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2.  Prolonged exposure to GH impairs insulin signaling in the heart 
Acromegaly is associated with cardiac hypertrophy, which is believed to be a direct consequence of chronically elevated GH and IGF1. Given that insulin is important for cardiac growth and function, and considering that GH excess induces hyperinsulinemia, insulin resistance, and cardiac alterations, it is of interest to study insulin sensitivity in this tissue under chronic conditions of elevated GH. Transgenic mice overexpressing GH present cardiomegaly and perivascular and interstitial fibrosis in the heart. Mice received an insulin injection, the heart was removed after 2 min, and immunoblotting assays of tissue extracts were performed to evaluate the activation and abundance of insulin-signaling mediators. Insulin-induced tyrosine phosphorylation of the insulin receptor (IR) was conserved in transgenic mice, but the phosphorylation of IR substrate 1 (IRS1), its association with the regulatory subunit of the phosphatidylinositol 3-kinase (PI3K), and the phosphorylation of AKT were decreased. In addition, total content of the glucose transporter GLUT4 was reduced in transgenic mice. Insulin failed to induce the phosphorylation of the mammalian target of rapamycin (mTOR). However, transgenic mice displayed increased basal activation of the IR/IRS1/PI3K/AKT/mTOR and p38 signaling pathways along with higher serine phosphorylation of IRS1, which is recognized as an inhibitory modification. We conclude that GH-overexpressing mice exhibit basal activation of insulin signaling but decreased sensitivity to acute insulin stimulation at several signaling steps downstream of the IR in the heart. These alterations may be associated with the cardiac pathology observed in these animals.
PMCID: PMC3746341  PMID: 21727153
3.  Magnetic resonance imaging in the prenatal diagnosis of neural tube defects 
Insights into Imaging  2013;4(2):225-237.
To assess the role of magnetic resonance imaging (MRI) in the prenatal diagnosis of neural tube defects (NTDs).
NTDs comprise a heterogeneous group of congenital anomalies that derive from the failure of the neural tube to close. Advances in ultrasonography and MRI have considerably improved the diagnosis and treatment of NTDs both before and after birth. Ultrasonography is the first technique in the morphological study of the fetus, and it often makes it possible to detect or suspect NTDs. Fetal MRI is a complementary technique that makes it possible to clear up uncertain ultrasonographic findings and to detect associated anomalies that might go undetected at ultrasonography. The progressive incorporation of intrauterine treatments makes an accurate diagnosis of NTDs essential to ensure optimal perinatal management. The ability of fetal MRI to detect complex anomalies that affect different organs has been widely reported, and it can be undertaken whenever NTDs are suspected.
We describe the normal appearance of fetal neural tube on MRI, and we discuss the most common anomalies involving the structures and the role of fetal MRI in their assessment.
Key Points
• To learn about the normal anatomy of the neural tube on MRI
• To recognise the MR appearance of neural tube defects
• To understand the value of MRI in assessing NTDs
PMCID: PMC3609962  PMID: 23456749
Prenatal diagnosis; Magnetic resonance imaging; Congenital abnormalities; Neural tube defects; Spinal dysraphism
4.  The Impact of Individual Human Immunodeficiency Virus Type 1 Protease Mutations on Drug Susceptibility Is Highly Influenced by Complex Interactions with the Background Protease Sequence▿ †  
Journal of Virology  2009;83(18):9512-9520.
The requirement for multiple mutations for protease inhibitor (PI) resistance necessitates a better understanding of the molecular basis of resistance development. The novel bioinformatics resistance determination approach presented here elaborates on genetic profiles observed in clinical human immunodeficiency virus type 1 (HIV-1) isolates. Synthetic protease sequences were cloned in a wild-type HIV-1 background to generate a large number of close variants, covering 69 mutation clusters between multi-PI-resistant viruses and their corresponding genetically closely related, but PI-susceptible, counterparts. The vast number of mutants generated facilitates a profound and broad analysis of the influence of the background on the effect of individual PI resistance-associated mutations (PI-RAMs) on PI susceptibility. Within a set of viruses, all PI-RAMs that differed between susceptible and resistant viruses were varied while maintaining the background sequence from the resistant virus. The PI darunavir was used to evaluate PI susceptibility. Single sets allowed delineation of the impact of individual mutations on PI susceptibility, as well as the influence of PI-RAMs on one another. Comparing across sets, it could be inferred how the background influenced the interaction between two mutations, in some cases even changing antagonistic relationships into synergistic ones or vice versa. The approach elaborates on patient data and demonstrates how the specific mutational background greatly influences the impact of individual mutations on PI susceptibility in clinical patterns.
PMCID: PMC2738252  PMID: 19587054
5.  Fruits and vegetables consumption and the risk of histological subtypes of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) 
Cancer Causes & Control   2009;21(3):357-371.
To examine the association between fruit and vegetable consumption and risk of different histological subtypes of lung cancer among participants of the European Prospective Investigation into Cancer and Nutrition study.
Multivariable Cox proportional hazard models were used to analyze the data. A calibration study in a subsample was used to reduce dietary measurement errors.
During a mean follow-up of 8.7 years, 1,830 incident cases of lung cancer (574 adenocarcinoma, 286 small cell, 137 large cell, 363 squamous cell, 470 other histologies) were identified. In line with our previous conclusions, we found that after calibration a 100 g/day increase in fruit and vegetables consumption was associated with a reduced lung cancer risk (HR 0.94; 95% CI 0.89–0.99). This was also seen among current smokers (HR 0.93; 95% CI 0.90–0.97). Risks of squamous cell carcinomas in current smokers were reduced for an increase of 100 g/day of fruit and vegetables combined (HR 0.85; 95% CI 0.76–0.94), while no clear effects were seen for the other histological subtypes.
We observed inverse associations between the consumption of vegetables and fruits and risk of lung cancer without a clear effect on specific histological subtypes of lung cancer. In current smokers, consumption of vegetables and fruits may reduce lung cancer risk, in particular the risk of squamous cell carcinomas.
PMCID: PMC2835631  PMID: 19924549
Fruits; Vegetables; Lung neoplasms; Small cell lung carcinoma; Non-small-cell lung carcinoma; Adenocarcinoma; Large cell carcinoma
6.  Postnatal Manganese Exposure Alters Dopamine Transporter Function in Adult Rats: Potential Impact on Nonassociative and Associative Processes 
Neuroscience  2008;154(2):848-860.
In the present study, we examined whether exposing rats to a high-dose regimen of manganese chloride (Mn) during the postnatal period would depress presynaptic dopamine functioning and alter nonassociative and associative behaviors. To this end, rats were given oral supplements of Mn (750 μg/day) on postnatal days (PD) 1–21. On PD 90, dopamine transporter (DAT) immunoreactivity and [3H]dopamine uptake were assayed in the striatum and nucleus accumbens, while in vivo microdialysis was used to measure dopamine efflux in the same brain regions. The effects of postnatal Mn exposure on nigrostriatal functioning were evaluated by assessing rotorod performance and amphetamine-induced stereotypy in adulthood. In terms of associative processes, both cocaine-induced conditioned place preference (CPP) and sucrose-reinforced operant responding were examined. Results showed that postnatal Mn exposure caused persistent declines in DAT protein expression and [3H]dopamine uptake in the striatum and nucleus accumbens, as well as long-term reductions in striatal dopamine efflux. Rotorod performance did not differ according to exposure condition, however Mn-exposed rats did exhibit substantially more amphetamine-induced stereotypy than vehicle controls. Mn exposure did not alter performance on any aspect of the CPP task (preference, extinction, or reinstatement testing), nor did Mn affect progressive ratio responding (a measure of motivation). Interestingly, acquisition of a fixed ratio task was impaired in Mn-exposed rats, suggesting a deficit in procedural learning. In sum, these results indicate that postnatal Mn exposure causes persistent declines in various indices of presynaptic dopaminergic functioning. Mn-induced alterations in striatal functioning may have long-term impact on associative and nonassociative behavior.
PMCID: PMC2517246  PMID: 18485605
dopamine transporter immunoreactivity; [3H]dopamine uptake; in vivo microdialysis; conditioned place preference; progressive ratio; stereotypy
7.  Comparison of risk patterns in carcinoma and melanoma of the skin in men: a multi-centre case–case–control study 
British Journal of Cancer  2006;94(5):743-751.
We directly compared risk factors between 214 histologically confirmed melanomas (CMM), 215 basal-cell carcinomas (BCC) and 139 squamous-cell carcinomas (SCC) in a multiple case–case–control study with 349 controls from patients without dermatological disease admitted to the same hospitals. Subjects with fair hair had a significant risk increase for all types of tumours at a comparable level (ORadj for blonde hair: CMM 2.3; SCC 2.4; BCC 2.3). The effect of pale eyes was significant and similar for CMM and BCC (ORadj 2.6). Intermittent sun exposure measured in hours spent at beach during holidays was significant for both CMM (ORadj 2.6 for more than 7000 lifelong hours) and BCC (ORadj 2.1 for more than 7000 lifelong hours), while SCC exhibited a significant risk increase for chronic exposure to sunlight measured in hours of outdoor work (ORadj 2.2 for more than 6000 lifelong hours). In the case–case comparison using a multinomial logistic regression model, we found a statistically significant risk difference for pale eyes, and number of naevi in the CMM group, compared to other skin cancers. For intermittent sun exposure, there was a significant risk difference of BCC when compared to the risk of SCC. Factors influencing risk of SCC are different, with chronic exposure to sun playing a major role in causing this type of carcinoma.
PMCID: PMC2361214  PMID: 16495934
skin cancer; melanoma; basal-cell carcinoma; squamous-cell carcinoma; case–case–control; sun exposure
8.  Rheumatic pneumonia 
Annals of the Rheumatic Diseases  2001;60(10):990-991.
PMCID: PMC1753378  PMID: 11589184
9.  P1. Immunoablation with t cell depleted autologous peripheral blood stem cell rescue produces complete remission in thrombocytopenic purpura (TTP) recidivant and refractory to standard treatment 
Espigado, I. | Rodriguez, J. | Carmona, M. | Alonso, D. | Rios, E. | Perez-Hurtado, J. | Martino, M. | Noguerol, P. | Vinuesa, M. | Parody, R. | Espigado, I. | Garcia, A. | Rodriguez, J. | Valenzuela, A. | Carmona, M. | Rios, E. | Parody, R. | Bornhauser, M. | Paul, K. | Gahr, M. | Nuesslein, H. | Meurer, M. | Oppermann, J. | Pfeiffer, C. | Luthke, K. | Schroder, H. | Ehninger, G. | Verburg, R. | Flierman, R. | Levahrt, E. | van den Hoogen, F. | Breedveld, F. | van Laar, J.M. | McKendry, R. | Atkins, H. | Huebsch, L. | Karsh, J. | Senterman, M. | Robertson, S. | Bingham, S. | Veale, D. | Reece, R. | Fearon, U. | Isaacs, J. | McGonagle, D. | Snowden, J. | Morgan, G. | Emery, P. | Novik, A. | Ionova, T. | Chelombit, L. | Denisov, P. | Melnichenko, V. | Kishtovich, A. | Lisukov, I. | Sizikova, S. | Kulagin, A. | Kruchkova, I. | Gilevich, A. | Chernykh, H. | Leplina, O. | Kozlov, V. | Gonzalez-Lopez, M. | Carreira, J. | Lavilla, E. | Arias, J. | de Andres, A. | Diaz, N. | Pego, R. | Graus, F. | Novik, A. | Odinak, M. | Melnichenko, V. | Voloshin, S. | Bisaga, G. | Novitsky, A. | Uspenskaja, O. | Willis, F. | Marsh, J | Bevan, D. | Killick, S. | Lucas, G. | Griffiths, R. | Ouwehand, W. | Hale, G. | Waldmann, H. | Gordon-Smith, E. | Kuemmerle-Deschne..., J. | Klingebiel, T. | Ihle, J. | Holzer, U. | Niethammer, D. | Dannecker, G. | Musa, M. | Al, J | Sahovic, E. | Nounou, R. | Spence, D. | Grau, J. | Laguno, M. | Perea, M. | Mohren, M. | Amberger, C. | Daikeler, T. | Guenaydin, I. | Kanz, L. | Koetter, I. | Daikeler, T. | Mohren, M. | Amberger, C. | Soekler, M. | Erley, C. | Risler, T. | Kanz, L. | Koetter, I. | Ciceri, F. | Magnani, G. | Zappone, E. | Servida, P. | Corradini, P. | Bregni, M. | Comi, G. | Roncarolo, M. | Bordignon, C. | Brunner, M. | Knobl, P. | Kalhs, P. | Machold, K. | Graninger, W. | Leitner, G. | Hocker, P. | Lechner, K. | Greinix, H. | Carreras, E. | Saiz, A. | Graus, F. | Marin, P. | Martinez, C. | Rovira, M. | Arbizu, T. | Casanova, B. | Berenguer, J. | Mazzara, R. | Tolosa, E. | Montserrat, E. | Nash, R. | Kraft, G. | Bowen, J. | McSweeney, P. | Pavletic, S. | Al-Omaishi, J. | Corboy, J. | Openshaw, H. | Storek, J. | Holmberg, L. | Zunt, J. | Prather, K. | Ryan, K. | Sullivan, K. | Saccardi, R. | Mancardi, G. | Bacigalupo, A. | Di, B | Gualandi, F. | Nasa, G. L. | Murialdo, A. | Pagliai, F. | Papineschi, F. | Marmont, A. | Hagglund, H. | Torkvist, L. | Mattsson, J. | Ljungman, P. | Ringden, O. | Rohrlich, P. | Legrand, F. | Faye, A. | Hugot, J | Duval, M. | Vilmer, E. | Hensel, M. | Schlenk, R. | Fiehn, C. | Breitbart, A. | Ho, A. | Zintl, F. | Kohler, A. | Muller, A. | Fuchs, D. | Sauerbrey, A. | Gruhn, B. | Oppermann, J. | Rosen, O. | Massenkeil, G. | Hiepe, F. | Thiel, A. | Radtke, H. | Gromnica-Ihle, E. | Burmester, G. | Radbruch, A. | Arnold, R. | Mancardi, G. | Saccardi, R. | Murialdo, A. | Gualandi, F. | Nasa, G. L. | Papineschi, F. | Di, B | Ledziowski, P. | Mensah, P. | Pitkowska-Jakubas, B. | Skotnicki, A. | Andolina, M. | Rabusin, M. | Lepore, L. | Maximova, N. | Parco, S. | Ponchel, F. | Bingham, S. | Douglas, S. | Emery, P. | Isaacs, J.
Annals of the Rheumatic Diseases  2001;60(7):708-716.
PMCID: PMC1753734
10.  Angiotensin converting enzyme and endothelial nitric oxide synthase DNA polymorphisms and late onset Alzheimer's disease 
OBJECTIVES—Several lines of evidence suggest that the endothelial constitutive nitric oxide synthase (ecNOS) and angiotensin converting enzyme (ACE) may have a role in Alzheimer's disease. ACE is widely expressed in the brain, and a DNA polymorphism at the ACE gene has been linked to the risk for late onset Alzheimer's disease. Nitric oxide (NO) production by microglial cells, astrocytes, and brain microvessels is enhanced in patients with Alzheimer's disease. There is a growing evidence that NO is involved in neuronal death in Alzheimer's disease, and the oxidative stress caused by NO in the brain could be a pathogenic mechanism in Alzheimer's disease. The objective was to determine if two DNA polymorphisms at the ecNOS and ACE genes that have been linked with different levels of enzyme expression, have some effect on the risk of developing late onset Alzheimer disease.
METHODS—A total of 400 healthy controls younger than 65 years and 350 patients with Alzheimer's disease (average age 72 years) were genotyped for the ACE and ecNOS polymorphisms. To define a possible role for these polymorphisms in longevity 117 healthy controls older than 85 years were also analysed. Genomic DNA was obtained and amplified by polymerase chain reaction, and genotypes were defined following a previously described procedure. Gene and genotype frequencies between patients and controls were compared statistically.
RESULTS—Gene and genotype frequencies for the ecNOS and ACE polymorphisms did not differ between both groups of healthy controls (<65 years and >85 years). EcNOS gene and genotype frequencies were similar between patients and controls. There was a slight but significantly increased frequency of the ACE-I allele among patients with Alzheimer's disease compared with controls (p=0.03; OR=1.28, 95%CI= 1.04;1.58).
CONCLUSIONS—The ACE-I allele was associated with a slightly increased risk of developing late onset Alzheimer's disease.

PMCID: PMC1736659  PMID: 10567488
11.  Urinary albumin excretion in patients with systemic lupus erythematosus without renal disease 
Annals of the Rheumatic Diseases  1997;56(6):386-389.
OBJECTIVES—To investigate the prevalence of microalbuminuria, urinary albumin excretion (UAE) between 20-200 µg/min, in systemic lupus erythematosus (SLE) patients without clinical renal disease, and to discover if this could predict the development of renal disease.
METHODS—This study made six monthly measurements of UAE, creatinine clearance, serological and clinical data in 22 ambulatory women patients with SLE, without clinical renal disease, hypertension, diabetes or heart failure. The patients were followed up for a period of 18 months (four measurements). Age and sex matched healthy controls were used as a comparative group. UAE was measured by nephelometry in three timed overnight urine samples at each visit.
RESULTS—There were no significant differences in the creatinine clearance between the control group and the SLE patients. Creatinine clearance did not show significant changes throughout the study period. SLE patients had wide variations in the UAE rate compared with healthy controls. In five patients (5 of 22; 23%), on occasions, there was mild, transient increase in UAE reaching the level of microalbuminuria. During follow up, one patient with basal (4.67 µg/min) and six month (4.73 µg/min) normal UAE rate, was admitted with a nephrotic syndrome confirmed on biopsy examination to be proliferative lupus nephritis. Six months after beginning treatment with prednisone and cyclophosphamide her UAE rate returned to normal values (4.65 µg/min).
CONCLUSION—SLE patients without clinical renal disease may have microalbuminuria, although this does not seem to warrant any specific action.

PMCID: PMC1752386  PMID: 9227170
12.  An allylic/acyclic adenosine nucleoside triphosphate for termination of DNA synthesis by DNA template-dependent polymerases. 
Nucleic Acids Research  1999;27(5):1271-1274.
An allylic adenosine triphosphate analog (AATP) was tested as a substrate for commercially available DNA polymerases. All but one of the enzymes assayed incorporated AATP opposite thymidine (T) with concomitant termination of the elongation reaction. A concentration of only 1 microM was sufficient for complete termination of the polymerization reaction for a short template mediated by Ampli Taq DNA polymerase FS (Taq FS). This result suggests that AATP could be used as a 2',3'-dideoxyadenosine-5'-triphosphate (ddA) surrogate. Kinetics of incorporation revealed that AATP was 48 times less efficiently incorporated than ddA. Furthermore, AATP was used in dye-primer sequencing as a substitute for ddA.
PMCID: PMC148311  PMID: 9973613
13.  The Coordinated Action of CC Chemokines in the Lung Orchestrates Allergic Inflammation and Airway Hyperresponsiveness  
The complex pathophysiology of lung allergic inflammation and bronchial hyperresponsiveness (BHR) that characterize asthma is achieved by the regulated accumulation and activation of different leukocyte subsets in the lung. The development and maintenance of these processes correlate with the coordinated production of chemokines. Here, we have assessed the role that different chemokines play in lung allergic inflammation and BHR by blocking their activities in vivo. Our results show that blockage of each one of these chemokines reduces both lung leukocyte infiltration and BHR in a substantially different way. Thus, eotaxin neutralization reduces specifically BHR and lung eosinophilia transiently after each antigen exposure. Monocyte chemoattractant protein (MCP)-5 neutralization abolishes BHR not by affecting the accumulation of inflammatory leukocytes in the airways, but rather by altering the trafficking of the eosinophils and other leukocytes through the lung interstitium. Neutralization of RANTES (regulated upon activation, normal T cell expressed and secreted) receptor(s) with a receptor antagonist decreases significantly lymphocyte and eosinophil infiltration as well as mRNA expression of eotaxin and RANTES. In contrast, neutralization of one of the ligands for RANTES receptors, macrophage-inflammatory protein 1α, reduces only slightly lung eosinophilia and BHR. Finally, MCP-1 neutralization diminishes drastically BHR and inflammation, and this correlates with a pronounced decrease in monocyte- and lymphocyte-derived inflammatory mediators. These results suggest that different chemokines activate different cellular and molecular pathways that in a coordinated fashion contribute to the complex pathophysiology of asthma, and that their individual blockage results in intervention at different levels of these processes.
PMCID: PMC2525544  PMID: 9653092
chemokines; allergic inflammation; bronchial hyperresponsiveness; eosinophilia; leukocytes
14.  Sordarins: In Vitro Activities of New Antifungal Derivatives against Pathogenic Yeasts, Pneumocystis carinii, and Filamentous Fungi 
Antimicrobial Agents and Chemotherapy  1998;42(11):2863-2869.
GM 193663, GM 211676, GM 222712, and GM 237354 are new semisynthetic derivatives of the sordarin class. The in vitro antifungal activities of GM 193663, GM 211676, GM 222712, and GM 237354 against 111 clinical yeast isolates of Candida albicans, Candida kefyr, Candida glabrata, Candida parapsilosis, Candida krusei, and Cryptococcus neoformans were compared. The in vitro activities of some of these compounds against Pneumocystis carinii, 20 isolates each of Aspergillus fumigatus and Aspergillus flavus, and 30 isolates of emerging less-common mold pathogens and dermatophytes were also compared. The MICs of GM 193663, GM 211676, GM 222712, and GM 237354 at which 90% of the isolates were inhibited (MIC90s) were 0.03, 0.03, 0.004, and 0.015 μg/ml, respectively, for C. albicans, including strains with decreased susceptibility to fluconazole; 0.5, 0.5, 0.06, and 0.12 μg/ml, respectively, for C. tropicalis; and 0.004, 0.015, 0.008, and 0.03 μg/ml, respectively, for C. kefyr. GM 222712 and GM 237354 were the most active compounds against C. glabrata, C. parapsilosis, and Cryptococcus neoformans. Against C. glabrata and C. parapsilosis, the MIC90s of GM 222712 and GM 237354 were 0.5 and 4 μg/ml and 1 and 16 μg/ml, respectively. The MIC90s of GM 222712 and GM 237354 against Cryptococcus neoformans were 0.5 and 0.25 μg/ml, respectively. GM 193663, GM 211676, GM 222712, and GM 237354 were extremely active against P. carinii. The efficacies of sordarin derivatives against this organism were determined by measuring the inhibition of the uptake and incorporation of radiolabelled methionine into newly synthesized proteins. All compounds tested showed 50% inhibitory concentrations of <0.008 μg/ml. Against A. flavus and A. fumigatus, the MIC90s of GM 222712 and GM 237354 were 1 and 32 μg/ml and 32 and >64 μg/ml, respectively. In addition, GM 237354 was tested against the most important emerging fungal pathogens which affect immunocompromised patients. Cladosporium carrioni, Pseudallescheria boydii, and the yeast-like fungi Blastoschizomyces capitatus and Geotrichum clavatum were the most susceptible of the fungi to GM 237354, with MICs ranging from ≤0.25 to 2 μg/ml. The MICs of GM 237354 against Trichosporon beigelii and the zygomycetes Absidia corymbifera, Cunninghamella bertholletiae, and Rhizopus arrhizus ranged from ≤0.25 to 8 μg/ml. Against dermatophytes, GM 237354 MICs were ≥2 μg/ml. In summary, we concluded that some sordarin derivatives, such as GM 222712 and GM 237354, showed excellent in vitro activities against a wide range of pathogenic fungi, including Candida spp., Cryptococcus neoformans, P. carinii, and some filamentous fungi and emerging invasive fungal pathogens.
PMCID: PMC105957  PMID: 9797217
15.  Tau expression in model adenocarcinomas correlates with docetaxel sensitivity in tumour-bearing mice. 
British Journal of Cancer  1998;78(7):871-877.
Docetaxel is a new taxoid with clinical activity in breast and lung cancer. Using docetaxel-sensitive and -refractory mammary and pancreatic murine tumours, as well as human-derived neoplasms, we investigated if a determinant of docetaxel sensitivity could be found at the level of its mechanism of action. Because microtubules represent the cellular targets of the drug, we studied their heterogeneity in the tumour models to try to explain the differences in drug sensitivity. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the expression of microtubular components showed that levels of Mbeta4-tubulin and Tau mRNAs were higher in the murine sensitive neoplasms than in the refractory ones. It was also found that Tau protein levels differed markedly among the tumours. In the human-derived sensitive neoplasm, beta-tubulins and some Tau isoforms were found to be more abundant than in the resistant one. Western blot analysis of MAP2 revealed the presence of several immunoreactive species. Some of these polypeptides were also found in higher amounts in the docetaxel-sensitive tumours. The possible meaning of these correlations is discussed in connection with the regulation of microtubule dynamics.
PMCID: PMC2063126  PMID: 9764577
16.  Eosinophil recruitment to the lung in a murine model of allergic inflammation. The role of T cells, chemokines, and adhesion receptors. 
Journal of Clinical Investigation  1996;98(10):2332-2345.
Eosinophil accumulation is a distinctive feature of lung allergic inflammation. Here, we have used a mouse model of OVA (ovalbumin)-induced pulmonary eosinophilia to study the cellular and molecular mechanisms for this selective recruitment of eosinophils to the airways. In this model there was an early accumulation of infiltrating monocytes/macrophages in the lung during the OVA treatment, whereas the increase in infiltrating T-lymphocytes paralleled the accumulation of eosinophils. The kinetics of accumulation of these three leukocyte subtypes correlated with the levels of mRNA expression of the chemokines monocyte chemotactic peptide-1/JE, eotaxin, and RANTES (regulated upon activation in normal T cells expressed and secreted), suggesting their involvement in the recruitment of these leukocytes. Furthermore, blockade of eotaxin with specific antibodies in vivo reduced the accumulation of eosinophils in the lung in response to OVA by half. Mature CD4+ T-lymphocytes were absolutely required for OVA-induced eosinophil accumulation since lung eosinophilia was prevented in CD4+-deficient mice. However, these cells were neither the main producers of the major eosinophilic chemokines eotaxin, RANTES, or MIP-1alpha, nor did they regulate the expression of these chemokines. Rather, the presence of CD4+ T cells was necessary for enhancement of VCAM-1 (vascular cell adhesion molecule-1) expression in the lung during allergic inflammation induced by the OVA treatment. In support of this, mice genetically deficient for VCAM-1 and intercellular adhesion molecule-1 failed to develop pulmonary eosinophilia. Selective eosinophilic recruitment during lung allergic inflammation results from a sequential accumulation of certain leukocyte types, particularly T cells, and relies on the presence of both eosinophilic chemoattractants and adhesion receptors.
PMCID: PMC507684  PMID: 8941651
17.  Linomide prevents the lethal effect of anti-Fas antibody and reduces Fas-mediated ceramide production in mouse hepatocytes. 
Journal of Clinical Investigation  1996;98(5):1245-1252.
Fas is an apoptosis-signaling receptor molecule expressed in vivo on thymocytes, liver, heart, and ovary. In vivo administration of the anti-Fas Jo2 antibody in mice induces severe apoptotic liver damage leading to fulminant hepatitis and death. Linomide, a quinoline 3-carboxamide, inhibits apoptosis of B and T cells induced by various stimuli including viruses, superantigens, and glucocorticoids. Mice treated with linomide survived the lethal effect of anti-Fas antibody, did not accumulate ceramide in hepatocytes, and recovered liver structure and function within 96 h of anti-Fas injection, as confirmed by histology and glutamic oxalacetic transaminase, glutamic pyruvic transaminase, and lactate dehydrogenase levels. Surviving mice showed severe depletion of cortical thymocytes, but medullar thymic cells expressing high CD3 and Fas levels also survived the treatment with anti-Fas in the presence of linomide. Heart, lung, and ovary showed no signs of apoptosis promoted by Fas ligation. These results suggest that linomide prevents cell death triggered by Fas ligation and can be useful for therapeutic intervention in fulminant hepatitis.
PMCID: PMC507547  PMID: 8787688
18.  The multicentre south European study 'Helios'. I: Skin characteristics and sunburns in basal cell and squamous cell carcinomas of the skin. 
British Journal of Cancer  1996;73(11):1440-1446.
The aim of this study was to investigate constitutional and environmental determinants of non-melanocytic skin cancer among different populations from south Europe. Between 1989 and 1993 we interviewed incident cases and a random population sample of controls from five centres where a cancer registry was operating, whereas we selected a sample of hospital-based cases and controls from three other centres. Controls were stratified according to the age and sex distribution of cases. In all, 1549 cases of basal cell carcinoma (BCC), 228 of squamous cell carcinoma (SCC) and 1795 controls were interviewed. Both cancers affected primarily sun-exposed sites such as face, head and neck, but the prevalence of BCC on the trunk was higher than for SCC. Pigmentary traits such as hair and eye colour as well as tendency to sunburn were strong and independent indicators of risk for both BCC and SCC. In SCC, adjusted odds ratios (ORs) ranged from 1.6 for fair hair colour to 12.5 for red hair. Light-blonde hair entailed a risk of about 2 for BCC. Pale eye colour was associated with a risk of 1.8 for SCC and 1.4 for BCC. Subjects who always burn and never tan showed an adjusted OR of 2.7 for BCC and 2.0 for SCC. A history of sunburns and a young age at first sunburn were associated with an increased risk for BCC only (OR 1.7). Pigmentary traits and sun sensitivity of the skin confirmed their role as risk indicators. The effect of sunburns, as an indicator of both exposure and sun sensitivity of the skin, is less clear. Nevertheless, its association with BCC suggests, by analogy with melanoma, a relationship with intense sun exposure. Conversely, SCC would require prolonged exposure to sunlight.
PMCID: PMC2074488  PMID: 8645595
19.  The multicentre south European study 'Helios'. II: Different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin. 
British Journal of Cancer  1996;73(11):1447-1454.
The role of sun exposure in development of basal cell and squamous cell carcinomas among different populations from south Europe was investigated. Between 1989 and 1993 we interviewed incident cases and a random population sample of controls from five centres where a cancer registry was operating, whereas we selected a sample of hospital-based cases and controls from the other three centres. We gathered information on life-long exposure to sunlight during different activities. Results are analysed for 1549 basal cell carcinoma (BCC) cases and 228 squamous cell carcinoma (SCC) cases compared with 1795 controls. We observed a statistically significant increase of risk of SCC with increasing sun exposure beyond a threshold of 70,000 cumulated hours of exposure in a lifetime. Sun exposures during work and holidays were, however, inversely correlated. Odds ratios (ORs) of SCC were up to eight or nine times the reference for the highest exposures (200,000 cumulated hours or more). BCC exhibited a 2-fold increase of risk for lower exposure (8000-10,000 cumulated hours in a lifetime) with a plateau and a slight decrease of risk for the highest exposures (100,000 cumulated hours or more). Outdoor work showed a significantly increased risk of SCC (OR 1.6 for more than 54,000 cumulated hours of exposure in a lifetime), whereas recreational activities such as sun exposure during holidays at the beach (OR 1.6 for more than 2600 cumulated hours of exposure in a lifetime) or during water sports (OR 1.6 for more than 2600 cumulated hours of exposure in a lifetime) were associated with an increased risk of BCC. Risk patterns were different in poor or good tanners with a significant risk trend for good tanners, whereas poor tanners were on a plateau of increased risk at any level of exposure. Solar radiation is associated with a risk of BCC even for relatively short periods of exposure such as during holidays and sports, whereas SCC develops later if exposure continues. The skin's ability to tan modulates the risk of BCC; subjects who tan poorly have a steady risk increase, whereas people who tan easily develop cancer only after prolonged exposures.
PMCID: PMC2074492  PMID: 8645596
20.  Comparison of enzyme-linked immunosorbent assay, indirect immunofluorescence assay, and virus isolation for detection of respiratory viruses in nasopharyngeal secretions. 
Journal of Clinical Microbiology  1991;29(3):470-474.
Nasopharyngeal secretions obtained from 94 children with acute respiratory illness were examined for the presence of respiratory syncytial virus (RSV), adenovirus, and influenza virus type A by virus culturing (virus isolation technique [VIT]), immunofluorescence assay (IFA), and enzyme-linked immunosorbent assay (ELISA). Similar results were obtained in at least two tests for RSV, influenza virus type A, and adenovirus in 92 (97.9%), 88 (93.6%), and 88 (93.6%) cases, respectively. Both rapid virus detection methods showed good specificity for the diagnosis of these virus infections (greater than or equal to 90.7%) and were more sensitive than was VIT for RSV detection. In a more accurate statistical analysis, the indexes of agreement between VIT and ELISA were substantial for RSV (kappa = 0.69; zeta = 5.5; P less than 0.0001), influenza virus type A (kappa = 0.67; zeta = 5.3; P less than 0.0001), and adenovirus (kappa = 0.71; zeta = 6.0; P less than 0.0001), while it was almost perfect for RSV when ELISA was compared with IFA (kappa = 0.88; zeta = 5.7; P less than 0.0001). Although the observed agreement was good in the comparison of these two tests for these three viruses (89%0, the indexes of agreement were moderate in the comparison of IFA and VIT for RSV (K = 0.55; Z = 2.0; P < 0.05), influenza virus type A (K = 0.42; Z = 9.7; P < 0.0001), and adenovirus (K = 0.41; Z = 6.5; P < 0.0001) and of ELISA and IFA for influenza virus type A (K = 0.55; Z = 7.0; P < 0.0001) and adenovirus (K = 0.59; Z = 6.8; P < 0.0001). All of the statistical evaluations demonstrated better agreement between ELISA and VIT for influenza virus type A and adenovirus.
PMCID: PMC269802  PMID: 2037663
21.  Multicenter prospective study of treatment of Brucella melitensis brucellosis with doxycycline for 6 weeks plus streptomycin for 2 weeks. 
The effectiveness of treating human brucellosis caused by Brucella melitensis with a 6-week course of doxcycline plus streptomycin for 2 of those weeks was analyzed by a multicenter prospective study of 139 patients. Subjects with central nervous system involvement, endocarditis, or spondylitis were excluded from the study. All but 5 of the 139 patients completed the full treatment schedule and became afebrile in the first week of therapy. Four patients suffered relapses during the follow-up period. Of the five patients who did not complete the treatment, two left because of adverse secondary effects (1.4%), another two left for noncomplicance with the treatment (1.4%), and the remaining patient was considered a therapeutic failure because his symptoms persisted after the first week of therapy (0.7%). We concluded that the combination of doxycycline and streptomycin is an effective treatment for the types of brucellosis included in our study.
PMCID: PMC171710  PMID: 2193624
22.  Oxidative polymorphism of debrisoquine in Parkinson's disease. 
Oxidative phenotype and metabolic ratio (MR) of debrisoquine (DBQ) have been determined in 87 patients with Parkinson's disease and in 556 healthy control subjects. Three patients (3.45%) and 34 control subjects (6.12%), having an MR greater than 12.6, were classified as poor metabolisers (PM) of DBQ (ns). The distribution of MR values in the 84 Parkinsonian patients classified as extensive metabolisers (EM) showed a less efficient oxidative rate when compared with controls of the same phenotype (p less than 0.001). This difference may be due to enzymatic inhibition caused by drug treatment in 40 of these patients. As in patients not taking any drug known to inhibit the oxidation of DBQ, distribution of MR values was not different from that in controls. A negative correlation (r = -0.36, p less than 0.02) was found between MR of DBQ and age at onset of disease in patients free of drugs known to interact with DBQ metabolism. A higher rate of DBQ oxidation could be a genetic factor that delays the clinical onset of Parkinson's disease in predisposed people.
PMCID: PMC1014165  PMID: 2341841
23.  Bronchoscopy findings in invasive pulmonary aspergillosis. 
Thorax  1989;44(10):822-823.
Two patients with invasive aspergillosis had unusual endobronchial appearances at fibreoptic bronchoscopy. Diagnosis was achieved by endobronchial biopsy.
PMCID: PMC1020851  PMID: 2595624
24.  Peripheral neuropathy detected on electrophysiological study as first manifestation of metachromatic leucodystrophy in infancy. 
A case of infantile metachromatic leucodystrophy is described in which symptoms started at 1 year of age with weakness and hypotonus in the lower extremities. The electrophysiological status was typical of a polyneuropathy, showing fibrillation and a reduction of the nerve conduction velocity to 30 percent of the average for normal children of the same age. Clinical signs of a central lesion and mental regression were not evident until a year later. Nerve biopsy showed metachromatic granules in the phagocytes and in the Schwann cells, confirming the diagnosis of metachromatic leucodystrophy. In peripheral neuropathy in infancy without obvious cause, a nerve biopsy is the most appropriate method for diagnosis of the metachromatic leucodystrophy.
PMCID: PMC491881  PMID: 1151398
1. Tolerance of male skin isografts has been regularly produced in female mice of the C57B1 strain sublines 1, 4, and 6 during adult life by repeated injection of completely disrupted spleen cells derived from male donors. The tolerant state is long-lasting since such grafts have remained in place more than 9 months. 2. Prolonged survival of homotransplants of skin has regularly been produced in DBA/2 mice during adult life by repeated injections of completely disrupted spleen cells from Balb/C donors. When injections of disrupted spleen cell material are continued over a sufficiently long period, permanent acceptance of the skin homografts may be obtained between these strains. 3. Immunological tolerance across even the strong H-2 histocompatibility barrier was obtained in the neonatal period and during adult life by repeated injection of disrupted spleen cell preparations. The tolerant state has been revealed by both mammary adenocarcinoma and skin homografting across this strong histocompatibility barrier. 4. In contradistinction to the tolerant state produced by injection of intact spleen cells in neonatal animals or during adult life or that produced by parabiotic union, the tolerance produced by repeated injection of disrupted spleen cell preparations cannot be transferred to syngenic neonatal mice with spleen cells of the tolerant animal. 5. The implications of these findings in transplantation biology and in consideration of the basic nature of tolerance are discussed.
PMCID: PMC2137681  PMID: 14087619

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