Evolution of tyrosinemia type 1 disease in patients treated with nitisinone in Spain.

Treatment with nitisinone (NTBC) has brought about a drastic improvement in the treatment and prognosis of hereditary tyrosinemia type I (HT1). We conducted a retrospective observational multicentric study in Spanish HT1 patients treated with NTBC to assess clinical and biochemical long-term evolution.We evaluated 52 patients, 7 adults and 45 children, treated with NTBC considering: age at diagnosis, diagnosis by clinical symptoms, or by newborn screening (NBS); phenotype (acute/subacute/chronic), mutational analysis; symptoms at diagnosis and clinical course; biochemical markers; doses of NTBC; treatment adherence; anthropometric evolution; and neurocognitive outcome.The average follow-up period was 6.1 ±â€Š4.9 and 10.6 ±â€Š5.4 years in patients with early and late diagnosis respectively. All patients received NTBC from diagnosis with an average dose of 0.82 mg/kg/d. All NBS-patients (n = 8) were asymptomatic at diagnosis except 1 case with acute liver failure, and all remain free of liver and renal disease in follow-up. Liver and renal affectation was markedly more frequent at diagnosis in patients with late diagnosis (P < .001 and .03, respectively), with ulterior positive hepatic and renal course in 86.4% and 93.2% of no-NBS patients, although 1 patient with good metabolic control developed hepatocarcinoma.Despite a satisfactory global nutritional evolution, 46.1% of patients showed overweight/obesity. Interestingly lower body mass index was observed in patients with good dietary adherence (20.40 ±â€Š4.43 vs 24.30 ±â€Š6.10; P = .08) and those with good pharmacological adherence (21.19 ±â€Š4.68 vs 28.58 ±â€Š213.79).intellectual quotient was ≥85 in all NBS- and 68.75% of late diagnosis cases evaluated, 15% of which need pedagogical support, and 6.8% (3/44) showed school failure.Among the 12 variants identified in fumarylacetoacetate hydrolase gene, 1 of them novel (H63D), the most prevalent in Spanish population is c.554-1 G>T.After NTBC treatment a reduction in tyrosine and alpha-fetoprotein levels was observed in all the study groups, significant for alpha-fetoprotein in no NBS-group (P = .03), especially in subacute/chronic forms (P = .018).This series confirms that NTBC treatment had clearly improved the prognosis and quality of life of HT1 patients, but it also shows frequent cognitive dysfunctions and learning difficulties in medium-term follow-up, and, in a novel way, a high percentage of overweight/obesity.

Simple Endoscopic Score of Crohn Disease and Magnetic Resonance Enterography in Children: Report From ImageKids Study.

OBJECTIVES: We aimed to explore the ability of magnetic resonance enterography (MRE) to impute the simple endoscopic score of Crohn disease (SES-CD) in children with CD, in whom failure of ileal intubation is common and may impair SES-CD calculation in clinical studies. METHODS: This is a substudy of the prospective ImageKids study in which children with CD underwent ileocolonoscopy (scored by SES-CD) and MRE (scored on a 100 mm visual analogue scale [VAS] and by MaRIA). Mucosal healing (MH) was defined as SES-CD <3, MRE-VAS <20 mm, and/or MaRIA <7. RESULTS: A total of 237 children (22 centers, age 11.5 ±â€Š3.3 years), were enrolled. Ileal intubation has failed in 40 of 237 (17%). The agreement between SES-CD and MRE was 75% (k = 0.508, P < 0.001) in the ileum, and 68% to 85% in the colonic segments (k = 0.21-0.50, P < 0.001). The sensitivity and specificity of ileal MRE-VAS for MH were 91.7% (95% confidence interval 0.84-0.96) and 53.1% (95% confidence interval 0.43-0.63), respectively. The ileal MaRIA score (calculated in 33/40) was higher in the children without ileal intubation than in the others (20.5 ±â€Š7.1 vs 15.1 ±â€Š10.8, respectively, P = 0.0018). In 7% (16/237) of children, isolated active ileal disease would have been missed when considering SES-CD only. A multivariable model predicted the ileal SES-CD subscore from the MaRIA: SES-CDileum = 1.145 + 0.169 × MaRIAileum rounded to the nearest whole number (R = 0.17). Applying this model to the children without ileal intubation revealed that 29 of 33 (88%) had ileal disease; 8 of 29 patients (28%) with normal colonic SES-CD had imputed ileal SES-CD ≥3. CONCLUSIONS: MRE is useful for imputing the ileal disease in pediatric clinical studies, overcoming the problem of ileal nonintubation.

Serine Phosphorylation of SLP76 Is Dispensable for T Cell Development but Modulates Helper T Cell Function.

The adapter protein SLP76 is a key orchestrator of T cell receptor (TCR) signal transduction. We previously identified a negative feedback loop that modulates T cell activation, involving phosphorylation of Ser376 of SLP76 by the hematopoietic progenitor kinase 1 (HPK1). However, the physiological relevance of this regulatory mechanism was still unknown. To address this question, we generated a SLP76-S376A-expressing knock-in mouse strain and investigated the effects of Ser376 mutation on T cell development and function. We report here that SLP76-S376A-expressing mice exhibit normal thymocyte development and no detectable phenotypic alterations in mature T cell subsets or other lymphoid and myeloid cell lineages. Biochemical analyses revealed that mutant T cells were hypersensitive to TCR stimulation. Indeed, phosphorylation of several signaling proteins, including SLP76 itself, phospholipase Cγ1 and the protein kinases AKT and ERK1/2, was increased. These modifications correlated with increased Th1-type and decreased Th2-type cytokine production by SLP76-S376A T cells, but did not result in significant changes of proliferative capacity nor activation-induced cell death susceptibility. Hence, our results reveal that SLP76-Ser376 phosphorylation does not mediate all HPK1-dependent regulatory effects in T cells but it fine-tunes helper T cell responses.

Key experimental evidence of chromosomal DNA transfer among selected tuberculosis-causing mycobacteria.

Horizontal gene transfer (HGT) is a major driving force of bacterial diversification and evolution. For tuberculosis-causing mycobacteria, the impact of HGT in the emergence and distribution of dominant lineages remains a matter of debate. Here, by using fluorescence-assisted mating assays and whole genome sequencing, we present unique experimental evidence of chromosomal DNA transfer between tubercle bacilli of the early-branching Mycobacterium canettii clade. We found that the obtained recombinants had received multiple donor-derived DNA fragments in the size range of 100 bp to 118 kbp, fragments large enough to contain whole operons. Although the transfer frequency between M. canettii strains was low and no transfer could be observed among classical Mycobacterium tuberculosis complex (MTBC) strains, our study provides the proof of concept for genetic exchange in tubercle bacilli. This outstanding, now experimentally validated phenomenon presumably played a key role in the early evolution of the MTBC toward pathogenicity. Moreover, our findings also provide important information for the risk evaluation of potential transfer of drug resistance and fitness mutations among clinically relevant mycobacterial strains.

Farmacocinética, eficacia y seguridad de la formulación de mesalazina MMX en el tratamiento de la colitis ulcerosa / Pharmacokinetics: efficacy and safety of MMX mesalamine formulation for treating ulcerative colitis

La mesalazina-MMX® es una formulación gastrorresistente de 5 ASA con tecnología Multi-Matrix para lograr la administración retardada y prolongada de alta dosis de mesalazina por todo el colon. En los ensayos clínicos se ha demostrado la eficacia clínica y endoscópica, para inducir remisión. Con dosis de 2,4-4,8 g/día (2-4 comprimidos en dosis única diaria) se consigue una remisión clínica y endoscópica del 29,2% al 41,2% tras 8 semanas de tratamiento, frente al placebo (12,9% y el 22,2%, respectivamente). Esta formulación ha demostrado eficacia similar al tratamiento tópico en la inducción de remisión en colitis izquierda (remisión clínica del 60% tras 8 semanas con mesalazina-MMX frente al 50% con tratamiento tópico). Aunque las tasas de remisión en el tratamiento de inducción son similares a las obtenidas con mesalazina convencional, los ensayos con mesalazina-MMX utilizan criterios más rigurosos (mejoría endoscópica). El 88,9% de los pacientes tratados con 2,4 g/día en dosis única no recidivaron tras 12 meses. El perfil de seguridad es similar al de las mesalazinas estándar. La formulación MMX es un tratamiento prometedor para pacientes con CU, por los datos de eficacia y la comodidad posológica que puede mejorar el cumplimiento terapéutico.

Lactobacillus fermentum CECT 5716 is safe and well tolerated in infants of 1-6 months of age: a randomized controlled trial.

The objective of the study was to evaluate the safety and tolerance of an infant formula supplemented with Lactobacillus fermentum CECT5716, a probiotic strain isolated from breast milk, in infants of 1-6 months of age. A randomized double blinded controlled study including healthy infants was conducted. One month aged infants received a prebiotic infant formula supplemented with L. fermentum (experimental group) or the same formula without the probiotic strain (control group) for 5 months. The primary outcome of the study was average daily weight gain between baseline and 4 months of age. Secondary outcomes were other anthropometric data (length and head circumference), formula consumption, and tolerance. Incidence of infections was also recorded by pediatricians. No significant differences in weight gain were observed between both groups, neither at 4 months of age (29.0±7.8 vs 28.9±5.7g/day) nor at 6 months (25.1±6.1 vs 24.7±5.2g/day). There were no statistically significant differences in the consumption of the formulae or symptoms related to the tolerance of the formula. The incidence rate of gastrointestinal infections in infants of the control group was 3 times higher than in the probiotic group (p=0.018). Therefore, consumption of a prebiotic infant formula enriched with the human milk probiotic strain L. fermentum CECT5716 from 1 to 6 months of life is well tolerated and safe. Furthermore, the consumption of this formula may improve the health of the infants by reducing the incidence of gastrointestinal infections.

Lanthanum carbonate reduces FGF23 in chronic kidney disease Stage 3 patients.

BACKGROUND: In chronic kidney disease (CKD) patients, the ability to excrete a phosphate load is impaired. Compensatory increase in parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) promote phosphaturia. Serum FGF23 concentration is considered an early biomarker of excess phosphate load and high levels of FGF23 have been associated with increased mortality. In the present study, we have evaluated the changes in plasma FGF23 after treatment with the phosphate binder lanthanum carbonate in patients with CKD-3 and a normal serum phosphate concentration. METHODS: Eighteen Caucasian CKD Stage 3a/3b patients with serum phosphate <4.5 mg/dL were recruited in a prospective longitudinal open-label study. Patients received a 4-week period of standardized phosphorus-restricted diet containing 0.8 g/Kg/day protein. Thereafter, the same diet was maintained and patients received lanthanum carbonate (750 mg with the three main meals) for 4 weeks. RESULTS: No significant changes were observed in serum phosphate, however, lanthanum carbonate significantly decreased urinary excretion of phosphate and fractional excretion of phosphate (P < 0.004). This was accompanied by a significant decrease in carboxyterminal FGF23 (median percent change from baseline -21.8% (interquartile range -4.5, -30%), P = 0.025). No changes were observed in PTH. CONCLUSIONS: In conclusion, lanthanum carbonate reduced phosphate load, as assessed by urinary phosphate excretion, and also reduced plasma FGF23 in CKD-3 patients. This occurs in the presence of unchanged normal serum phosphate levels.

Estudio de la situación de discapacidad en pacientes psiquiátricos crónicos atendidos en el Centro Alfonso Cortez / Study the situation of disability in chronic psychiatric patients treated at the Center Alfonso Cortez

Se realizó un estudio descriptivo de corte transversal en el Centro de Atención Psicosocial (CAPS) “Alfonso Cortez” de la Ciudad de León, Nicaragua para identificar el grado de discapacidad de sus pacientes psiquiátricos crónicos, como resultado de la aplicación de una estrategia de rehabilitación psicosocial ambulatoria.Para medir el nivel de discapacidad, se aplicó el instrumento WHO/DAS de la OMS, el cual evalúa las cuatro áreas del funcionamiento: higiene personal, funcionamiento ocupacional, funcionamiento familiar y funcionamiento en el contexto social general. Se obtuvo como resultado que la mayoría de los pacientes se encontraban entre los 15 y los 49 años de edad, con un nivel educacional de primaria, provenientes del área urbana, de religión católica y del sexo masculino. El diagnóstico predominante fue el de epilepsia y la discapacidad tenia al menos un año de duración en la totalidad de los casos. Todos los pacientes presentaron al menos un grado de discapacidad en alguna de las áreas del funcionamiento, sin embargo todos los casos fueron en el rango de las disfunciones mínimas a moderadas. El área mas afectada para los hombres fue la del funcionamiento familiar y para las mujeres la del funcionamiento ocupacional. La estrategia de rehabilitación ambulatoria basada en la comunidad utilizada por el personal del CAPS se tradujo en un menor deterioro del funcionamiento global de sus usuarios crónicos y una mayor calidad de vida de los mismos.A pesar de no contar con un Protocolo en Rehabilitación la gran mayoría del personal tiene conocimientos adecuados acerca del concepto, objetivo, fases e importancia de la misma...

[Retrospective analysis of the efficacy and tolerability of anagrelide in patients with essential thrombocytemia: Spanish registry of essential thrombocytemia]. / Análisis retrospectivo de la eficacia y la tolerabilidad de anagrelida en pacientes con trombocitemia esencial: registro español de trombocitemia esencial.

BACKGROUND AND OBJECTIVE: A retrospective analysis of a registration database was used to assess the efficacy and tolerability of anagrelide for treating essential thrombocythemia (ET). The study was conducted by analysing information on response to treatment, time to response and tolerability. PATIENTS AND METHOD: A total of 411 patients with ET from 54 centres in Spain were included in a retrospective chart review. Patients who had started treatment with anagrelide as a first- or second-line therapy before December 31, 2004 were included. RESULTS: Of 411 patients, anagrelide was given as a first-line therapy in 110 patients, following hydroxyurea in 280 patients, and following other drugs in 21 patients. Overall response (OR) with anagrelide was 81.2% (77,0-84,9; p=0,05). Complete response (platelets <400x10(9)/L) was observed in 53.6% (48,6-58,5; p=0,05) and partial response (<600x10(9)/L) in 27.6% (23,4-32,2; p=0,05) of patients. There was no significant correlation of previous treatment with OR rate (p=0.103) despite a higher OR for previously untreated patients (86.4%) than for previously treated patients (79.3%). The most frequent treatment-related adverse reactions were headache (13.1%), palpitations (10.2%) and tachycardia (7.5%). CONCLUSIONS: The observed response rates and tolerability profile are similar to those reported previously. Anagrelide is well tolerated and effective in reducing platelets to target levels in patients with ET.

Análisis retrospectivo de la eficacia y la tolerabilidad de anagrelida en pacientes con trombocitemia esencial: registro español de trombocitemia esencial / Retrospective analysis of the efficacy and tolerability of anagrelide in patients with essential thrombocytemia: Spanish registry of essential thrombocytemia

Fundamento y objetivo: Se efectuó un registro retrospectivo para valorar la eficacia y la tolerabilidad de la anagrelida en el tratamiento de la trombocitemia esencial (TE). Se analizó la información de la respuesta al tratamiento, el tiempo transcurrido hasta la respuesta y la tolerabilidad. Pacientes y método: Registro retrospectivo de 411 pacientes con TE de 54 centros españoles. Se incluyó a enfermos que habían empezado a recibir anagrelida como tratamiento de primera o segunda línea antes del 31 de diciembre de 2004. Resultados: De los 411 pacientes, a 110 se les administró anagrelida como tratamiento de primera línea, a 280 después de hidroxicarbamida y a 21 después de otros fármacos. La respuesta global (RG) con anagrelida fue del 81,2% (intervalo de confianza [IC] del 95%: 77,0 a 84,9). Se observó una respuesta completa (recuento de plaquetas<400×109/l) en el 53,6% de los pacientes (IC del 95%: 48,6 a 58,5) y una respuesta parcial (<600×109/l) en el 27,6% (IC del 95%: 23,4 a 32,2). No hubo una correlación significativa entre el tratamiento previo y la tasa de RG (p=0,103), a pesar de una RG mayor en los pacientes no tratados previamente (86,4%) que en los tratados previamente (79,3%). Los acontecimientos adversos más frecuentes relacionados con el tratamiento fueron cefalea (13,1%), palpitaciones (10,2%) y taquicardia (7,5%). Conclusiones: Las tasas de respuesta y el perfil de tolerabilidad son similares a los descritos con anterioridad. La anagrelida tiene buena tolerancia y es eficaz en la reducción de las plaquetas hasta los valores deseados en los pacientes con TE

Background and objective: A retrospective analysis of a registration database was used to assess the efficacy and tolerability of anagrelide for treating essential thrombocythemia (ET). The study was conducted by analysing information on response to treatment, time to response and tolerability. Patients and method: A total of 411 patients with ET from 54 centres in Spain were included in a retrospective chart review. Patients who had started treatment with anagrelide as a first- or second-line therapy before December 31, 2004 were included. Results: Of 411 patients, anagrelide was given as a first-line therapy in 110 patients, following hydroxyurea in 280 patients, and following other drugs in 21 patients. Overall response (OR) with anagrelide was 81.2% (77,0 84,9; p=0,05). Complete response (platelets <400×109/L) was observed in 53.6% (48,6 58,5; p=0,05) and partial response (<600×109/L) in 27.6% (23,4 32,2; p=0,05) of patients. There was no significant correlation of previous treatment with OR rate (p=0.103) despite a higher OR for previously untreated patients (86.4%) than for previously treated patients (79.3%). The most frequent treatment-related adverse reactions were headache (13.1%), palpitations (10.2%) and tachycardia (7.5%). Conclusions: The observed response rates and tolerability profile are similar to those reported previously. Anagrelide is well tolerated and effective in reducing platelets to target levels in patients with ET

Inhaled IL-2 induces systemic immunomodulation in patients with renal cell carcinoma and lung metastasis.

The peripheral blood lymphocytes of eight patients with metastatic renal cell carcinoma, and of eight healthy volunteers were analyzed by four-color flow cytometry to characterize the immunophenotypic alterations manifested, determine the prevalence of lymphocyte apoptosis, and detect evidence of the systemic effect of inhaled IL-2. The T, B and NK lymphocytes of untreated patients were found to have undergone profound changes characterized by an increase in susceptibility to both spontaneous and mitogen-induced ex vivo apoptosis, a modified distribution of the main lymphocyte populations in the peripheral blood, and alterations in activation status. An increase in the proportion of regulatory T cells was also seen in these patients. Treatment with inhaled IL-2, however, normalized the rate of apoptosis in all the lymphocyte subpopulations studied, as well as their distribution and activation status. These findings demonstrate that inhaled IL-2 has systemic immunomodulatory effects.

Retrospective review in patients with pulmonary metastases of renal cell carcinoma receiving inhaled recombinant interleukin-2.

Pulmonary metastases of renal cell carcinoma are associated with poor prognosis. Systemic interleukin-2 is used to treat pulmonary metastases of renal cell carcinoma; however, its toxicity limits its use. The objective of this study was to evaluate the efficacy and safety of inhaled interleukin-2 in pulmonary metastases of renal cell carcinoma patients. The study was designed as a retrospective chart review in pulmonary metastases of renal cell carcinoma patients treated with inhaled interleukin-2. Between 2000 and 2004, 19 centres in Spain and two in Portugal recruited 51 patients. The treatment schedule was as follows: three cycles of 36 MIU interleukin-2 per day for 5 days/week for 12 weeks (with 1 treatment-free week between cycles) in Spain and for 3 weeks (out of each 4 weeks) for 12 weeks in Portugal. Efficacy was assessed by best response following each treatment cycle and at final evaluation. Kaplan-Meier method was used to estimate progression-free survival and overall survival. Safety data were analysed using descriptive statistics, with toxicities expressed in number of weeks, which were reported. Overall objective response rate was 13.7% (95% confidence interval: 5.7-26.3). Median progression-free survival and overall survival were 8.6 (95% confidence interval: 3.45-16.5) and 23 (95% confidence interval: 11.5-34.5) months. The most common toxicities were cough (40% of cycles) and fatigue (7%). The majority of weeks of toxicities were reported to be only grade 1 or 2 in severity. Inhaled interleukin-2 shows efficacy and mild toxicity of pulmonary metastases of renal cell carcinoma patients, and might be considered as an alternative treatment to the systemic administration of this drug in these patients.

Interleukin-2 for the treatment of solid tumors other than melanoma and renal cell carcinoma.

Interleukin-2 (IL-2) is a lymphokine produced by T cells whose main function is to stimulate the growth and cytotoxic response of activated T lymphocytes. It has been used to stimulate the immune system for the treatment of multiples tumors. This article is intended to review the reports published from 1990 to 2004 on the IL-2 treatment of tumors other than melanoma and renal carcinoma. A literature search was made in various databases (MEDLINE, EMBASE and BioAssay), focused on IL-2 clinical efficacy in such tumors. A selection was made over 150 publications reporting on administration of IL-2 in multiple tumors: lung carcinoma (small cell and non-small cell), colorectal, gastric, pancreatic, ovarian and breast cancer, sarcomas, hepatocarcinoma, mesothelioma, and brain, urological, and head and neck tumors. IL-2 was mainly used in metastatic disease, associated with other immunotherapy or chemotherapy schedules. We conclude that adjuvant IL-2 may be of value in early stages combined with standard treatment for colon and pancreas cancers. In other neoplasms, the indication for adjuvant IL-2 has been sporadic and does not allow conclusions to be drawn. Assessment of the efficacy of IL-2 combined with chemotherapy as treatment for advanced stages is complex, due to the lack of a control, and the variety of dosages and schemes. The activity of IL-2 in monotherapy or in association with immunotherapy is clinically relevant in hepatocarcinoma, mesothelioma and in malignant overflows as palliative treatment. Randomized trials would be required in order to be able to draw conclusions about its indication in other tumors.