Cytogenetic characterisation of childhood acute lymphoblastic leukemia in Nicaragua

BACKGROUND: Within the frame of a twinning programme with Nicaragua, The La Mascota project, we evaluated in our study the contribution of cytogenetic characterization of acute lymphoblastic leukemia (ALL) as prognostic factor compared to clinical, morphological, and immunohistochemical parameters. METHODS: All patients with ALL treated at the only cancer pediatric hospital in Nicaragua during 2006 were studied prospectively. Diagnostic immunophenotyping was performed locally and bone marrow or blood samples were sent to the cytogenetic laboratory of Zurich for fluorescence in situ hybridization (FISH) analysis and G-banding. RESULTS: Sixty-six patients with ALL were evaluated. Their mean age at diagnosis was 7.3 years, 31.8% were >or=10 years. Thirty-four patients (51.5%) presented with hyperleucocytosis >or=50 x 10(9)/L, 45 (68.2%) had hepatosplenomegaly. Immunophenotypically 63/66 patients (95%) had a B-precursor, 2 (3%) a T- and 1 (1.5%) a B-mature ALL. FISH analysis demonstrated a TEL/AML1 fusion in 9/66 (14%), BCR/ABL fusion in 1 (1.5%), MLL rearrangement in 2 (3.1%), iAMP21 in 2 (3.1%), MYC rearrangement in 1 (1.5%), and high-hyperdiploidy in 16 (24%). All patients but two with TEL/AML1 fusion and high-hyperdiploidy were clinically and hematologically in the standard risk group whereas those with poor cytogenetic factors had clinical high-risk features and were treated intensively. CONCLUSIONS: Compared to Europe, the ALL population in Nicaragua is older, has a higher proportion of poor prognostic clinical and hematological features and receives more intensive treatment, while patients with TEL/AML1 translocations and high-hyperdiploidy are clinically in the standard risk group. Cytogenetics did not contribute as an additional prognostic factor in this setting.

Involvement of nuclear factor-kappaB in macrophage migration inhibitory factor gene transcription up-regulation induced by interleukin- 1 beta in ectopic endometrial cells.

OBJECTIVE: To investigate the involvement of the nuclear factor (NF)-kappaB in the interleukin (IL)-1 beta-mediated macrophage migration inhibitory factor (MIF) gene activation. DESIGN: Prospective study. SETTING: Human reproduction research laboratory. PATIENT(S): Nine women with endometriotic lesions. INTERVENTION(S): Endometriotic lesions were obtained during laparoscopic surgery. MAIN OUTCOME MEASURE(S): The MIF protein secretion was analyzed by ELISA, MIF mRNA expression by quantitative real-time polymerase chain reaction (PCR), NF-kappaB translocation into the nucleus by electrophoresis mobility shift assay, I kappaB phosphorylation and degradation by Western blot, and human MIF promoter activity by transient cell transfection. RESULT(S): This study showed a significant dose-dependent increase of MIF protein secretion and mRNA expression, the NF-kappaB translocation into the nucleus, I kappaB phosphorylation, I kappaB degradation, and human MIF promoter activity in endometriotic stromal cells in response to IL-1 beta. Curcumin (NF-kappaB inhibitor) significantly inhibited all these IL-1 beta-mediated effects. Analysis of the activity of deletion constructs of the human MIF promoter and a computer search localized two putative regulatory elements corresponding to NF-kappaB binding sites at positions -2538/-2528 bp and -1389/-1380 bp. CONCLUSION(S): This study suggests the involvement of the nuclear transcription factor NF-kappaB in MIF gene activation in ectopic endometrial cells in response to IL-1 beta and identifies a possible pathway of endometriosis-associated inflammation and ectopic cell growth.

La força de prensió manual com a factor pronòstic de mortalitat en pacients oncològics terminals a una unitat de cures pal•liatives.

L’objectiu de l’estudi va ser determinar si la força de prensió manual (FPM) era factor pronòstic de mortalitat en malalts amb càncer avançant ingressats a una Unitat de cures pal•liatives (UCP). Es va determinar la força de prensió a l’ingrés i l’evolució de la FPM els primers 12 dies mitjançant un dinamòmetre. Ni la FPM inicial ni a l’evolució va demostrar diferències significatives entre els malalts donats d’alta vius i els que van morir a la UCP. Conclusions: la determinació de FPM no va ser factor pronòstic de supervivència en malalts ingressats per càncer en una UCP.

Expressió de VEGF com a factor pronòstic independent de recaiguda a la malaltia de Hodgkin.

El paper del fenomen angiogènic en els diferents tumors sòlids ha estat l’objectiu de nombrosos estudis en els darrers anys. La importància d’aquest procés en les neoplàsies d’origen hematològic encara és bastant desconeguda. En aquest treball hem estudiat l’expressió immunohistoquímica del factor de creixement de l’endoteli vascular (VEGF) en els “tissue microarrays” (TMA) de 252 pacients diagnosticats de limfoma de Hodgkin tractats de forma homogènia (poliquimioteràpia esquema ADVD amb o sense radioteràpia) entre els anys 1978 i 2003. Els resultats s’han correlacionat amb l’evolució dels pacients i s’ha avaluat la seva importància en la supervivència lliure de malaltia i supervivencia global de la sèrie.

Blunted glucose-induced thermogenesis in 'overweight' patients: a factor contributing to relapse of obesity.

Glucose-induced thermogenesis was studied in 12 overweight patients (9F and 3M) before (mean body weight +/- s.e.m. 83 +/- 2 kg) and after weight loss (68 +/- 2 kg), and in eight of the same patients following relapse of body weight gain (84 +/- 5 kg). Expressed as a percentage of the energy content of the 100 g oral glucose load, glucose-induced thermogenesis was lower in the overweight before weight loss (6.5 +/- 0.5 per cent, P less than 0.05), after weight loss (3.9 +/- 0.6 per cent, P less than 0.01) and after weight regain (6.3 +/- 0.9 per cent, P less than 0.05) than in a group of lean control subjects, matched for sex and age (8.3 +/- 0.5 per cent). Basal energy expenditure was lower after weight reduction than before (1.16 +/- 0.04 vs 1.41 +/- 0.08 kcal/min, P less than 0.01). In the formerly overweight patients, the combined effect of a decreased basal energy expenditure and an attenuation of glucose induced thermogenesis resulted in a postprandial energy expenditure which was markedly lower than in the overweight state (P less than 0.001). Following relapse of obesity, glucose-induced thermogenesis remained attenuated compared to control subjects. These results suggest that a lowered basal energy expenditure and a reduced glucose-induced thermogenesis contribute to the positive energy balance which results in relapse of body weight gain after cessation of a hypocaloric diet.

Role of fibroblast growth factor (FGF) signaling in the neuroendocrine control of human reproduction.

Fibroblast growth factor (FGF) signaling is critical for a broad range of developmental processes. In 2003, Fibroblast growth factor receptor 1 (FGFR1) was discovered as a novel locus causing both forms of isolate GnRH Deficiency, Kallmann syndrome [KS with anosmia] and normosmic idiopathic hypogonadotropic hypogonadism [nIHH] eventually accounting for approximately 10% of gonadotropin-releasing hormone (GnRH) deficiency cases. Such cases are characterized by a broad spectrum of reproductive phenotypes from severe congenital forms of GnRH deficiency to reversal of HH. Additionally, the variable expressivity of both reproductive and non-reproductive phenotypes among patients and family members harboring the identical FGFR1 mutations has pointed to a more complex, oligogenic model for GnRH deficiency. Further, reversal of HH in patients carrying FGFR1 mutations suggests potential gene-environment interactions in human GnRH deficiency disorders.

Actividad de la vía PI3K-AKT-FOXOp27 como factor pronóstico en tumores astrocitarios

Els tumors astrocitaris són entitats poc freqüents i el seu pronòstic és pobre. Recentment s'ha descrit l'alta freqüència d'alteració de la via de PI3K a aquests tumors. L'objectiu d'aquest estudi és valorar la possible correlació entre la supervivència lliure de progressió d'una sèrie de pacients intervinguts per tumors astrocitarios en el nostre centre i l'activació de la via de PI3K definida mitjançant expressió inmunohistoquímica. Es van analitzar un total de 83 pacients. A més dels factors correlacionats en la literatura amb la supervivència lliure de progressió (grau, cirurgia i edat), l'estudi mostra una correlació directament proporcional amb els nivells de pFOXO i inversament proporcional amb p27. El valor d'aquestes troballes haurà de ser validat posteriorment.

The mycobacterial cord factor adjuvant analogue trehalose-6,6'-dibehenate (TDB) activates the Nlrp3 inflammasome.

The success of a vaccine consists in the induction of an innate immune response and subsequent activation of the adaptive immune system. Because antigens are usually not immunogenic, the addition of adjuvants that activate innate immunity is required. The mycobacterial cord factor trehalose-6,6'-dimycolate (TDM) and its synthetic adjuvant analogue trehalose-6,6'-dibehenate (TDB) rely on the C-type lectin Mincle and the signaling molecules Syk and Card9 to trigger innate immunity. In this study, we show that stimulation of bone marrow-derived dendritic cells (BMDCs) with TDB induces Nlrp3 inflammasome-dependent IL-1β secretion. While Card9 is required for NF-κB activation by TDB, it is dispensable for TDB-induced activation of the Nlrp3 inflammasome. Additionally, efflux of intracellular potassium, lysosomal rupture, and oxygen radical (ROS) production are crucial for caspase-1 processing and IL-1β secretion by TDB. In an in vivo inflammation model, we demonstrate that the recruitment of neutrophils by TDB is significantly reduced in the Nlrp3-deficient mice compared to the wild-type mice, while the production of chemokines in vitro is not influenced by the absence of Nlrp3. These results identify the Nlrp3 inflammasome as an essential mediator for the induction of an innate immune response triggered by TDB.

¿Es el sexo femenino un factor de riesgo quirúrgico en la cirugía de valvular?

RESULTADOS: Se intervino un 60,7% de los pacientes de SV aórtica, un 25,7% de SV mitral , un 13,6% de doble SV. Además, en el 22,5% se realizó revascularización coronaria. Las mujeres presentaban más edad, SV mitral, reintervención, fibrilación auricular, anemia y peor clase funcional. Los varones presentaron más tabaquismo, SV aórtica, enfermedad coronaria, cirugía de revascularización coronaria, función sistólica deprimida y tiempo de clampaje aórtico. En el análisis bivariado relacionado con mortalidad hospitalaria (8,35%) fueron significativos la edad, el sexo, la clase funcional, la posición de la prótesis, la superficie corporal, la anemia, el número de concentrados de hematíes y el tiempo de clampaje aórtico. Se constató como factores de riesgo independientes el sexo (OR 2,92; 95% intervalo confianza 1,05-8,14) y la anemia (OR 4,23; 95% intervalo confianza 1,66-10,8) tras ajustarlos con los factores de riesgo, factores confusores y el año de intervención. CONCLUSIONES: El sexo femenino es un factor de riesgo independiente para la mortalidad hospitalaria en la cirugía de sustitución valvular.

Compressed Sensing Single-Breath-Hold CMR for Fast Quantification of LV Function, Volumes, and Mass.

OBJECTIVES: The purpose of this study was to compare a novel compressed sensing (CS)-based single-breath-hold multislice magnetic resonance cine technique with the standard multi-breath-hold technique for the assessment of left ventricular (LV) volumes and function. BACKGROUND: Cardiac magnetic resonance is generally accepted as the gold standard for LV volume and function assessment. LV function is 1 of the most important cardiac parameters for diagnosis and the monitoring of treatment effects. Recently, CS techniques have emerged as a means to accelerate data acquisition. METHODS: The prototype CS cine sequence acquires 3 long-axis and 4 short-axis cine loops in 1 single breath-hold (temporal/spatial resolution: 30 ms/1.5 × 1.5 mm(2); acceleration factor 11.0) to measure left ventricular ejection fraction (LVEFCS) as well as LV volumes and LV mass using LV model-based 4D software. For comparison, a conventional stack of multi-breath-hold cine images was acquired (temporal/spatial resolution 40 ms/1.2 × 1.6 mm(2)). As a reference for the left ventricular stroke volume (LVSV), aortic flow was measured by phase-contrast acquisition. RESULTS: In 94% of the 33 participants (12 volunteers: mean age 33 ± 7 years; 21 patients: mean age 63 ± 13 years with different LV pathologies), the image quality of the CS acquisitions was excellent. LVEFCS and LVEFstandard were similar (48.5 ± 15.9% vs. 49.8 ± 15.8%; p = 0.11; r = 0.96; slope 0.97; p < 0.00001). Agreement of LVSVCS with aortic flow was superior to that of LVSVstandard (overestimation vs. aortic flow: 5.6 ± 6.5 ml vs. 16.2 ± 11.7 ml, respectively; p = 0.012) with less variability (r = 0.91; p < 0.00001 for the CS technique vs. r = 0.71; p < 0.01 for the standard technique). The intraobserver and interobserver agreement for all CS parameters was good (slopes 0.93 to 1.06; r = 0.90 to 0.99). CONCLUSIONS: The results demonstrated the feasibility of applying the CS strategy to evaluate LV function and volumes with high accuracy in patients. The single-breath-hold CS strategy has the potential to replace the multi-breath-hold standard cardiac magnetic resonance technique.

The Role and Future Development of Supportive Housing for Older People in Ireland

The Role and Future Development of Supportive Housing for Older People in Ireland The standard and suitability of older peopleâ?Ts accommodation is vital to their health and quality of life and a key factor in their capacity to take care of themselves or to be cared for should they become dependent. The NCAOP, therefore, welcomes an increased national policy focus on older peopleâ?Ts housing circumstances, as demonstrated in the current partnership agreement, Towards 2016: Ten-Year Framework Social Partnership Agreement 2006-2015 (Government of Ireland, 2006), and the National Action Plan for Social Inclusion 2007-2016 (Government of Ireland, 2007). Click here to download PDF 3mb

Leukemic cluster growth in culture is an independent risk factor for acute myeloid leukemia and short survival in patients with myelodysplastic syndrome

In patients with myelodysplastic syndrome (MDS) precursor cell cultures (colony-forming unit cells, CFU-C) can provide an insight into the growth potential of malignant myeloid cells. In a retrospective single-center study of 73 untreated MDS patients we assessed whether CFU-C growth patterns were of prognostic value in addition to established criteria. Abnormalities were classified as qualitative (i.e. leukemic cluster growth) or quantitative (i.e. strongly reduced/absent growth). Thirty-nine patients (53%) showed leukemic growth, 26 patients (36%) had strongly reduced/absent colony growth, and 12 patients showed both. In a univariate analysis the presence of leukemic growth was associated with strongly reduced survival (at 10 years 4 vs. 34%, p = 0.004), and a high incidence of transformation to AML (76 vs. 32%, p = 0.01). Multivariate analysis identified leukemic growth as a strong and independent predictor of early death (relative risk 2.12, p = 0.03) and transformation to AML (relative risk 2.63, p = 0.04). Quantitative abnormalities had no significant impact on the disease course. CFU- C assays have significant predictive value in addition to established prognostic factors in MDS. Leukemic growth identifies a subpopulation of MDS patients with poor prognosis.

Increased plasma levels of tumor necrosis factor-alpha in asymptomatic/"indeterminate" and Chagas disease cardiomyopathy patients

We compared plasma tumor necrosis factor-alpha (TNF-alpha) levels among asymptomatic/"indeterminate" Chagas disease patients (ASY) and patients across the clinical spectrum of chronic Chagas disease cardiomyopathy (CCC). Idiopathic dilated cardiomyopathy (DCM) patients and normal controls (NC) were included as controls. ASY Chagas disease patients had significantly higher plasma TNF-alpha levels than NC. TNF-alpha levels among severe CCC patients with significant left ventricular (LV) dysfunction were similar to those of DCM patients, showing average 2-fold higher levels than CCC patients without LV dysfunction and ASY patients, and 8-fold higher levels than NC. In Chagas disease, chronic TNF-a production prior to heart failure may play a role in CCC progression.