Late first relapses in APL treated with all-trans-retinoic acid- and anthracycline- based chemotherapy: the European APL group experience (APL 91 and APL 93 trials).
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Adult↗
Biomedical subjects
M Sanz
Publications and source records attributed to M Sanz.
Curriculum structure and the European Credit Transfer System for European dental schools: part I.
This paper presents a proposed curriculum structure and system of European Credit Transfer (ECTS) for undergraduate dental schools throughout Europe. It is the result of the work of a Taskforce ('Taskforce II'), appointed by DentEd, a thematic network of European dental schools and the Association for Dental Education in Europe (ADEE). There has been pan-European discussion of the document in draft stages (it was distributed to 200 dental schools) and following amendment, it was agreed formally at the National Assembly of ADEE in Athens, Greece, in September 2005. The main elements of the paper relate to: (i) a description of the framework proposed with relevance to the Bologna recommendations and common directive on recognition for professional qualifications as they apply to Dentistry; (ii) the structure of an undergraduate dental curriculum; (iii) student exchange and ECTS. In addition, the paper presents a series of requirements, guidelines and recommendations for action. ADEE expects that the 'requirements' proposed will be followed by dental schools in Europe, whilst the 'guidelines' and 'recommendations' also provided are open to local interpretation. The paper is also published on the ADEE website.
Advisory Committees↗
The RIM101 pathway contributes to yeast cell wall assembly and its function becomes essential in the absence of mitogen-activated protein kinase Slt2p.
The Saccharomyces cerevisiae ynl294cDelta (rim21Delta) mutant was identified in our lab owing to its moderate resistance to calcofluor, although it also displayed all of the phenotypic traits associated with its function as the putative sensor (Rim21p) of the RIM101 pathway. rim21Delta also showed moderate hypersensitivity to sodium dodecyl sulfate, caffeine, and zymolyase, and the cell wall compensatory response in this mutant was very poor, as indicated by the almost complete absence of Slt2 phosphorylation and the modest increase in chitin synthesis after calcofluor treatment. However, the cell integrity pathway appeared functional after caffeine treatment or thermal stress. rim21Delta and rim101Delta mutant strains shared all of the cell-wall-associated phenotypes, which were reverted by the expression of Rim101-531p, the constitutively active form of this transcription factor. Therefore, the absence of a functional RIM101 pathway leads to cell wall defects. rim21Delta, as well as rim101Delta, was synthetic lethal with slt2Delta, a synthetic defect alleviated by osmotic stabilization of the media. The double mutants grown in osmotically stabilized media were extremely hypersensitive to zymolyase and showed thicker cell walls, with poorly defined mannoprotein layers. In contrast, rim21Delta rlm1Delta and rim101Delta rlm1Delta double mutants were fully viable. Taken together, these results show that the RIM101 pathway participates directly in cell wall assembly and that it acts in parallel with the protein kinase C pathway (PKC) in this process independently of the transcriptional effect of the compensatory response mediated by this route. In addition, these results provide new experimental evidence of the direct involvement of the PKC signal transduction pathway through the Sltp2 kinase in the construction of yeast cell walls.
Cell Wall↗
[Abdominal pain with very uncommon etiology].
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Abdominal Pain↗
Rickettsia slovaca infection: DEBONEL/TIBOLA.
This study describes the epidemiological, clinical, and microbiological characteristics of a new tick-borne disease in Spain-Dermacentor-borne necrosis erythema lymphadenopathy (DEBONEL). The clinical presentations include an eschar at the site of the tick bite, surrounded by an erythema and painful regional lymphadenopathy. The disease appears during the colder months and its vector is Dermacentor marginatus (D. marginatus). From January 1990 to December 2004, 54 patients presented at Hospital of La Rioja with these clinical and epidemiological data. The ratio of females to males was 32/22. The average age was 37 years. In all cases tick bites were located on the upper body (90% on the scalp). The median incubation period was 4.7 days. Signs and symptoms were mild in all cases. Only a small number of patients presented mild and nonspecific abnormalities in a complete blood cell count and mild elevation of erythrocyte sedimentation rates and C-protein reactive and liver enzyme levels. Serological evidence of acute rickettsiosis was observed in 19 patients (61%). In 29% sera tested by polymerase chain reactions (PCRs) were positive. The sequence obtained from a PCR product revealed 98% identity with Rickettsia sp. strains RpA4, DnS14, and DnS28. All ticks removed from patients were PCR-positive. Sequencing showed 8 of them identified as R. slovaca and 2 as Rickettsia sp. strains RpA4, DnS14, and DnS28.
Animals↗
Prevalence of spotted fever group Rickettsia species detected in ticks in La Rioja, Spain.
Our objective was to learn the prevalence of spotted fever group (SFG) Rickettsia detected in ticks in La Rioja, in the north of Spain. From 2001 to 2005, 496 ticks representing 7 tick species were analysed at the Hospital de La Rioja. Ticks were removed from humans with or without rickettsial syndrome (n = 59) or collected from mammals (n = 371) or from vegetation by dragging (n = 66). The presence of SFG Rickettsia in these ticks was investigated by semi-nested PCR (ompA gene) and sequencing. A phylogenetic tree using Clustal method (neighbor-joining) was constructed with these data. Only 3 of 170 Hyalomma marginatum ticks carried SFG Rickettsia. Sequencing analysis demonstrated the presence of Rickettsia aeschlimannii (1.8%). Furthermore, Rickettsia massiliae and BAR29 were found in 3 of 120 Rhipicephalus sanguineus specimens (2.5%). In contrast, 81 of 83 tested Dermacentor marginatus ticks were PCR-positive (97%). Rickettsia slovaca (40.6%) and Rickettsia sp. strains RpA4, DnS14, DnS28 and JL-02 (59.3%) were found within this tick species. No SFG Rickettsia was detected using ompA primers when Ixodes ricinus, Rhipicephalus bursa, Rhipicephalus turanicus, Rhipicephalus eversti eversti, Hyalomma detritum scupense and Rhipicephalus sp. were analyzed. We detected 17.5% of ticks associated with different SFG Rickettsia: R. aeschlimannii, R. massiliae, BAR29, R. slovaca and Rickettsia sp. strains RpA4, DnS14, DnS28 and JL-02. Their presence has to be taken into account since most of them have been recognized as human pathogens.
Animals↗
A Neandertal mandible from the Cova del Gegant (Sitges, Barcelona, Spain).
A human mandible from the site of Cova del Gegant is described here for the first time and compared with other Middle and Upper Pleistocene representatives of the genus Homo from Europe and Southwest Asia. The specimen was recovered from sediments which also yielded Mousterian stone tools and Pleistocene fauna. The preserved morphology of the mandible, particularly in the region of the mental foramen, clearly aligns it with the Neandertals, making the Cova del Gegant the only known site in Catalonia documenting diagnostic human skeletal remains in association with Middle Paleolithic stone tools. This represents an important new addition to the human fossil record from the Iberian Peninsula and joins the Bañolas mandible in documenting the course of human evolution in the northern Mediterranean region of Spain.
Age Determination by Teeth↗
Outcome of acute promyelocytic leukemia treated with all trans retinoic acid and chemotherapy in elderly patients: the European group experience.
We analyzed the outcome of patients aged more than 60 included in a multicenter trial in newly diagnosed acute promyelocytic leukemia (APL93 trial), which tested the role of early addition of chemotherapy to all trans retinoic acid (ATRA) and of maintenance with ATRA and/or low-dose chemotherapy. In total, 129/533 (24.2%) patients included in this trial were older than 60. The CR rate was 86% in patients older than 60 as compared to 94.5% in younger patients (P=0.0014), due to a higher incidence of early deaths in elderly patients. The 4-year incidence of relapse was 15.6% in adults older than 60 and 23.2% in younger adults although most elderly patients received less intensive consolidation chemotherapy. However, 18.6% of the patients older than 60 years who achieved CR died in CR, mainly from sepsis during consolidation course or maintenance treatment, as compared to 5.7% of younger adults (P<0.001). Thus, overall 4-year survival of elderly patients was 57.8% as compared to 78% in younger adults (P<0.0001). APL in elderly patients appears as sensitive to ATRA-Chemotherapy based regimen as in younger adults. Less favorable outcome is mainly due to an increase of early deaths and to toxicity of consolidation treatment, strongly suggesting a beneficial role for less intensive consolidation chemotherapy and possibly introduction of arsenic derivates in the treatment of APL in the elderly.
Adolescent↗
Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group.
Internal tandem duplications (ITDs) of the FLT3 gene have been observed in about 35% of APL cases. If FLT3-ITD is associated with a worse outcome in patients with acute myeloid leukemia (AML) in general, its prognostic value in acute promyelocytic leukemia (APL) is still a matter of debate. We investigated incidence, associated clinical features, and prognostic implication of FLT3-ITD, but also FLT3-D835 point mutation and N-Ras or K-Ras mutations in 119 APL patients, all prospectively enrolled in the two consecutive APL-93 and APL-2000 trials. Mutation incidences were 38, 20, and 4%, for FLT3-ITD, FLT3-D835, and Ras, respectively. The presence of FLT3-ITD was associated with high white blood cell count, high Sanz index, M3-variant subtype, and V/S PML-RAR alpha isoforms. Complete remission (CR), induction death, and death in CR rates were not affected by FLT3 or Ras mutations, as well as cumulative incidence of relapse. However, a trend for a shorter overall survival (P=0.09) was observed in FLT3-ITD patients, because of a very poor postrelapse survival (P=0.02). This feature, which has been also reported in patients with AML in general, is suggestive of an underlying genetic instability in FLT3-ITD patients, leading to the acquisition of additional unknown bad-prognosis gene mutations at relapse.
Adult↗
Antimicrobial profiles of periodontal pathogens isolated from periodontitis patients in The Netherlands and Spain.
BACKGROUND AND AIM: Antimicrobial resistance of periodontal pathogens towards currently used antibiotics in periodontics has been investigated in a previous study. Microbial resistance in the periodontal microflora was more frequently observed in Spanish patients in comparison with Dutch patients. The aim of the present study was to compare antimicrobial susceptibility profiles of five periodontal bacteria isolated from periodontitis patients in Spain and in The Netherlands. MATERIAL AND METHODS: Subgingival plaque samples from adult patients with periodontitis were collected and cultured on selective and non-selective plates. Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum and Micromonas micros were isolated and used for minimal inhibitory concentration tests using the Epsilometer (E-test) technique. Eight different antibiotics were tested on all bacterial isolates. MIC50 and MIC90 values for each antibiotic and each species were determined and the percentage of resistant strains was calculated. RESULTS: Significantly higher MIC values were noted in Spanish strains of F. nucleatum for penicillin, ciprofloxacin, of P. intermedia for penicillin, amoxicillin and tetracycline, of M. micros for tetracycline, amoxicillin and azithromycin, and of P. gingivalis for tetracycline and ciprofloxacin. Based on breakpoint concentrations, a higher number of resistant strains in Spain were found in F. nucleatum for penicillin, amoxicillin and metronidazole, in Prevotella intermedia for tetracycline and amoxicillin, and in A. actinomycetemcomitans for amoxicillin and azithromycin. Resistance of P. gingivalis strains was not observed for any of the antibiotics tested both in Spain and The Netherlands. CONCLUSIONS: Differences exist in the susceptibility profiles of periodontal pathogens isolated from periodontitis patients in Spain and in The Netherlands. This implicates that antibiotic susceptibility testing is necessary to determine efficacy of antimicrobial agents. Also, clinical studies with antibiotics should take these differences into account. The information from the present study indicates that it may not be possible to develop uniform protocols for usage of antibiotics in the treatment of severe periodontitis in the European Union.
Adult↗
Advances in the aetiology of periodontitis. Group A consensus report of the 5th European Workshop in Periodontology.
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Aggregatibacter actinomycetemcomitans↗
Use of arsenic trioxide in haematological malignancies: insight into the clinical development of a novel agent.
BACKGROUND: Arsenic trioxide delivers high rates of complete clinical remission in patients with relapsed/refractory acute promyelocytic leukaemia (APL), and is associated with high rates of molecular remission as indicated by PCR negativity for the PML-RARalpha gene. OBJECTIVE: Mitochondria are considered to be the primary intracellular target of arsenic trioxide, and preclinical and mechanistic studies suggest that this agent may have broad applicability in haematological and other malignancies. Investigations of this agent are ongoing in a range of haematological malignancies, and studies in newly diagnosed APL, acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS), multiple myeloma (MM) and chronic myelogenous leukaemia (CML) are reviewed here using published articles and presentations at international congresses to June 2004. Medline was used to source published preclinical and clinical data, and abstract databases and publications from relevant major international haematology/oncology congresses were searched to source updates of preclinical and clinical trial data. FINDINGS: Accumulating data indicate that arsenic trioxide may be a useful addition to the therapeutic regimens that have been so successful in treating newly diagnosed APL, and investigations are ongoing to incorporate this agent into the first-line APL treatment paradigm. Preliminary data from clinical studies indicate that arsenic trioxide has clinical activity as a single agent in MDS and MM, and combination therapies are being investigated. In MM, the combination regimens under study incorporate ascorbic acid, which can enhance the efficacy of arsenic trioxide by reducing intracellular glutathione concentrations. In CML, arsenic trioxide is being investigated in combination with imatinib mesylate in patients who have failed initial imatinib treatment. In AML, although results with single-agent arsenic trioxide were not encouraging, treatment using arsenic trioxide in combination with ascorbic acid is a proposed strategy in elderly patients not able to withstand intensive chemotherapy. CONCLUSION: This versatile agent has a predictable and manageable safety profile and avoids many of the severe toxicities associated with conventional chemotherapies. Ongoing clinical studies will help to define the role of arsenic trioxide in the treatment of haematological malignancies.
Antineoplastic Agents↗
Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group.
PURPOSE: To retrospectively determine the outcome of acute promyelocytic leukemia (APL) patients who underwent autologous or allogeneic stem-cell transplantation (SCT) during second complete remission. PATIENTS AND METHODS: Of 122 relapsing patients included in two successive multicenter APL trials who achieved hematological second complete remission (generally after a salvage regimen of all-trans-retinoic acid [ATRA] combined with chemotherapy), 73 (60%) received allogeneic (n = 23) or autologous (n = 50) SCT. RESULTS: Seven-year relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) in the autologous SCT group were 79.4%, 60.6%, and 59.8%, respectively, with a transplant-related mortality (TRM) of 6%. Of the 28 and two patients autografted with negative and positive, respectively, reverse transcriptase-polymerase chain reaction before auto SCT, three (11%) and one relapsed, respectively. In the allogeneic SCT group, 7-year RFS, EFS, and OS were 92.3%, 52.2%, and 51.8%, respectively, with 39% TRM. OS was significantly better in the autologous SCT group than in the allogeneic SCT group (P = .04), whereas RFS and EFS did not differ significantly (P = .19 and P = .11, respectively). In patients not receiving transplantation, 7-year RFS, EFS, and OS were 38%, 30.4%, and 39.5%, respectively. CONCLUSION: These retrospective data suggest that autologous SCT is very effective in APL relapsing after treatment with ATRA if performed in molecular remission. Allogeneic SCT yields few relapses, but it is associated with high TRM when performed after salvage with very intensive chemotherapy. Salvage with arsenic trioxyde, which has lower toxicity, should further improve the outcome of relapsing APL, especially before allogeneic SCT.
Adult↗
Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy.
PURPOSE: To determine the results of treatment combining all-trans-retinoic acid (ATRA) and chemotherapy (CT) in childhood acute promyelocytic leukemia (APL). PATIENTS AND METHODS: Children (< 18 years) with newly diagnosed APL were included in the APL93 trial, treated by ATRA followed or combined with daunorubicin-cytarabine, and then randomly assigned between no maintenance, intermittent ATRA, continuous CT, or both. RESULTS: Of the 576 patients included in APL93 trial, 31 (5%) were children, including 22 girls (71%) and nine boys (29%). Thirty of the children (97%) obtained complete remission (CR). ATRA syndrome occurred in four children (13%), who all achieved CR, and headaches occurred in 12 children (39%), with signs of pseudotumor cerebri in five children (16%). Seven patients (23%) relapsed. None of the eight patients who received both ATRA and CT for maintenance relapsed. All relapsing patients achieved a second CR. Twenty-two patients remained in first CR after 43+ to 96+ months, six remained in second CR after 17+ to 66+ months, and three patients had died. The 5-year event-free survival (EFS), relapse, and overall survival rates were 71%, 27%, and 90%, respectively. No difference between adults and children included in the APL93 trial was seen for CR rate, 5-year relapse rate, EFS, and overall survival, but significantly better survival was seen in children after adjustment on WBC counts (P =.02) and incidence of microgranular M3 variant (P =.04). CONCLUSION: ATRA combined with CT for induction and also probably for maintenance provides as favorable results in children with APL as in adults and currently constitutes the reference first-line treatment in both age groups.
Adolescent↗
Saccharomyces cerevisiae Bni4p directs the formation of the chitin ring and also participates in the correct assembly of the septum structure.
In Saccharomyces cerevisiae cytokinesis is efficiently achieved when a concerted series of events take place at the neck region, leading to septum formation. Here it is shown that Bni4p plays a crucial role in this process. Deltabni4 mutants contain normal amounts of chitin and show normal chitin synthase III (CSIII) activity, but are partially resistant to Calcofluor White (CFW), probably due to the striking pattern of chitin distribution. CFW vital staining shows that chitin is synthesized in daughter cells and that it is also asymmetrically deposited at the mother-side of the neck in large-budded cells. This specific pattern coincides with that of Chs4p and Chs3p proteins. Alternatively, staining of unbudded cultures confirmed that Bni4p directs early chitin ring assembly, but is no longer required for the chitin deposition that occurs late in the cell cycle at cytokinesis. Consequently, this work provides a strategy to genetically discriminate between the absence of chitin synthesis (Deltachs3 mutant) and failure in chitin ring assembly (Deltabni4 mutants). The characterization of double mutants affected in chitin synthesis and primary septum (PS) assembly (Deltamyo1 and Deltachs2) provides evidence for the cooperation of Bni4p in PS formation besides its role in chitin ring assembly. In addition, it is shown that the chitin ring, but not the late deposition of chitin, cooperates in the correct assembly of the actomyosin ring and the PS when the biological function of the septins is compromised. We conclude that Bni4p is not only required for the assembly of the chitin ring, but is also involved in septum architecture and the maintenance of neck integrity.
Cell Cycle Proteins↗
Biofilms and the tongue: therapeutical approaches for the control of halitosis.
Due to its location and functions, the tongue is one of the most important anatomic structures in the oral cavity. However, knowledge in regards to its role and implications in oral health and disease is scarce. Moreover, although the dorsum of the tongue seems to harbour one of the most complex microbiological niches in human ecology, the knowledge of the role of tongue flora in health and disease is also very limited. Similarly, the nature of the tongue coating and the factors that influence its development and composition are almost unknown. The interest in the study of the tongue niche has increased in recent years due to its association with oral halitosis and to its role as a suitable reservoir for periodontal pathogens. The structure of the tongue favours a unique and complex bacterial biofilm, in which periodontal pathogens are frequently found. However, little is known about how to control this bacterial niche, and factors affecting tongue coating composition and aspect are not fully understood. Studies available on the influence of mechanical or antimicrobial approaches against tongue biofilm are very limited. Mechanical treatments showed a transient reduction in halitosis-related variables but were limited in time. Different antimicrobials agents have been evaluated: chlorhexidine, chlorine dioxide, metal ions, triclosan, formulations containing essential oils, and hydrogen peroxide. However, most studies were designed as short-term models. Some of these studies demonstrated that the reduction in halitosis-related variables was associated with significant changes in the tongue microflora.
Anti-Infective Agents, Local↗
Transmission measurements in wedge-shaped absorbing samples: an experiment for observing negative refraction.
We report on experiments of light transmissivity, at wavelengths of 532 nm and 400 nm, through an Au film with a wedge shape. Our results exhibit a resemblance with those reported for observing negative refraction in proposed left-handed materials. This resemblance is present even though the medium that we used is well known to be right handed with its refractive index, therefore, having a positive real part. Analogous results are obtained with a glass wedge at 320 nm where absorption dominates. The experiment is explained by the wave losses that dominate over propagation, as in the already reported observation of negative refraction in developed metamaterial wedges. We design and propose an experiment with metamaterials by using thicker wires and parallel face slabs, in correspondence with light measurements that we have carried out in positive refractive index samples. This experimental configuration should conclusively determine whether refraction is positive or negative.
Journal Article↗
Therapy-related acute promyelocytic leukemia.
PURPOSE: To analyze patient cases of therapy-related acute promyelocytic leukemia (tAPL), occurring after chemotherapy (CT), radiotherapy (RT) or both for a prior disorder, diagnosed during the last 20 years in three European countries. PATIENTS AND METHODS: The primary disorder and its treatment, interval from primary disorder to tAPL, characteristics of tAPL, and its outcome were analyzed in 106 patients. RESULTS: Eighty of the 106 cases of tAPL were diagnosed during the last 10 years, indicating an increasing incidence of tAPL. Primary disorders were predominantly breast carcinoma (60 patients), non-Hodgkin's lymphoma (15 patients), and other solid tumors (25 patients). Thirty patients had received CT alone, 27 patients had received RT alone, and 49 patients had received both. CT included at least one alkylating agent in 68 patients and at least one topoisomerase II inhibitor in 61 patients, including anthracyclines (30 patients), mitoxantrone (28 patients), and epipodophyllotoxins (19 patients). Median interval from primary disorder to tAPL diagnosis was 25 months (range, 4 to 276 months). Characteristics of tAPL were generally similar to those of de novo APL. With treatment using anthracycline-cytarabine-based CT or all-trans-retinoic acid combined with CT, actuarial survival was 59% at 8 years. CONCLUSION: tAPL is not exceptional, and develops usually less than 3 years after a primary neoplasm (especially breast carcinoma) treated in particular with topoisomerase II-targeted drugs (anthracyclines or mitoxantrone and less often etoposide). Characteristics and outcome of tAPL seem similar to those of de novo APL.
Adult↗