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Biomedical subjects

S Alonso

Publications and source records attributed to S Alonso.

At least 37 records · Page 2Linked to original sources
PubMed2004

Compound haplotypes at Xp11.23 and human population growth in Eurasia.

To investigate patterns of diversity and the evolutionary history of Eurasians, we have sequenced a 2.8 kb region at Xp11.23 in a sample of African and Eurasian chromosomes. This region is in a long intron of CLCN5 and is immediately flanked by a highly variable minisatellite, DXS255, and a human-specific Ta0 LINE. Compared to Africans, Eurasians showed a marked reduction in sequence diversity. The main Euro-Asiatic haplotype seems to be the ancestral haplotype for the whole sample. Coalescent simulations, including recombination and exponential growth, indicate a median length of strong linkage disequilibrium, up to approximately 9 kb for this area. The Ka/Ks ratio between the coding sequence of human CLCN5 and its mouse orthologue is much less than 1. This implies that the region sequenced is unlikely to be under the strong influence of positive selective processes on CLCN5, mutations in which have been associated with disorders such as Dent's disease. In contrast, a scenario based on a population bottleneck and exponential growth seems a more likely explanation for the reduced diversity observed in Eurasians. Coalescent analysis and linked minisatellite diversity (which reaches a gene diversity value greater than 98% in Eurasians) suggest an estimated age of origin of the Euro-Asiatic diversity compatible with a recent out-of-Africa model for colonization of Eurasia by modern Homo sapiens.

Animals↗
PubMed2004

Biweekly paclitaxel plus gemcitabine in advanced breast cancer: phase II trial and predictive value of HER2 extracellular domain.

BACKGROUND: We wanted to assess the toxicity and efficacy of paclitaxel plus gemcitabine in advanced breast cancer and to confirm whether circulating HER2 extracellular domain (ECD) correlates with treatment response. PATIENTS AND METHODS: Forty-three patients received paclitaxel 150 mg/m2 followed by gemcitabine 2500 mg/m2, both on day 1 of 14-day cycles, with a maximum of eight cycles. Serum levels of HER2 ECD were assessed by ELISA. RESULTS: All patients were evaluable for toxicity and 42 for efficacy. Overall toxicity was low. Grade 3 neutropenia occurred in 12% of patients and grade 4 in 17%, and other grade 3 toxicities in <5%. One patient had an allergic infusion reaction. Overall response rate was 71% [95% confidence interval (CI) 62% to 81%], with 11 patients achieving a complete response (26%). With a median follow-up of 26 months, the median time to progression was 16.6 months. Response rate correlated significantly with HER2 ECD, with 42% of HER2 ECD-positive patients responding versus 83% of HER2 ECD-negative patients (P = 0.02). Furthermore, response duration was shorter in patients with positive HER2 ECD levels (7.9 versus 14.4 months; P = 0.04). CONCLUSIONS: Paclitaxel plus gemcitabine given as an every 2-weeks schedule is a well tolerated and active regimen in advanced breast carcinoma. This is an attractive combination to use when anthracyclines are not indicated, such as in HER2 positive cases that receive trastuzumab. In addition, elevated levels of HER2 ECD adversely affect the efficacy of treatment.

Adenocarcinoma↗
PubMed2003

Adjuvant activity of free Bordetella pertussis filamentous haemagglutinin delivered by mucosal routes.

The development of safe and potent mucosal adjuvants remains a major objective in vaccinology. The potential usefulness of filamentous haemagglutinin (FHA) of Bordetella pertussis as an adjuvant was assessed in a mouse model. The glutathione-S-transferase of Schistosoma mansoni (Sm28GST) was used for intranasal administration, while the gut-resistant keyhole limpet haemocyanin (KLH) was administrated by the oral route. For both antigens, coadministration with FHA increased antigen-specific immunoglobulin titres. This adjuvant effect did not require chemical cross-linking or direct interaction between FHA and the antigen tested. FHA also behaved as an adjuvant by the subcutaneous route, indicating that its adjuvanticity is not restricted to binding to mucosal surfaces. The FHA-induced adjuvanticity was also observed in mice with high anti-FHA antibody titres as a result of antipertussis vaccination, indicating that pre-existing anti-FHA antibodies do not impair FHA adjuvanticity. No mRNA coding for proinflammatory cytokines was induced in the lungs after intranasal FHA administration. However, an increase in the levels of mRNAs coding for B7-1, transforming growth factor (TGF)-beta and major histocompatibility complex (MHC)-II was detected in the lungs after FHA administration. Although the molecular mechanisms of the FHA-induced adjuvanticity remain to be elucidated, the data presented here indicate that this adhesin, already assessed for human use as a pertussis vaccine constituent, represents a promising adjuvant to improve the humoral immune response when given by mucosal routes.

Adhesins, Bacterial↗
PubMed2003

Risk factors in the development of early technetium-99m dimercaptosuccinic acid renal scintigraphy lesions during first urinary tract infection in children.

AIM: To establish the variables that correlate with uptake defects in dimercaptosuccinic acid (DMSA) scintigraphy performed in the acute phase of a first episode of urinary tract infection (UTI). METHODS: A prospective observational study was conducted in a cohort of 158 consecutive children with a first episode of symptomatic UTI. The therapeutic delay time (TDT) was recorded. DMSA scintigraphy was performed in all children and voiding cystourethrography in 150 of them. RESULTS: 85% of the patients were younger than 2 y. Mean TDT was 33.5 h. The aetiological agent was Escherichia coli in 140 children. DMSA scintigraphy was normal in 81. Vesicoureteric reflux was detected in 33. After a multivariate logistic regression analysis the following variables were retained in the final model: TDT > or = 48 h, growth of bacteria other than E. coli, percentage of polymorphonuclear cells > or = 60% and C-reactive protein > or = 30 mg l(-1). CONCLUSION: TDT > or = 48 h, bacteria other than E. coli, percentage of polymorphonuclear cells > or = 60% and CRP > or = 30 mg l(-1) influence the findings detected in the DMSA scintigraphy performed in the acute phase of a first episode of UTI.

Acute Disease↗
PubMed2003

Colonic wall thickening in patients with cirrhosis and portal hypertension.

OBJECTIVE: To determine the prevalence of colonic wall thickening (CWT) and its relation with other clinical and radiological findings of portal hypertension. EXPERIMENTAL DESIGN: Retrospective observational study. The follow-up period was at least 1 year. The colon wall was considered to be thickened when it measured > 6 mm. SUBJECTS: The study included 63 patients, what were admitted in Liver Unit of University and General Hospital of Alicante with hepatic cirrhosis who had an abdominal CT scan performed between March 1996 and December 1998. RESULTS: 21 (33.3%) patients showed CWT. This finding was particularly associated with the presence of collateral circulation [ OR = 10.3(1.5-100.8)] and portal thrombosis [OR = 12.8(1.4-118.4)] p<0.05. Patients with CWT tended to develop spontaneous bacterial peritonitis (CWT 14.3% vs no CWT 4.8%) [RR = 3(0.5 -16.6)] but this did not reach statistical significance (p= 0.18). CONCLUSIONS: A third of the patients with cirrhosis and portal hypertension present colonic wall thickening. This finding is related to radiological features and clinical consequences of portal hypertension.

Aged↗
PubMed2002

Excitability transitions and wave dynamics under spatiotemporal structured noise.

We present an analytic and numerical study of the effects of external fluctuations in active media. Our analytical methodology transforms the initial stochastic partial differential equations into an effective set of deterministic reaction-diffusion equations. As a result we are able to explain and make quantitative predictions on the systematic and constructive effects of the noise, for example, target patterns created out of noise and traveling or spiral waves sustained by noise. Our study includes the case of realistic noises with temporal and spatial structures.

Journal Article↗
PubMed2002

The role of granulocyte colony-stimulating factor (G-CSF) in the post-transplant period.

The administration of G-CSF post transplant has been shown to accelerate the time to neutrophil engraftment. However, this does not necessarily translate into a meaningful clinical benefit to the patient. This randomized study was designed to determine the role of G-CSF following transplantation in patients with breast cancer (BC). A total of 241 evaluable patients with BC were included. There were 200 patients with high-risk BC, and 41 had disseminated BC in complete remission. All patients received conventional dose chemotherapy prior to transplantation. Patients were mobilized with G-CSF, received the STAMP V regimen, were transplanted with > or = 2.5 x 10(6) of CD34(+) cells/kg and were then randomized to receive 5 microg/kg of G-CSF starting on the day of infusion (arm A), five days later (arm B), or no G-CSF (arm C). The need for transfusion support, infectious complications and length of hospitalization were the variables chosen to demonstrate clinical benefit. Patients receiving G-CSF reached 500 and 1000 neutrophils significantly faster (P = 0.001) than patients with no G-CSF. This translated into a significantly (P < 0.05) shorter hospitalization time for patients receiving G-CSF. Arm C was closed and, after recruiting 110 patients in arm A, and 106 in arm B, the significant difference in neutrophil recovery persisted with no difference in the time of hospitalization between arms A and B. Therefore, G-CSF significantly accelerates the time to neutrophil engraftment. This translates into a shorter time of hospitalization. There is no difference in this variable regarding the time of administering the G-CSF: day 0 vs day +5. Therefore, G-CSF on day +5 should be the standard in this setting.

Adult↗
PubMed2002

[Percutaneous intrahepatic portosystemic shunting as a treatment for refractory hepatic hydrothorax].

Hepatic hydrothorax is an infrequent complication of portal hypertension in liver cirrhosis. Treatment with saline restriction and diuretics is usually effective but when this fails, the therapeutic approach is difficult and multiple complications occur. Transjugular percutaneous intrahepatic portosystemic shunt (IPS) is associated with a marked decrease in portal pressure and consequently this technique has been used in the treatment of refractory ascites. The aim of this study was to analyze the efficacy, safety and outcome of refractory hepatic hydrothorax treated by IPS. The procedure was performed in 5 patients who were all grade B or C in the Child-Pugh classification. Three patients showed complete response to the treatment, of whom 1 underwent transplantation 20 days later. The fourth patient showed partial response with a reduction in the need to perform thoracocentesis and the fifth patient showed no response to IPS and died after 17 days of follow-up. Albumin levels and Child classification remained unchanged. Two patients presented recurrence with reappearance of hydrothorax due to shunt dysfunction and 2 patients presented hepatic encephalopathy that responded to medical treatment. Refractory hepatic hydrothorax can be controlled by IPS in a large number of patients but its efficacy is restricted by shunt dysfunction, the risk of encephalopathy and by its limited effect on survival.

Aged↗
PubMed2001

Tetanus toxin fragment C-specific priming by intranasal infection with recombinant Bordetella pertussis.

As an alternative to parenteral administration, mucosal administration offers several advantages including the ease of administration, safety and the ability to induce mucosal immunity. As a first step towards nasal administration of important childhood vaccines, we have previously developed attenuated Bordetella pertussis strains able to protect mice against pertussis upon nasal vaccination. Since pertussis vaccines are generally combined with tetanus and diphtheria vaccines, we constructed recombinant B. pertussis strains producing the non-toxic protective tetanus toxin fragment C (TTFC). TTFC was genetically fused to the N-terminal domain of the B. pertussis filamentous haemagglutinin. The hybrid gene was introduced into B. pertussis both on a multi-copy replicative plasmid and as a single copy inserted into the chromosome of a pertussis toxin-producing strain and a toxin-deficient attenuated strain. The hybrid protein was secreted by the recombinant strains. However, the recombinant multi-copy plasmid was unstable in vivo, and immunisation could only be carried out with the strains containing the single-copy chromosomal integration. Both the toxin-producing and the toxin-deficient recombinant B. pertussis strains were able to prime mice for the production of anti-TTFC serum antibodies upon intranasal administration, suggesting the feasibility of using recombinant attenuated B. pertussis for the development of combined childhood vaccines.

Administration, Intranasal↗
PubMed2001

Nasal vaccination using live bacterial vectors.

Live recombinant bacteria represent an attractive means to induce both mucosal and systemic immune responses against heterologous antigens. Several models have now been developed and shown to be highly efficient following intranasal immunization. In this review, we describe the two main classes of live recombinant bacteria: generally recognized as safe bacteria and attenuated strains derived from pathogenic bacteria. Among the latter, we have differentiated the bacteria, which do not usually colonize the respiratory tract from those that are especially adapted to respiratory tissues. The strategies of expression of the heterologous antigens, the invasiveness and the immunogenicity of the recombinant bacteria are discussed.

Administration, Intranasal↗
PubMed2001

Regular wave propagation out of noise in chemical active media.

A pacemaker, regularly emitting chemical waves, is created out of noise when an excitable photosensitive Belousov-Zhabotinsky medium, strictly unable to autonomously initiate autowaves, is forced with a spatiotemporal patterned random illumination. These experimental observations are also reproduced numerically by using a set of reaction-diffusion equations for an activator-inhibitor model, and further analytically interpreted in terms of genuine coupling effects arising from parametric fluctuations. Within the same framework we also address situations of noise-sustained propagation in subexcitable media.

Journal Article↗
PubMed2001

Coronavirus derived expression systems.

Both helper dependent expression systems, based on two components, and single genomes constructed by targeted recombination, or by using infectious cDNA clones, have been developed. The sequences that regulate transcription have been characterized mainly using helper dependent expression systems and it will now be possible to validate them using single genomes. The genome of coronaviruses has been engineered by modification of the infectious cDNA leading to an efficient (>20 microg ml(-1)) and stable (>20 passages) expression of the foreign gene. The possibility of engineering the tissue and species tropism to target expression to different organs and animal species, including humans, increases the potential of coronaviruses as vectors. Thus, coronaviruses are promising virus vectors for vaccine development and, possibly, for gene therapy.

Coronavirus↗
PubMed2001

The heparin-binding haemagglutinin of M. tuberculosis is required for extrapulmonary dissemination.

Tuberculosis remains the world's leading cause of death due to a single infectious agent, Mycobacterium tuberculosis, with 3 million deaths and 10 million new cases per year. The infection initiates in the lungs and can then spread rapidly to other tissues. The availability of the entire M. tuberculosis genome sequence and advances in gene disruption technologies have led to the identification of several mycobacterial determinants involved in virulence. However, no virulence factor specifically involved in the extrapulmonary dissemination of M. tuberculosis has been identified to date. Here we show that the disruption of the M. tuberculosis or Mycobacterium bovis Bacille Calmette-Guérin (BCG) hbhA gene encoding the heparin-binding haemagglutinin adhesin (HBHA) markedly affects mycobacterial interactions with epithelial cells, but not with macrophage-like cells. When nasally administered to mice, the mutant strains were severely impaired in spleen colonization, but not in lung colonization. Coating wild-type mycobacteria with anti-HBHA antibodies also impaired dissemination after intranasal infection. These results provide evidence that adhesins such as HBHA are required for extrapulmonary dissemination, and that interactions with non-phagocytic cells have an important role in the pathogenesis of tuberculosis. They also suggest that antibody responses to HBHA may add to immune protection against tuberculosis.

Animals↗
PubMed2001

Noise-induced Brownian motion of spiral waves.

We study the erratic displacement of spiral waves forced to move in a medium with random spatiotemporal excitability. Analytical work and numerical simulations are performed in relation to a kinematic scheme, assumed to describe the autowave dynamics for weakly excitable systems. Under such an approach, the Brownian character of this motion is proved and the corresponding dispersion coefficient is evaluated. This quantity shows a nontrivial dependence on the temporal and spatial correlation parameters of the external fluctuations. In particular, a resonantlike behavior is neatly evidenced in terms of the noise correlation time for the particular situation of spatially uniform fluctuations. Actually, this case turns out to be, to a large extent, exactly solvable, whereas a pair of dispersion mechanisms are discussed qualitatively and quantitatively to explain the results for the more general scenario of spatiotemporal disorder.

Journal Article↗
PubMed2001

A highly variable segment of human subterminal 16p reveals a history of population growth for modern humans outstide Africa.

We have sequenced a highly polymorphic subterminal noncoding region from human chromosome 16p13.3 flanking the 5' end of the hypervariable minisatellite MS205, in 100 chromosomes sampled from different African and Euroasiatic populations. Coalescence analysis indicates that the time to the most recent common ancestor (approximately 1 million years) predates the appearance of anatomically modern human forms. The root of the network describing this variability lies in Africa. African populations show a greater level of diversity and deeper branches. Most Euroasiatic variability seems to have been generated after a recent out-of-Africa range expansion. A history of population growth is the most likely scenario for the Euroasiatic populations. This pattern of nuclear variability can be reconciled with inferences based on mitochondrial DNA.

Africa↗
PubMed2001

Sorting nexin-14, a gene expressed in motoneurons trapped by an in vitro preselection method.

A gene-trap strategy was set up in embryonic stem (ES) cells with the aim of trapping genes expressed in restricted neuronal lineages. The vector used trap genes irrespective of their activity in undifferentiated totipotent ES cells. Clones were subjected individually to differentiation in a system in which ES cells differentiated into neurons. Two ES clones in which the trapped gene was expressed in ES-derived neurons were studied in detail. The corresponding cDNAs were cloned, sequenced, and analysed by in situ hybridisation on wild-type embryo sections. Both genes are expressed in the nervous system. One gene, YR-23, encodes a large intracellular protein of unknown function. The second clone, YR-14, represents a sorting nexin (SNX14) gene whose expression in vivo coincides with that of LIM-homeodomain Islet-1 in several tissues. Sorting nexins are proteins associated with the endoplasmic reticulum (ER) and may play a role in receptor trafficking. Gene trapping followed by screening based on in vitro preselection of differentiated ES recombinant clones, therefore, has the potential to identify integration events in subsets of genes before generation of mouse mutants.

Animals↗
PubMed2001

Juxtaposition of CNR protocadherins and reelin expression in the developing spinal cord.

The CNR (cadherin-related neuronal receptors) family of protocadherins is of great interest because of their potential roles as molecular tags in the formation of specific synaptic connections, and as receptors for reelin, during neuronal migration, and cell body positioning. In order to know more about potential functions of CNRs we have mapped their expression during mouse nervous system development and compared their expression with that of reelin and its intracellular effector Dab1 in several tissues. In spinal cord, CNRs and Dab1 are expressed in motoneurons, while reelin is located in adjacent cells. In the hindbrain, there is a differential expression of CNRs and Dab1 in various motor nuclei. In the retina and olfactory system, we observe CNR and reelin expression but not that of Dab1. These results provide new insights into the potential functions of CNRs and their possible integration in the reelin pathway during development.

Animals↗