Assessment of Confirmed Clinical Hypersensitivity to Rituximab in Patients Affected with B-Cell Neoplasia.

Rituximab hypersensitivity reactions are rare but are one of the main causes of rituximab elimination from antilymphoma immunochemotherapy treatments. While the clinical picture may be indistinguishable from other infusion-related reactions, hypersensitivity reactions (HSR) do not disappear and instead become more intense with subsequent administrations. Objective. To describe the use of the 12-step protocol for desensitization to intravenous rituximab in clinical practice and the complementary study of a possible IgE-mediated HSR in the context of B-cell lymphoma treatment. Methods. A 12-step rituximab desensitization protocol was performed prospectively within clinical practice in 10 patients with a history of severe infusion reactions or in patients who had a repeated reaction at subsequent doses despite taking more intense preventive measures. Skin prick tests were performed at the time of reaction and at a later time to eliminate false negatives due to possible drug interference. Results. Overall, with the desensitization protocol, 70% of patients were able to complete the scheduled immunochemotherapy. Two patients had to discontinue the therapy due to clinical persistence and the third due to lymphoma progression. Intradermal tests with 0.1% rituximab were positive in only 20% of cases, demonstrating a mechanism of hypersensitivity. Conclusions. The 12-step desensitization protocol is very effective and assumable within healthcare practice. There is a need to determine the mechanism underlying the infusion reaction in a large proportion of cases due to the risk of future drug exposure.

Iliac Artery Reconstruction with Femoral Vein After Bare Metal Stent Infection.

INTRODUCTION: Primary infection of a bare metal stent is a rare condition, associated with significant morbidity and mortality. Definitive treatment includes stent removal and arterial reconstruction. REPORT: This study details a common iliac stent infection after re-intervention for iliac stent occlusion, complicated by pseudoaneurysm formation and septic embolisation. Potential risk factors for stent infection were identified. An open surgical resection of the affected artery along with all stent material was performed, followed by reconstruction with autologous interposition superficial femoral vein. There were no complications and no recurrent infection at 6 months follow-up. CONCLUSION: Although rare, bare metal stent infection may occur, and a high index of suspicion is required. Stent surgical removal and arterial in situ reconstruction with autologous femoral vein proved to be a definitive procedure with no mid-term morbidity.

Biweekly vinorelbine and tegafur/uracil in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: GEICAM 2000-02 phase II study

INTRODUCTION: To assess the efficacy and safety profile of biweekly vinorelbine and tegafur/uracil (UFT) as treatment in patients with metastatic breast cancer previously treated with anthracyclines and taxanes. PATIENTS AND METHODS: Patients with histologically confirmed breast cancer, measurable disease, no more than one prior chemotherapy regimen for metastatic disease, an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and adequate bone marrow, renal and liver function were eligible. Patients received vinorelbine (30 mg/m(2) on day 1) and UFT (250 mg/m(2) daily) every two weeks for 12 cycles unless progression or unacceptable toxicity was observed. RESULTS: Thirty-seven patients were included and received 311 cycles of chemotherapy. Efficacy and toxicity analyses were carried out on an intention-to-treat basis. The overall response rate was 35% (95% CI: 20-53). With a median follow-up of 18.6 months (95% CI: 1.0-74.3), the median time to progression was 7.0 months (96% CI: 5.2-8.9) and the median overall survival was 19.4 months (95% CI: 11.1-27.8). The most common severe toxicities were neutropenia (38% of patients) and asthenia (11% of patients). CONCLUSION: The combination of biweekly vinorelbine and UFT in patients with metastatic breast cancer pretreated with anthracyclines and taxanes is a well tolerated and effective regimen. AEMPS Trial Registration No.: 00-0534 (AU)

Alteraciones genéticas en el trastorno por déficit de atención con hiperactividad: relación con variables neuropsicológicas / Genetic variations in attention deficit hyperactivity disorder: relationship with neuropsychological variables

El Trastorno por Déficit de Atención con Hiperactividad (TDAH) es una patología frecuente de la infancia con una fuerte contribución genética. Tras unos años dedicados al estudio de los genes específicos que explicaban la sintomatología nuclear del trastorno (inatención, hiperactividad e impulsividad), en la actualidad el interés de los investigadores se ha ampliado, considerando la repercusión neuropsicológica que estas alteraciones genéticas tienen en los sujetos afectos de esta patología. En este trabajo revisamos la literatura existente sobre los correlatos genéticos de los déficits cognitivos del TDAH. Estas nuevas estrategias de investigación, necesariamente multidisciplinares, pretenden conseguir, además del incremento en la caracterización neurobiológica de esta patología, líneas de tratamiento alternativas a las existentes que respondan a la relación comentada entre genes y cognición en el TDAH

Attention Deficit/Hyperactivity Disorder (ADHD) is a frequent disorder in childhood with a strong genetic contribution. After a few years studying the specific genes that could explain the nuclear symptomatology of the disorder (inattention, hyperactivity, and impulsivity), actual research has been extended considering the neuropsychological repercussion that these genetic alterations have in subjects with ADHD. In this work we review the existing literature on the genetic basis of the cognitive deficits in ADHD. These new research strategies, necessarily multidisciplinary, try to explain a better neurobiological characterization of this pathology, plus alternative new lines of treatment based on the relationship between genes and cognition in ADHD

[Are IL2 receptor antagonist useful in high risk acute tubular necrosis kidney recipients?]. / Respuesta estructurada a preguntas clínicas (CAT: Critical Appraisal Topics) : en receptores con alto riesgo de desarrollar necrosis tubular aguda (NTA) post-trasplante. ?es útil la inducción con anticuerpos contra el receptor de la interleukina dos?

The questions are if old recipients from old donor have more incidence of delayed graft function and if antagonists of Il-2 receptors use decreased the incidence of NTA post-transplant. To answer the first question we have come to information from registry and uni or multicenter studies. We have used the Irish normograme that included 16 clinical questions from donors, recipients and kidney transplant. We concluded that age of donors increases likelihood of delayed graft function. The second question is answered in the literature with information of a meta-analysis with 38 clinical studies. Of them 9 (1.380 patients) studied delayed graft function and are against placebo. The odds ratio for delayed graft function was 0.87(IC 95% 0,72 a 1,06). Therefore, at the moment, we can conclude that the utilization of antagonists of Il-2 receptors does not have protective effect to NTA.

Respuesta estructurada a preguntas clínicas (CAT: Critical Appraisal Topics): en receptores con alto riego de desarrollar necrosis tubular aguda (NTA) post-trasplante. ¿Es útil la inducción con anticuerpos contra el receptor de la interleukina dos? / Are IL2 receptors antagonist useful in high risk acute tubular necrosis kidney recipients?

Se plantea si los receptores añosos de donantes añosos tienen más incidencia de NTA y si el uso de antagonistas del receptor de la IL2 contribuiría a disminuir la incidencia de función renal retrasada. Para responder a la primera cuestión se ha acudido a datos publicados de registros y a estudios uni o multicéntricos y se ha seleccionado el normograma de Irish que integra 16 variables clínicas del donante, receptor y trasplante, y se concluye que la edad del donante aumenta la probabilidad de desarrollar NTA. La segunda cuestión está respondida en la literatura en un meta-análisis que incluye 38 ensayos clínicos. De estos solamente 9 estudios (1.380 pacientes) registran la incidencia de función renal retrasada y están realizados contra placebo. En este subgrupo el riesgo relativo de padecer función renal retrasada en pacientes en los que se utilizan anticuerpos contra el receptor de la IL-2 vs placebo no alcanzó la significación estadística (0,87 IC95% 0,72 a 1,06). Por lo que de momento y hasta nuevos análisis podemos concluir que la utilización de antagonistas del receptor de la IL2 no tiene efecto protector para la aparición de NTA

The questions are if old recipients from old donor have more incidence of delayed graft function and if antagonists of Il-2 receptors use decreased the incidence of NTA post-transplant. To answer the first question we have come to information from registry and uni or multicenter studies. We have used the Irish normograme that included 16 clinical questions from donors, recipients and kidney transplant. We concluded that age of donors increases likelihood of delayed graft function. The second question is answered in the literature with information of a meta-analysis with 38 clinical studies. Of them 9 (1.380 patients) studied delayed graft function and are against placebo. The odds ratio for delayed graft function was 0.87(IC 95% 0,72 a 1,06). Therefore, at the moment, we can conclude that the utilization of antagonists of Il-2 receptors does not have protective effect to NTA

Weekly docetaxel as second-line therapy for patients with advanced breast cancer resistant to previous anthracycline treatment.

This phase II trial evaluated the efficacy and toxicity of weekly docetaxel as treatment of advanced metastatic breast cancer patients resistant to prior anthracycline chemotherapy. After the first 18 patients, the initial dose (40 mg/m2, 30-min i.v. infusion for 6 consecutive weeks, followed by 2-week rest) was reduced to 36 mg/m2 in the remaining 17 patients due to the incidence of toxicity (28% grade 3-4 asthenia). Overall response rate was 34% (95% CI, 19-50): two complete (6%) and ten partial responses (28%) were found. The median duration of response was 6.8 months, the median time to disease progression was 8.4 months, and the median overall survival was 13.6 months (median follow-up of 11.4 months). Neutropenia was the only severe hematologic toxicity (17% of patients), whereas asthenia, nail, ocular and skin disorders were the most common nonhematologic toxicities. Only one death during further follow-up was related to toxicity (caused by pulmonary fibrosis). In conclusion, we found weekly docetaxel to be an active and safe chemotherapy regimen for patients with metastatic breast resistant to previous anthracyclines. This weekly regimen caused minimal myelosupression, while retaining significant activity against advanced breast cancer. Both factors provide attractive possibilities for the development of combination therapies incorporating weekly docetaxel. Nevertheless, the number of patients receiving either dose (40 and 36 mg/m2) which we studied is low and our results require confirmation on larger groups of patients.

Effect of the surface treatment of plain carbon fiber posts on the retention of the composite core: an in vitro evaluation.

This study aims to evaluate the role of surface treatments performed on plain carbon fiber posts, in relation to serrated carbon fiber posts, in the retention of the composite core. Fifty carbon fiber posts received surface treatments in order to verify their influence on the retention of the core material. An acrylic resin mold was developed in order to precisely fit the post, leaving a machined space to accommodate a self-curing composite resin. After the surface treatment, a primer was applied on the coronal portion of all posts, which were then dried. They were fitted to the mold and received a 3 mm composite core. All specimens were thermocycled and then stored in distilled water for a week. Tension test was performed at a speed of 0.5 mm/min until there was lack of adhesion or fracture of the core. The conclusions were: a) the values of retention related to aluminum oxide spray (group A), depth cutter diamond burs (group C) and posts with machined coronal portion (group D) were comparable to those of serrated posts (group E), although no statistically significant difference between these groups was found; b) the mean values of core retention in group B (medium grit diamond burs) were statistically lower than those of other groups.

Tetramer dissociation and monomer partial unfolding precedes protofibril formation in amyloidogenic transthyretin variants.

Amyloid fibril formation and deposition is a common feature of a wide range of fatal diseases including spongiform encephalopathies, Alzheimer's disease, and familial amyloidotic polyneuropathies (FAP), among many others. In certain forms of FAP, the amyloid fibrils are mostly constituted by variants of transthyretin (TTR), a homotetrameric plasma protein. Recently, we showed that transthyretin in solution may undergo dissociation to a non-native monomer, even under close to physiological conditions of temperature, pH, ionic strength, and protein concentration. We also showed that this non-native monomer is a compact structure, does not behave as a molten globule, and may lead to the formation of partially unfolded monomeric species and high molecular mass soluble aggregates (Quintas, A., Saraiva, M. J. M., and Brito, R. M. M. (1999) J. Biol. Chem. 274, 32943-32949). Here, based on aging experiments of tetrameric TTR and chemically induced protein unfolding experiments of the non-native monomeric forms, we show that tetramer dissociation and partial unfolding of the monomer precedes amyloid fibril formation. We also show that TTR variants with the least thermodynamically stable non-native monomer produce the largest amount of partially unfolded monomeric species and soluble aggregates under conditions that are close to physiological. Additionally, the soluble aggregates formed by the amyloidogenic TTR variants showed morphological and thioflavin-T fluorescence properties characteristic of amyloid. These results allowed us to conclude that amyloid fibril formation by some TTR variants might be triggered by tetramer dissociation to a compact non-native monomer with low conformational stability, which originates partially unfolded monomeric species with a high tendency for ordered aggregation into amyloid fibrils. Thus, partial unfolding and conformational fluctuations of molecular species with marginal thermodynamic stability may play a crucial role on amyloid formation in vivo.

Aesthetic and adhesive cementation for contemporary porcelain crowns.

The evolution of aesthetic restorative materials has led to the development of new preparation designs and cementation protocols. While conventional cements were able to provide mechanical and macromechanical retention for restorations with limited aesthetic expectations, resin cements with micromechanical retention have been formulated as aesthetic alternatives. The objective of the present article is to establish the differences between conventional and adhesive crown cementation techniques, as well as to provide guidelines for reducing postoperative sensitivity and improving aesthetic and functional results.

Comparative calorimetric study of non-amyloidogenic and amyloidogenic variants of the homotetrameric protein transthyretin.

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant hereditary type of amyloidosis involving amino acid substitutions in transthyretin (TTR). V30M-TTR is the most frequent variant, and L55P-TTR is the variant associated with the most aggressive form of FAP. The thermal stability of the wild-type, V30M-TTR, L55P-TTR and a non-amyloidogenic variant, T119M-TTR, was studied by high-sensitivity differential scanning calorimetry (DSC). The thermal unfolding of TTR is a spontaneous reversible process involving a highly co-operative transition between folded tetramers and unfolded monomers. All variants of transthyretin are very stable to the thermal unfolding that occurs at very high temperatures, most probably because of their oligomeric structure. The data presented in this work indicated that for the homotetrameric form of the wild-type TTR and its variants, the order of stability is as follows: wild-type TTR approximately > T119M-TTR > L55P-TTR > V30M-TTR, which does not correlate with their known amyloidogenic potential.

Aesthetic posts and cores for metal-free restoration of endodontically treated teeth.

Utilization of contemporary post and core systems has facilitated the aesthetic restoration of endodontically treated teeth. Light transmission and biocompatibility have been enhanced by the introduction of metal-free post systems. The periodontal and endodontic status, root length, and histological structure of the devitalized teeth must be considered in order to achieve successful restoration following endodontic treatment. This article presents various restorative criteria for the aesthetic placement and buildup of post and core materials, as well as the preservation of maximum coronal and root structure.

The tetrameric protein transthyretin dissociates to a non-native monomer in solution. A novel model for amyloidogenesis.

In amyloidosis, normally innocuous soluble proteins polymerize to form insoluble fibrils. Amyloid fibril formation and deposition have been associated with a wide range of diseases, including spongiform encephalopathies, Alzheimer's disease, and familial amyloid polyneuropathies (FAP). In certain forms of FAP, the amyloid fibrils are mostly constituted by variants of transthyretin (TTR), a homotetrameric plasma protein implicated in the transport of thyroxine and retinol. The most common amyloidogenic TTR variant is V30M-TTR, and L55P-TTR is the variant associated with the most aggressive form of FAP. Recently, we reported that TTR dissociates to a monomeric species at pH 7.0 and nearly physiological ionic strengths (Quintas, A., Saraiva, M. J., and Brito, R. M. (1997) FEBS Lett. 418, 297-300). Here, we show that the tetramer dissociation is apparently irreversible; and based on intrinsic tryptophan fluorescence and fluorescence quenching experiments, we show that the monomeric species formed upon tetramer dissociation is non-native. We also show, based on 1-anilino-8-naph-thalenesulfonate binding studies, that this monomeric species appears not to behave like a molten globule. These data allowed us to propose a model for TTR amyloidogenesis based on tetramer dissociation occurring naturally under commonly observed physiological solution conditions.

Correlation and prognostic value of serum soluble ICAM-1, beta-2 microglobulin, and IL-2alphaR levels in non-Hodgkin's lymphoma.

Serum levels of sICAM-1, sIL-2alphaR, and beta-2 microglobulin were measured in 63 patients with non-Hodgkin's lymphoma (NHL). The correlation between these serum markers as well as their relationship with NHL features and disease outcome were analyzed. Although in high-grade NHL sICAM-1 levels correlated with tumor mass, no correlation was found between sICAM-1 levels and tumor burden in low-grade NHL. When compared with sICAM-1 and beta-2 microglobulin, sIL-2alphaR showed the strongest correlation with the tumor burden. However, in multivariate analysis, including serum markers employed as continuous variables, the only parameteres which entered the regression model were beta-2 microglobulin (p=0.012) and sICAM-1 (p=0.019). In a dichotomized model, beta-2 microglobulin, aggressive histology, sICAM-1, age and number of nodal involved sites were found to be prognostically significant. Finally, by combining sICAM-1 and beta-2 microglobulin serum levels, a simple prognostic model useful for NHL was obtained.

Stomatococcus mucilaginosus septicemia in a patient with acute lymphoblastic leukaemia.

A 16-year-old patient with acute lymphoblastic leukaemia which had relapsed for the third time developed clinical signs and symptoms of septicemia during a period of neutropenia. The patient had signs of oral mucositis, and Stomatococcus mucilaginosus was isolated from blood cultures. The patient responded well to antibiotic therapy. The biochemical characteristics and antimicrobial susceptibility patterns of 68 other pharyngeal isolates of Stomatococcus mucilaginosus from immunocompromised patients are presented.

The role of poly(ADP-ribose)polymerase in the induction of sister chromatid exchanges and micronuclei by mitomycin C in Down's syndrome cells as compared to euploid cells.

Inhibitors of poly(ADP-ribose)polymerase (PARP; EC 2.4.2.30), such as 3-aminobenzamide (3-AB), can be used to assess the role of the enzyme in the induction of DNA lesions in euploid cells as compared to cells of genetic conditions known to exhibit increased susceptibility to chemical or physical mutagens, such as Down's syndrome (DS) lymphocytes. We report in this work on the effect of PARP inhibition by 3-AB in the induction of sister chromatid exchanges (SCE) and micronuclei (MN) in DS lymphocytes as compared to lymphocytes from normal controls exposed in vitro to a gradient of mitomycin C (MMC). For both types of cells, DS and normal lymphocytes, MMC induces a significant increase in frequencies of SCE and MN in the absence and in the presence of 3-AB. In the presence of 3-AB the yield of SCE and MN induced by MMC was significantly higher in normal lymphocytes as compared to lymphocytes from DS patients. The molecular mechanisms by which 3-AB affects the yield of SCE and MN remains to be fully elucidated; however, it seems clear that DS patients display a different behavior in what concerns poly(ADP-ribosyl)ation as compared to normal individuals.

The amyloidogenic potential of transthyretin variants correlates with their tendency to aggregate in solution.

Amyloid fibril formation and deposition are the basis for a wide range of diseases, including spongiform encephalopathies, Alzheimer's and familial amyloidotic polyneuropathies. However, the molecular mechanisms of amyloid formation are still poorly characterised. In certain forms of familial amyloidotic polyneuropathy (FAP), the amyloid fibrils are mostly constituted by variants of transthyretin (TTR). V30M-TTR is the most frequent variant, and L55P-TTR is the variant associated with the most aggressive form of amyloidosis. Here, we report gel filtration chromatography experiments to characterise the aggregation states of WT-, V30M-, L55P-TTR and a non-amyloidogenic variant, T119M-TTR, in solution, at nearly physiological pH. These studies show that all four protein tetramers dissociate to monomer upon dilution, in the submicromolar range, at pH 7.0. The amyloidogenic proteins V30M- and L55P-TTR show a complex equilibrium between monomers, tetramers and high molecular weight aggregate species. These aggregates dissociate directly to monomer upon dilution. This study shows that the tendency to form aggregates among the four studied proteins correlates with their known amyloidogenic potential. Thus, the amyloidogenic mutations could perturb the structure and/or stability of the monomeric species leading initially to the formation of soluble aggregates and at a later stage to insoluble amyloid fibrils.