Severe combined immunodeficiency in Brazil: management, prognosis, and BCG-associated complications.

BACKGROUND: Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency. The objectives of this study were to analyze the diagnosis, treatment, and prognosis of SCID in Brazil and to document the impact of BCG vaccine. METHODS: We actively searched for cases by contacting all Brazilian referral centers. RESULTS: We contacted 23 centers and 70 patients from 65 families. Patients were born between 1996 and 2011, and 49 (70%) were male. More than half (39) of the diagnoses were made after 2006. Mean age at diagnosis declined from 9.7 to 6.1 months (P = .058) before and after 2000, respectively, and mean delay in diagnosis decreased from 7.9 to 4.2 months (P = .009). Most patients (60/70) were vaccinated with BCG before the diagnosis, 39 of 60 (65%) had complications related to BCG vaccine, and the complication was disseminated in 29 of 39 (74.3%). Less than half of the patients (30, 42.9%) underwent hematopoietic stem cell transplantation (HSCT). Half of the patients died (35, 50%), and 23 of these patients had not undergone HSCT. Disseminated BCG was the cause of death, either alone or in association with other causes, in 9 of 31 cases (29%, no data for 4 cases). CONCLUSIONS: In Brazil, diagnosis of SCID has improved over the last decade, both in terms of the number of cases and age at diagnosis, although a much higher number of cases had been expected. Mortality is higher than in developed countries. Complications of BCG vaccine are an important warning sign for the presence of SCID and account for significant morbidity during disease progression.

Morphometry and morphology of fish otoliths on the coast of the state of Maranhão, Brazil.

The main objective of this study was to evaluate the biometric relationships between the species Bagre bagre, Lutjanus synagris and Nebris microps and their otoliths. The relationship between the size of the otolith (length and weight) and the size of the fish (standard length and total weight) was determined using the linear regression model (y = a + bx). For the morphological description, the otoliths of three specimens were selected by standard length class (10mm). The morphological characters analyzed were chosen according to traditional literature. Three hundred eight specimens of B. bagre, 200 of L. synagris and 237 of N. microps were analyzed. Throughout the collection period, the source of the capture of individuals was the municipality of Raposa. The linear correlations for fish and otolith length for B. bagre were 0.9129 and 0.9652, respectively. For L. synagris, the coefficients were 0.8634 and 0.8672, while for N. microps, 0.9597 and 0.8636, respectively. The morphological classification of L. synagris and N. microps is of the Saggita type, and the B. bagre species is of the Lapillus type. From the data presented here, it is possible to observe that otolith morphometric and morphological data can serve as a parameter to estimate the relationship between the fish and the otolith in terms of its biomass and the length of an individual and a population.

Impact of mother donor, peripheral blood stem cells and measurable residual disease on outcomes after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide in children with acute leukaemia.

Haploidentical hematopoietic-cell transplantation using post-transplant cyclophosphamide(Haplo-PTCy) is a feasible procedure in children with haematologic malignancies. However, data of a large series of children with acute leukaemia(AL) in this setting is missing. We analysed 144 AL Haplo-PTCy paediatric recipients; median age was 10 years. Patients had acute lymphoblastic(ALL; n = 86) or myeloblastic leukaemia(AML; n = 58) and were transplanted in remission(CR1: n = 40; CR2: n = 57; CR3+: n = 27) or relapse (n = 20). Bone marrow was the graft source in 57%; donors were father (54%), mother (35%), or sibling (11%). Myeloablative conditioning was used in 87%. Median follow-up was 31 months. At day +100, cumulative incidence (CI) of neutrophil recovery and acute GVHD (II-IV) were 94% and 40%, respectively. At 2-years, CI of chronic GVHD and relapse, were 31%, 40%, and estimated 2-year overall survival (OS), leukaemia-free survival (LFS) and graft-versus-host-relapse-free survival (GRFS) were 52%, 44% and 34% respectively. For patients transplanted in remission, positive measurable residual disease (MRD) prior to transplant was associated with decreased LFS (p = 0.05) and GRFS (p = 0.003) and increased risk of relapse (p = 0.02). Mother donor was associated with increased risk of chronic GVHD (p = 0.001), decreased OS (p = 0.03) and GRFS (p = 0.004). Use of PBSC was associated with increased risk of chronic GVHD (p = 0.04). In conclusion, achieving MRD negativity pre-transplant, avoiding use of mother donors and PBSC as graft source may improve outcomes of Haplo-PTCy in children with AL.

Publisher Correction: Model-Based Therapy Planning Allows Prediction of Haemodynamic Outcome after Aortic Valve Replacement.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Model-Based Therapy Planning Allows Prediction of Haemodynamic Outcome after Aortic Valve Replacement.

Optimizing treatment planning is essential for advances in patient care and outcomes. Precisely tailored therapy for each patient remains a yearned-for goal. Cardiovascular modelling has the potential to simulate and predict the functional response before the actual intervention is performed. The objective of this study was to proof the validity of model-based prediction of haemodynamic outcome after aortic valve replacement. In a prospective study design virtual (model-based) treatment of the valve and the surrounding vasculature were performed alongside the actual surgical procedure (control group). The resulting predictions of anatomic and haemodynamic outcome based on information from magnetic resonance imaging before the procedure were compared to post-operative imaging assessment of the surgical control group in ten patients. Predicted vs. post-operative peak velocities across the valve were comparable (2.97 ± 1.12 vs. 2.68 ± 0.67 m/s; p = 0.362). In wall shear stress (17.3 ± 12.3 Pa vs. 16.7 ± 16.84 Pa; p = 0.803) and secondary flow degree (0.44 ± 0.32 vs. 0.49 ± 0.23; p = 0.277) significant linear correlations (p < 0.001) were found between predicted and post-operative outcomes. Between groups blood flow patterns showed good agreement (helicity p = 0.852, vorticity p = 0.185, eccentricity p = 0.333). Model-based therapy planning is able to accurately predict post-operative haemodynamics after aortic valve replacement. These validated virtual treatment procedures open up promising opportunities for individually targeted interventions.

Haploidentical BMT and post-transplant Cy for severe aplastic anemia: a multicenter retrospective study.

Patients with refractory severe aplastic anemia (SAA) who lack a matched sibling or unrelated donor need new therapeutic approaches. Hematopoietic SCT (HSCT) using mismatched or haploidentical related donors has been used in the past, but was associated with a significant risk of GVHD and mortality. Recently, the use of post-transplant cyclophosphamide (Cy) has been shown to be an effective strategy to prevent GVHD in recipients of haploidentical HSCT, but the majority of reports have focused on patients with hematology malignancies. We describe the outcome of 16 patients who underwent haploidentical transplantation using a reduced-intensity conditioning regimen with post-transplant Cy. Stem cell sources were BM (N=13) or PBSCs (N=3). The rate of neutrophil engraftment was 94% and of platelet engraftment was 75%. Two patients had secondary graft failure and were successfully salvaged with another transplant. Three patients developed acute GVHD being grades 2-4 in two. Five patients have died and the 1-year OS was 67.1% (95% confidence interval: 36.5-86.4%). In our small series, the use of a reduced-intensity conditioning with post-transplant Cy in haploidentical BMT was associated with high rates of engraftment and low risk of GVHD in patients with relapsed/refractory SAA.

Trypanosoma cruzi: the fate of bloodstream trypomastigote, amastigote, metacyclic trypomastigote and epimastigote forms in the peritoneal macrophages of immune and non-immune mice in vivo.

Experiments were done in vivo in order to compare the ability of Trypanosoma cruzi bloodstream trypomastigotes (BTr), amastigotes (Am), metacyclic trypomastigotes (MTr) and epimastigotes (Ep) to proliferate in the peritoneal macrophages of the following groups of A/Sn mice: actively immunized with increasing doses of living BTr (AIM); mice passively immunized with homologous immune serum (ISTM); mice passively transfused with normal homologous serum (NSTM) and normal mice (NM). Parasite load was evaluated by counting the number of infected peritoneal macrophages harvested on the 4th day after i.p. challenge with one of the forms. All four parasite stages infected NM. AIM seldom showed parasitized macrophages after challenge with any of the forms. ISTM always harboured numerous parasitized macrophages. The only form susceptible to humoral immunity was the Am.

[Endovascular treatment of aneurysms of the descending thoracic aorta--a new therapeutic perspective]. / Tratamento endovascular de aneurisma da aorta torácica descendente--uma nova perspectiva terapêutica.

Endovascular treatment of aneurysmal disease of descending thoracic aorta and infra-renal abdominal aorta, has become an accepted technique, in selected cases due to the reduction of neurological morbidity, paraparesis or paraplegic and renal ischemia, associated with conventional surgery. The authors describe the first case performed in Portugal of a 75-year-old female with an expanding thoracic aneurysm managed by endovascular exclusion of the aneurysm with an EXCLUDER endoprosthesis, without any complications or evidence of endoleak, achieving complete exclusion of the aneurysm.

[Prevalence of extracranial carotid occlusive disease. Non-invasive study]. / Prevalência da doença carotídea oclusiva extracraneana. Estudo não-invasivo.

Cerebrovascular disease is the most important cause of mortality and morbility in some European Countries, but the prevalence of carotid occlusive disease has not been adequately assessed. From 1985 to 1987, 1,143 patients were consecutively evaluated in the Vascular Laboratory in order to determine the presence of extracranial carotid occlusive disease. 638 (55.8%) were males and 505 (44.2%) females and mean age was 58 years (16-87). 509 had previously focal brain ischemia, ocular and/or hemispheric (Group I), 78 had assymptomatic cervical bruit (Group II), 55 non-hemispheric neurologic dysfunction (Group III) and 501 had atypical symptoms for cerebrovascular disease (Group IV). Diagnostic criteria for carotid disease: were peak frequency greater than 4.0 KHz; spectral broadening greater than 40% and late sysstolic turbulence. Global prevalence of carotid disease was 31.8% and the results in each group were: Gr. I-37.2%; Gr. II-57.7%; Gr. III-43.6%; Gr. IV-21.2%. 49% of the patients had hypertension, 22.8% dyslipidemia, 22.4% evidence of coronary disease and 13.6% had diabetes. Hypertension, diabetes, coronary disease and the coexistence of two risk factors were significantly more prevalent in the group of patients with carotid disease. These results confirm a high prevalence of carotid disease in this population, which is comparable to the one is northern european populations.

Biomarcadores histológicos em brânquias de Sciades herzbergii (Siluriformes, Ariidae) capturados no Complexo Estuarino de São Marcos, Maranhão / Histological biomarkers in gills of Sciades herzbergii (Siluriformes, Ariidae) caught in the Estuarine Complex of São Marcos, Maranhão

Neste estudo, objetivou-se avaliar a qualidade ambiental de duas áreas do complexo estuarino de São Marcos, utilizando-se as alterações branquiais em Sciades herzbergii como biomarcadores de contaminação aquática. Foram realizadas coletas no período de estiagem (setembro/dezembro de 2015) e no período chuvoso (março/junho de 2016). Foram capturados 40 exemplares de S. herzbergii em dois locais distintos do complexo estuarino: A1) Porto do Itaqui Bacanga (área potencialmente impactada); A2) Igarapé do Puca, Alcântara (área controle). Foram registradas as variáveis abióticas: salinidade, temperatura, pH e oxigênio dissolvido. No laboratório, as brânquias de cada espécime foram fixadas em formol a 10% e mantidas em álcool a 70% até a execução da técnica histológica usual. As alterações branquiais identificadas nos peixes da área potencialmente contaminada foram: deslocamento do epitélio (DE), congestão (CO), aneurisma (AN), fusão lamelar (FL), hiperplasia (HI), dilatação capilar (DC), necrose (NE) e proliferação de células epiteliais (PCE). As alterações na região controle foram: deslocamento do epitélio (DE), fusão lamelar (FL), necrose (NE) e proliferação de células epiteliais (PCE). As alterações branquiais foram mais frequentes na região portuária (84%) do que na região controle (16%). Esses resultados indicam que os peixes da área potencialmente contaminada estão apresentando respostas biológicas ao estresse local.(AU)

This study aimed to compare an environmental quality of two areas of the estuarine complex of São Marcos using gills of changes in Sciades herzbergii as biomarkers of aquatic contamination. Samples were made during the dry season (September/ December 2015) and rainy season (March/ June 2016). They were captured 40 specimens of S. herzbergii at two different points of the estuarine complex: A1) Itaqui port (potentially contaminated area); A2) Igarapé do Puca, Alcântara (control area). Abiotic variables were recorded: salinity, temperature, pH and dissolved oxygen. In the laboratory, the gills of each species were fixed in 10% formaldehyde and kept in 70% alcohol until the usual histological technique was performed. The gill alterations identified in the fish of the potentially contaminated area were: epithelial displacement (DE), congestion (CO), aneurysm (AN), lamellar fusion (FL), hyperplasia (HI), capillary dilation (DC), necrosis and epithelial cell proliferation (PCE). The changes in the control region were: epithelial displacement (DE), lamellar fusion (FL), necrosis (NE) and epithelial cell proliferation (PCE). Gill alterations were more frequent in the port region (84%) than in the control region (16%). These results indicate that fish from the potentially contaminated area are presenting biological responses to local stress.(AU)

Mu killer-Mediated and Spontaneous Silencing of Zea mays Mutator Family Transposable Elements Define Distinctive Paths of Epigenetic Inactivation.

Mu killer contains a partial inverted duplication of the mudrA transposase gene and two copies of the terminal inverted repeat A (TIRA) region of the master MuDR element of maize. Mu killer can effectively silence single copy MuDR/Mu lines, and it is proposed that a ∼4 kb hairpin RNA is generated by read through transcription from a flanking gene and that this transcript serves as a substrate for siRNA production. Mu killer was sequenced, except for a recalcitrant portion in the center of the locus, and shown to be co-linear with mudrA as originally proposed. The ability of the dominant Mu killer locus to silence a standard high copy number MuDR/Mu transposon line was evaluated. After two generations of exposure, about three quarters of individuals were silenced indicating reasonable effectiveness as measured by the absence of mudrA transposase transcripts. Mu killer individuals that effectively silenced MuDR expressed two short antisense transcripts. In contrast, Mu killer individuals that failed to silence MuDR expressed multiple sense transcripts, derived from read through transcription initiating in a flanking gene, but no antisense transcripts were detected.

Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia.

Individual differences in drug efficacy or toxicity can be influenced by genetic factors. We investigated whether polymorphisms of pharmacogenes that interfere with metabolism of drugs used in conditioning regimen and graft-versus-host disease (GvHD) prophylaxis could be associated with outcomes after HLA-identical hematopoietic stem cell transplantation (HSCT). Pharmacogenes and their polymorphisms were studied in 107 donors and patients with leukemia receiving HSCT. Candidate genes were: P450 cytochrome family (CYP2B6), glutathione-S-transferase family (GST), multidrug-resistance gene, methylenetetrahydrofolate reductase (MTHFR) and vitamin D receptor (VDR). The end points studied were oral mucositis (OM), hemorrhagic cystitis (HC), toxicity and venoocclusive disease of the liver (VOD), GvHD, transplantation-related mortality (TRM) and survival. Multivariate analyses, using death as a competing event, were performed adjusting for clinical factors. Among other clinical and genetic factors, polymorphisms of CYP2B6 genes that interfere with cyclophosphamide metabolism were associated with OM (recipient CYP2B6(*)4; P=0.0067), HC (recipient CYP2B6(*)2; P=0.03) and VOD (donor CYP2B6(*)6; P=0.03). Recipient MTHFR polymorphisms (C677T) were associated with acute GvHD (P=0.03), and recipient VDR TaqI with TRM and overall survival (P=0.006 and P=0.04, respectively).Genetic factors that interfere with drug metabolisms are associated with treatment-related toxicities, GvHD and survival after HLA-identical HSCT in patients with leukemia and should be investigated prospectively.

Humoral and cellular immune responses to Blomia tropicalis and concanavalin A-binding fractions in atopic patients.

Blomia tropicalis, Dermatophagoides pteronyssinus and D. farinae are prevalent house dust mites. Concanavalin A-binding components derived from B. tropicalis (Bt-ConA extract) are highly immunogenic in allergic diseases. The aim of the present study was to evaluate the humoral and cellular immune responses to B. tropicalis in mite-sensitized patients. A total of 137 patients with allergic rhinitis with/without asthma and 109 non-atopic subjects were selected and analyzed by the skin prick test, and for total serum IgE and specific IgE levels to both Bt-total and Bt-ConA extracts, their proliferative response and cytokine (IFN-gamma and IL-5) production by peripheral blood mononuclear cells (PBMC) stimulated with both extracts. Skin prick test showed that 70% of the patients were sensitized to Bt (Bt+) and similar levels of specific IgE to Bt-total and Bt-ConA extracts were demonstrable in Bt+ patients. Significant PBMC proliferation was observed in response to Bt-total extract in Bt+, but not in Bt- patients and non-atopic subjects (P < 0.001). Bt-ConA extract induced increased proliferative responses in all patient groups compared to medium alone (P < 0.05), but these responses were significantly decreased in the presence of the mannopyranoside ConA inhibitor (P < 0.05). Significant IFN-gamma production was observed after Bt-ConA stimulation of Bt+ patients (P < 0.05), while Bt-total extract had no effect. IL-5 production was consistently detected in Bt+ patients after allergen-specific stimulation or with no stimulus, indicating that PBMC from allergic patients are prone to produce Th2 profile cytokines, spontaneously or inductively by allergen restimulation. These data showed that ConA-binding components isolated from B. tropicalis may contain relevant antigens that are involved in both humoral and cellular immune responses. However, without an additional purification procedure to eliminate the residual contamination with ConA, its use in immunotherapeutic procedures cannot be recommended.

Carotid plaque 3D compound imaging and echo-morphology analysis: a Bayesian approach.

This paper describes a method for volume reconstruction of the carotid plaque and presents a novel local characterization of its echo-morphology. The data is composed by a series of nearly parallel ultrasound images (3D Compound Imaging) and the acquisition is performed using traditional non-invasive ultrasound equipment available in most medical facilities, without need of a spatial locator device. The reconstruction algorithm uses the observed pixels inside the plaque, which were obtained in a pre-segmentation stage performed under medical guidance [1]. The paper proposes a Bayesian algorithm which estimates the underlying volume inside the plaque, by filtering and interpolating the data in order to remove speckle noise and fill non-observed regions, respectively. This volume is further used in plaque echo-morphology analysis. The observation model is based on the Rayleigh distribution, commonly used to model speckle noise in ultrasound images. A prior model based on the edge preserving Total Variation Gibbs distribution is also used to fill the gaps on non-evenly spaced observations. An energy function is derived from these models and an iterative algorithm computes its minimizer. The estimated function, defined in a given volume of interest, is used in global and local plaque characterization, namely to estimate its average levels of stenosis, echo-morphology and to identify vulnerable foci inside the plaque. The goal is to make atherosclerosis diagnosis more accurate and complete than using traditional 2D ultrasound analysis.