were isolated and perfused initially at a constant perfusion pressure (55 mmHg) with a modified Krebs-Ringer's solution equilibrated with 97% O2 and 3% CO2 at 37 degrees C. Heart rate, left ventricular pressure, CF, and effluent pH, pCO2, pO2, and NO generated current were monitored continuously on-line. Effluent was sampled for L-citrulline. Percent O2 extraction and O2 consumption were calculated. [NO] was quantitated with a sensitive amperometric sensor (sensitivity > or = 1 nmol/l approximately 3 pA) and a selective gas permeable membrane. RESULTS: The electrode was not sensitive to changes in solution pO2, flow, or pressure. The electrode was sensitive to pCO2 (-0.50 nmol/l/mmHg) and temperature (+24.5 nmol/l/degree C), so coronary effluent pCO2 was measured to compensate for a small decrease in pCO2 that occurred with an increase in coronary flow, and effluent temperature was rigidly controlled. Serotonin, bradykinin, and nitroprusside increased NO release along with CF, whereas nifedipine, butanedione monoxime, zaprinast, and bimakalim comparably increased CF but did not increase [NO] or NO release. Increases in CF (ml/g/min) and NO release (pmol/g/min), respectively, were 5.0 +/- 1 and 100 +/- 17 for 1 mumol/l serotonin, 7.5 +/- 1 and 148 +/- 18 for 100 nmol/l bradykinin, and 7.8 +/- 1 and 173 +/- 28 for 100 mumol/l nitroprusside. The increases in effluent NO by bradykinin were proportional to the increases in L-citrulline. Tetraethylammonium decreased CF, but did not change NO release, indomethacin changed neither CF nor NO release, and NG-nitro-L-arginine methyl ester (L-NAME) reduced CF by 2.6 +/- 1 ml/g/min and NO release by 25 +/- 8 pmol/g/min. An increase of CF of 8.0 +/- 0.3 ml/g/min, produced by increasing perfusion pressure from 25 to 90 mmHg, increased [NO] by 30 +/- 4 nmol/l; L-NAME but did not reduce the pressure-induced increase in CF, but reduced the increase in [NO] to 10 +/- 5 nmol/l. CONCLUSIONS: This study demonstrates in intact hearts real-time release of NO by several vasodilator drugs and by pressure-induced increases in flow (shear stress) and attenuation of these effects by L-NAME.     

FR139317, a specific ETA-receptor antagonist, inhibits cerebral activation by intraventricular endothelin-1 in conscious rats

A comprehensive series of time-related behavioral, physiological and cerebral metabolic studies was conducted using conscious Sprague-Dawley rats to discern the anti-endothelin (ET) properties of the specific ETA receptor antagonist, FR139317. Endothelin-1 (9 pmol given by injection into one lateral ventricle, i.c.v.) produced convulsions, acute arterial hypertension, arterial hyperglycemia, and hyperventilation. Brain structures close to the i.c.v. site of injection, such as the caudate nucleus, lateral septal nucleus, corpus callosum and hippocampal CA3 medial lamellae, as well as 14 other individual structures, displayed moderate-to-intense levels of metabolic activation after endothelin. Data were assessed quantitatively by means of the autoradiographic [14C]deoxyglucose technique combined with image analysis. Neural circuits in the efferent projection paths of the stimulated forebrain structures, such as the midbrain oculomotor complex, amygdaloid nuclei, substantia nigra pars reticulata and caudal subicular subregions of the hippocampal formation, were stimulated focally by endothelin. Specific medullary nuclei and cerebellar cortical subregions displayed high rates of glucose metabolism following endothelin injection at the time of maximum behavioral and physiological stimulation. I.c.v. treatment with > or = 14 nmol FR139317 before endothelin significantly inhibited the effects produced by the peptide. At the highest dose of FR139317 (28 nmol), there was only mild behavioral stimulation following endothelin injection, and hypermetabolic responses in the brain were abolished except in two specific areas of the cerebellar cortex (approx 40% increases in metabolic activity in the copula pyramis and paramedian lobule). The results indicate that the cerebral stimulatory effects of i.c.v. endothelin are mediated by the A type of endothelin receptor. By itself, i.c.v. FR139317 had no effects on the parameters assessed. Further evaluation of FR139317 is warranted as a possible therapeutic agent for neuropathologies suspected of deriving from central neural or vascular stimulation by endothelin, such as aneurysmal vasospasm, ischemia, excitotoxicity, and peptide-mediated epilepsies.     

Partial splenic embolization for treatment of disseminated intravascular coagulation in lymphangiomatosis

A 1-year-old boy presented with pericardial effusion, pulmonary infiltrates, and disseminated intravascular coagulation; lung biopsy indicated pulmonary lymphangiomatosis. He did not respond to medical therapy and was a poor surgical candidate; therefore, he underwent partial splenic embolization. The procedure resulted in a complete disappearance of the DIC and marked improvement in his cardiorespiratory status. He continues to thrive and is transfusion-independent 2 years after the procedure.     

A combined COMPACT and HazardExpert study of 40 chemicals for which information on mutagenicity and carcinogenicity is known, including the results of human epidemiological studies

The COMPACT approach for defining structural criteria for substrates and inducers of cytochrome P450 (CYP) enzymes which mediate the formation of reactive intermediates is discussed in the context of prediction of potential carcinogenicity. This is broadened to encompass structural studies on mammalian P450s, including those relevant to genetic polymorphism in man. The use of the COMPACT system, in parallel with the structure alert program HazardExpert (now incorporated into the Pallas system), for evaluating human carcinogenicity data is reported, as an example of the possible employment of a battery of short-term test procedures for safety evaluation. In particular, the importance of using the log P value (as a measure of compound lipophilicity) to assess the likelihood of a potentially toxic compound reaching the site of activation, is emphasized by the finding that most procarcinogens requiring metabolic activation by P450s are lipophilic in nature.     

Thrombin receptor (PAR-1) antagonists. Heterocycle-based peptidomimetics of the SFLLR agonist motif

Phorbol ester treatment of MCF-7 cells led to the tyrosine phosphorylation and activation of PKC delta. However, through Western blot analysis and in vitro immunecomplex kinase assays, we detected a differential localization of tyrosine-phosphorylated PKC delta and catalytically active PKC delta. Catalytically active PKC delta was concentrated in Triton X-100 solubilized-membrane fractions while tyrosine-phosphorylated PKC delta was localized to the cytosol fraction. Phorbol ester treatment of MCF-7 cells stimulated both the time-dependent in vivo association of Src with PKC delta, evidenced in Src immunoprecipitates by the co-immunoprecipitation of PKC delta, and activation of Src, evidenced in Src immunoprecipitates as an increase in reactivity with a Src antibody (clone 28) reactive only with active Src (dephosphorylated on residue 530) and in Src and PKC delta immunoprecipitates by an increase in Src kinase activity. While our data are consistent with reports in the literature showing the activator/stimulus-dependent tyrosine phosphorylation of PKC delta, our data show that the tyrosine phosphorylation of PKC delta is not essential for kinase activity. These results are the first to demonstrate an in vivo association between PKC delta and active Src in the absence of over-expression of either PKC delta or Src, and support the association of Src and PKC delta towards a physiological function.