Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Children and Adolescents with Fanconi Anemia.

We describe haploidentical bone marrow transplantation with post-transplant cyclophosphamide (PT-CY) for 30 patients with Fanconi anemia (FA). Twenty-six patients were transplanted upfront, and the preparatory regimens included fludarabine 150 mg/m2 + total body irradiation 200 to 300 cGy ± CY 10 mg/kg without (n = 12) or with rabbit antithymocyte globulin (r-ATG) 4 to 5 mg/kg (n = 14). Four patients were rescued after primary or secondary graft failure after related or unrelated donor transplantation with the above regimen with (n = 2) or without r-ATG (n = 2). PT-CY at 25 mg/kg/day (total dose, 50 mg/kg) followed by cyclosporine and mycophenolate mofetil was given to all patients. All patients engrafted in the subgroup of patients who did not receive r-ATG (n = 14), but their transplant course was complicated by high rates of acute and chronic graft-versus-host disease (GVHD), and only 8 patients are alive. In the subgroup that received r-ATG (n = 16), 14 patients had sustained engraftment, severe GVHD rates were lower, and 13 patients are alive. Hemorrhagic cystitis occurred in 50% of patients, whereas cytomegalovirus reactivation occurred in 75%. One-year overall survival for the entire cohort was 73% (95% CI, 64% to 81%), and all surviving patients achieved full donor chimerism. In conclusion, haploidentical donor transplantation with PT-CY is a suitable option for FA patients without a matched related or unrelated donor.

Orchiectomy attenuates oxidative stress induced by aluminum in rats.

The aim of this work was to study whether the increase in antioxidant defenses associated with orchiectomy may account for the reduced susceptibility to aluminum (Al) in male kidney and also to examine whether the reduced antioxidant defenses are associated with androgen levels in orchiectomized (ORX) rats treated with testosterone propionate (TP). Rats were divided into nine groups, namely, intact males (without treatment, treated with sodium lactate, and treated with Al), sham males, ORX males (without treatment, treated with sodium lactate, treated with TP, treated with Al, and treated with TP and Al). Al groups were chronically treated with aluminum lactate for 12 weeks (0.575 mg Al/100 g of body weight, intraperitoneally, three times per week). We reported that ORX rats treated with Al had significantly less lipid peroxidation and an increased level of reduced glutathione (GSH) and GSH/oxidized glutathione ratio in the kidney when compared with intact and TP-treated ORX rats. The activity of superoxide dismutase, catalase, and glutathione peroxidase in ORX rats was much greater than in intact or TP-administered ORX rats. Castration reduced the glomerular alterations caused by Al as well as the number of necrotic tubular cells and nuclear abnormalities. However, we observed a slight alteration in brush border, dilation of proximal tubules, mononuclear infiltrates, and interstitial fibrosis. Castrated males treated with TP showed that this intervention cancels the protective effect of the ORX. This finding suggests that androgens contribute to the development of renal alterations and proteinuria in rats treated with Al. Our results showed that ORX rats are protected against the induction of oxidative stress by Al, but the morphological damage to the kidney tissue induced by the cation was only reduced. Male intact rats treated with Al had more severe glomerulosclerosis, tubular damage, and proteinuria than ORX rats.

The Impact of Flt3 Gene Mutations in Acute Promyelocytic Leukemia: A Meta-Analysis.

The association of FLT3 mutations with white blood cell (WBC) counts at diagnosis and early death was studied in patients with acute promyelocytic leukemia (APL). Publications indexed in databases of biomedical literature were analyzed. Potential publication bias was evaluated by analyzing the standard error in funnel plots using the estimated relative risk (RR). Mixed-effect models were used to obtain the consolidated RR. All analyses were conducted using the R statistical software package. We used 24 publications in the final meta-analysis. Of 1005 males and 1376 females included in these 24 publications, 645 had FLT3-ITD (internal tandem duplication) mutations. Information on FLT3-D835 mutations was available in 10 publications for 175 patients. Concurrent occurrence of the two mutations was rare. WBC count at diagnosis was ≥10 × 109/L in 351 patients. For patients with the FLT3-ITD mutation, RR was 0.59 for overall survival (OS) and 1.62 for death during induction. For those with FLT3-D835 mutations, the RR was 0.50 for OS and 1.77 for death during induction. RR for WBC count ≥10 × 109/L was 3.29 and 1.48 for patients with FLT3-ITD and FLT3-D835, respectively. APL patients with FLT3-ITD or FLT3-D835 are more likely to present with elevated WBC counts and poorer prognosis than those without these mutations.

The Prognostic Role of CD8+ T Lymphocytes in Childhood Adrenocortical Carcinomas Compared to Ki-67, PD-1, PD-L1, and the Weiss Score.

Adrenocortical carcinoma (ACC) is a rare disease among children. Our goal was to identify prognostic biomarkers in 48 primary ACCs from children (2.83 ± 2.3 y; mean age ± SD) by evaluating the tumor stage and outcome for an age of diagnosis before or after 3 years, and association with ACC cluster of differentiation 8 positive (CD8+) cytotoxic T lymphocytes (CD8+-CTL) and Ki-67 immunohistochemical expression (IHC). Programmed death 1(PD-1)/Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) in ACC was analyzed in a second, partially overlapping cohort (N = 19) with a similar mean age. All patients and control children were carriers of the germline TP53 R337H mutation. Survival without recurrence for less than 3 years and death unrelated to disease were excluded. Higher counts of CD8+-CTL were associated with patients diagnosed with ACC at a younger age and stage I, whereas a higher percentage of the Ki-67 labeling index (LI) and Weiss scores did not differentiate disease free survival (DFS) in children younger than 3 years old. No PD-1 staining was observed, whereas weakly PD-L1-positive immune cells were found in 4/19 (21%) of the ACC samples studied. A high CD8+-CTL count in ACC of surviving children is compelling evidence of an immune response against the disease. A better understanding of the options for enhancement of targets for CD8+ T cell recognition may provide insights for future pre-clinical studies.

Spatial trends in congenital malformations and stream water chemistry in Southern Brazil.

The incidence of variable congenital malformation (CM) among 399 municipalities in the state of Paraná, southern Brazil, suggests the etiological role of environmental factors. This study examined a) environmental concentrations of chlorine anions (Cl-) associated with organochlorines (OCs) and b) associations between these chemicals and agricultural output with CMs using a geographical information system. In one of the three years during the sampling period (2008, 2009 or 2010) Cl-, dichlorodiphenyltrichloroethane (p,p'-DDT), dichlorodiphenyldichloroethylene (p,p'-DDE), dichlorodiphenyldichloroethane (p,p'-DDD), and endosulfan levels were measured in 465 (465/736, 63%) catchment basins. Agricultural outputs for crops during 2006-2010 were also evaluated (t/km2). Further, CM kernel density for the 399 municipalities in Paraná during 2007-2014 was investigated. Cl- levels increased significantly in one of the three years (2008, 2009 or 2010) in western catchment basins, compared to 1996 (p < 0.0001). The municipalities were divided according to the obtained Cl- levels, where sub-region C2 (central-southern) < 1.8 mg/L ≤ sub-regions C1 (northern-western) and C3 (eastern-southern). We identified 8756 cases of CMs among 1,221,287 newborns (NB) in all sub-regions. C1 had higher DDT-DDE-DDD (p,p'-DDT + p,p'-DDE + p,p'-DDD) concentrations, agricultural output, and CM kernel density. C2 and C3 had minor agricultural outputs (per square kilometer) and CM densities. A 2.96 mg/L increase in Cl- between sub-regions C1 and C2 was co-localized with a 45% increase in CM density (spatial relative risk = 1.45, CI 95%: 1.36-1.55). C1 had the highest log likelihood ratios (p = 0.001) identified via SaTScan clustering analyses. Organochlorines and other toxic chlorinated chemicals may contribute to CMs in humans, and these chemicals are ultimately transformed and release Cl- in rivers. Higher Cl- levels were correlated significantly with higher agricultural productivity, DDT-DDE-DDD levels, and CMs in some parts of the northern and western sub-regions (C1).

Penetrance of the TP53 R337H Mutation and Pediatric Adrenocortical Carcinoma Incidence Associated with Environmental Influences in a 12-Year Observational Cohort in Southern Brazil.

The TP53 R337H mutation is associated with increased incidence of pediatric adrenocortical tumor (ACT). The different environmental conditions where R337H carriers live have not been systematically analyzed. Here, the R337H frequencies, ACT incidences, and R337H penetrance for ACT were calculated using the 2006 cohort with 4165 R337H carriers living in Paraná state (PR) subregions. The effectiveness of a second surveillance for R337H probands selected from 42,438 tested newborns in PR (2016 cohort) was tested to detect early stage I tumor among educated families without periodical exams. Estimation of R337H frequencies and ACT incidence in Santa Catarina state (SC) used data from 50,115 tested newborns without surveillance, ACT cases from a SC hospital, and a public cancer registry. R337H carrier frequencies in the population were 0.245% (SC) and 0.306% (PR), and 87% and 95% in ACTs, respectively. The ACT incidence was calculated as ~6.4/million children younger than 10 years per year in PR (95% CI: 5.28; 7.65) and 4.15/million in SC (CI 95%: 2.95; 5.67). The ACT penetrance in PR for probands followed from birth to 12 years was 3.9%. R337H carriers living in an agricultural subregion (C1) had a lower risk of developing pediatric ACT than those living in industrial and large urban subregion (relative risk = 2.4). One small ACT (21g) without recurrence (1/112) was detected by the parents in the 2016 cohort. ACT incidence follows R337H frequency in each population, but remarkably environmental factors modify these rates.

Adverse effects in kidney function, antioxidant systems and histopathology in rats receiving monosodium glutamate diet.

We investigated the effects of adding of monosodium glutamate (MSG) to a standard diet on oxidative stress in kidney, nitric oxide excretion, renal ions handling and blood pressure. We examined the association of these changes with the effects on renal histology. The study was performed on male Wistar rats (5 weeks old) divided into 3 groups: 1) MSG group were fed a diet supplemented with 3g of MSG/kg b.w./day, five days a week, and spontaneous ingestion of a 1% MSG solution during 16 weeks; 2) NaCl group were fed a diet with NaCl (1g/kg b.w./day) and 0.35% NaCl solution permanently alone at the same frequency and time; 3) control group were fed the normal chow and tap water. Sodium, potassium, calcium, phosphorus, creatinine, protein and nitric oxide excretion were analyzed in urine. We utilized clearance techniques to examine glomerular filtration rate and cortical renal plasma flow. We determined the oxidative state and the histopathological changes of renal tissue. Following MSG treatment, absolute and fractional sodium and potassium excretion decreased although there was hyperfiltration. The MSG group showed similar increase in blood pressure than the NaCl group, but nitric oxide excretion was significantly reduced. Although no increase in lipid peroxidation was verified, its observed alteration in the reduced glutathione/oxidized cycle and their enzymes GPx and GR. These changes were accompanied by alterations histological both glomerular as well as tubular level and by interstitial fibrosis with mononuclear cells accumulation. These results indicate that the addition of MSG in the diet decreases the excretion of Na, K and water with hyperfiltration. NaCl retention that leads to hypertension was accompanied by renal pathologic changes, intrarenal oxidative stress and reduction of nitric oxide excretion.

Alteraciones histológicas hepáticas provocadas por la ingesta crónica de glutamato monosódico / Histological liver changes caused by chronic intake of monosodium glutamate

ntroducción. El glutamato es un aminoácido que está implicado en numerosas reacciones relacionadas con el metabolismo hepático, por lo que la sobreactivación de los receptores de glutamato por acción de la ingesta de glutamato monosódico (GMS) proveniente de la dieta, podría llevar a daño del tejido hepático. Este estudio se realizó con el objetivo de evaluar los cambios histológicos producidos en el hígado de ratas sometidas a la administración crónica de GMS. Metodología. Se trabajó con dos lotes de animales, uno experimental y otro control, cada uno de ellos constituido por seis ratas machos cepa Wistar de cinco semanas de edad. Al grupo experimental se le administró diariamente 0,1 g de queso de bajas calorías que contenía GMS monohidrato de 99% de pureza (grado alimentario puro), diluido en 50 µL de agua desionizada (0,3 g/100 g de peso corporal). Al grupo control se le administró la misma cantidad de sodio que el que contenía el GMS del grupo tratado, pero bajo la forma de NaCl. Al concluir el tratamiento, las ratas pertenecientes a ambos grupos se pesaron y sacrificaron, y se les extrajo el hígado para el estudio histológico. Se obtuvieron cortes histológicos que fueron coloreados con hematoxilina-eosina, PAS y coloración con tricrómico de Masson. El análisis de los cortes histológicos se llevó a cabo por observación directa en microscopio óptico con objetivo de 40x. Resultados. Se observó en general, conservación y apariencia normal de las características histológicas de los acinos hepáticos en el grupo control, en tanto que el hígado de las ratas tratadas con GMS presentó diferentes grados de degeneración hidrópica, cantidades variables de cuerpos hialinos eosinófilos, infiltración inflamatoria de células mononucleares y necrosis focal, principalmente en la zona 1 del acino hepático. Conclusión. Los resultados encontrados permiten aportar evidencias en torno a las alteraciones histopatológicas que la ingesta crónica de GMS provoca sobre el tejido hepático. Se recomienda alertar a la población para reducir la ingesta de alimentos que poseen GMS como saborizante.

Introduction. Glutamate is an amino acid that is involved in numerous reactions related to liver metabolism, so the overactivation of glutamate receptors due to the ingestion of monosodium glutamate (MSG) from the diet could lead to liver tissue damage. The aim of this study was to evaluate the histological changes produced in the liver of rats subjected to chronic administration of MSG. Methodology. Two sets of animals were used, an experimental and a control group, each consisting of six five-week-old Wistar male rats. The experimental group was administered 0.1 g of low-calorie cheese containing 99% purity MSG monohydrate (pure food grade) diluted in 50 µL of deionized water (0.3 g/100 g of weight) daily. The control group was administered the same amount of sodium as that contained in the MSG of the treated group, but in the form of NaCl. At the end of the treatment, the rats belonging to both groups were weighed and sacrificed, and their liver was removed for histological analysis. Histological sections were obtained and stained with hematoxylineosin, PAS and Masson's trichrome. The analysis of the histological sections was carried out by direct observation with an optical microscope and a 40x objective. Results. In general, conservation and normal appearance of the histological characteristics of the liver acini were observed in the control group, while the liver of the rats treated with MSG presented different degrees of hydropic degeneration, variable amounts of eosinophilic hyaline bodies, inflammatory infiltration of mononuclear cells and focal necrosis, that affected mainly zone 1 of the liver acinus. Conclusion. The results allow us to provide evidence about the histopathological alterations that the chronic intake of MSG causes on the liver tissue. It is recommended to alert the population to reduce the intake of foods that have GMS for flavoring.

Monosodium glutamate intake affect the function of the kidney through NMDA receptor.

AIMS: We investigated whether the chronic intake of monosodium glutamate (MSG) with food affects kidney function, and renal response to glycine. We also established if the NMDA receptors are involved in the changes observed. MAIN METHODS: Male Wistar rats (5weeks old) were fed a diet supplemented with MSG (3g/kg b.w./day), five days a week, and spontaneous ingestion of a 1% MSG solution during 16weeks. NaCl rats were fed a diet with NaCl (1g/kg b.w./day) and 0.35% NaCl solution at the same frequency and time. Control group was fed with normal chow and tap water. We utilized clearance techniques to examine glomerular filtration rate (GFR) and cortical renal plasma flow (CRPF) response to glycine and glycine+MK-801 (antagonist NMDA-R), and we determined NMDA-R1 in kidney by immunohistochemistry. KEY FINDINGS: The addition of MSG in the diet of rats increased both GFR and CRPF with an increase of absolute sodium reabsorption. However, hyperfiltration was accompanied with a normal response to glycine infusion. Immunostain of kidney demonstrate that the NMDA receptor is upregulated in rats fed with MSG diet. NMDA-R antagonist MK-801 significantly reduced both the GFR and CRPF; however the percentage of reduction was significantly higher in the group MSG. MK-801 also reduces fractional excretion of water, sodium and potassium in the three groups. SIGNIFICANCE: Renal NMDAR may be conditioned by the addition of MSG in the diet, favoring the hyperfiltration and simultaneously Na retention in the body.

Conhecimento e implementação de medidas de controle ambiental no manejo da asma e da rinite alérgica / Knowledge and implementation of environmental control measures in the management of asthma and allergic rhinitis

Objetivo: Avaliar o conhecimento de pais ou responsáveis por pacientes sobre medidas de controle ambiental no manejo da asma e da rinite alérgica, bem como a implementação destas medidas. Métodos: Estudo transversal, descritivo, que incluiu pacientes entre 5 e 18 anos, com asma e/ou rinite alérgica, sensibilizados a alérgenos inalatórios domésticos. Os entrevistados responderam questionário sobre sensibilização alérgica, medidas de controle ambiental e exposição ao tabagismo passivo. Resultados: Foram incluídos 122 pais ou responsáveis. Embora 97% acreditassem que seu filho tinha uma doença alérgica, apenas 43% conseguiam relacionar os sintomas da doença à presença de alérgenos. O percentual de pais capaz de referir os alérgenos para os quais seus filhos estavam sensibilizados foi de 88% para ácaros, 56% para fungos, 41% para baratas e gatos, e 40% para cães. Medidas para controle de ácaros foram adotadas por 83% das famílias, com exceção das capas antiácaros, utilizadas por 39%. Entre donos de cães e gatos, 57% não permitiam que seus animais entrassem na casa; 21% dedetizavam a casa contra baratas. Entre os familiares tabagistas, 14% pararam de fumar. Conclusões: A maioria dos entrevistados reconheceu que seu filho tinha uma doença alérgica, mas grande parte não relacionou os sintomas da doença à exposição a alérgenos. Grande percentagem dos entrevistados cujos filhos eram sensibilizados a fungos, baratas, gatos e cães não soube referir este resultado. Os entrevistados aplicavam medidas gerais para controle de alérgenos, mas a maioria não implementava algumas medidas com benefício comprovado para uma estratégia abrangente de controle ambiental.

Objective: To assess the knowledge of patients' caregivers on environmental control measures in the management of asthma and allergic rhinitis, as well as their adherence to such measures. Methods: This cross-sectional, descriptive study included patients aged between 5 and 18 years with a diagnosis of asthma and/ or allergic rhinitis and sensitivity to indoor inhaled allergens. Caregivers answered a questionnaire on allergen sensitization, environmental control measures, and exposure to secondhand smoke. Results: A total of 122 parents/guardians were recruited. Even though 97% of the caregivers believed that their children had an allergic disease, only 43% were able to relate disease symptoms with the presence of allergens. The percentage of caregivers who were able to list the allergens to which their child was sensitive resulted in 88% of correct answers for house dust mites, 56% for fungi, 41% for cockroaches and cats, and 40% for dogs. Moreover, 83% of the families adopted general house dust mite control measures, but only 39% used allergen-proof mattress and pillow covers. Among the families who had pets, 57% kept the pets outdoors; chemical control of cockroaches was adopted by 21% of the families. Among the caregivers who smoked, only 14% quit the habit. Conclusions: Even though the majority of caregivers were aware of the allergic status of their child, most of them did not understand the relationship between allergic disease symptoms and exposure to allergens. Furthermore, a large percentage of caregivers failed to recognize their children's sensitization to fungi, cockroaches, cats, and dogs. Caregivers applied general allergen control measures in their homes, but the majority did not implement some specific measures with proven benefit as part of a broad environmental control strategy.

Beneficios de incorporar un simbiótico a la dieta de adultos mayores con infecciones recurrentes / Benefits of adding symbiotic food to the diet of elderly people with recurrent infections

El propósito de este trabajo fue estudiar la evolución clínica de un grupo de adultos mayores, proclives a padecer infecciones bacterianas principalmente de las vías respiratorias, al adicionar a su dieta un alimento simbiótico con Lactobacillus casei, Lactobacillus acidophillus y fructanos y, además, correlacionar los resultados obtenidos con modificaciones en los parámetros inmunológicos medidos. Se incluyeron 90 pacientes adultos mayores de 65 años, todos con antecedentes de infecciones bacterianas recurrentes de las vías respiratorias. Cada individuo suplementó su dieta habitual con una dosis diaria del simbiótico SanCor Bio con fructanos. La administración se realizó durante los meses de época invernal. Se realizó un seguimiento clínico, se hizo recuento de Lactobacillus spp en materia fecal, se cuantificaron subpoblaciones linfocitarias CD4 y CD8 y se evaluó la activación de monocitos en sangre periférica. Se observó disminución de los cuadros virales (gripales) y ausencia de infecciones bacterianas de vías respiratorias; además, aumentó el número de Lactobacillus spp en materia fecal y se estimuló la respuesta inmune principalmente inespecífica. Esto sugiere que dicho simbiótico puede ser utilizado como terapia preventiva en grupos vulnerables a infecciones y con depleciones del sistema inmunológico.

The aim of this work was to study the clinical evolution of a group of elderly people who had a tendency to suffer from bacterial infections, mainly of the respiratory tract, after having added food with Lactobacillus casei, Lactobacillus acidophilus and fructans to their diet, and then to correlate the results obtained with alterations in immunological parameters previously set. Ninety patients who were older than 65 and had a background of recurrent bacterial infections in their respiratory tract were included in this study. Their daily diet was supplemented with a dose of Sancor Bio during winter months in 2007. A clinical analysis was carried out, Lactobacillus spp in faeces were counted, CD4 and CD8 lymphocytes were quantified and the activation of monocytes in peripheral blood was evaluated. In conclusion, the administration of this symbiotic food proved to be biochemical and clinically effective, showing to be a good colony of the intestinal mucose, promoting the principally unspecific immune response, everything correlated with clinical information. All this suggests that this food can be used asa preventive therapy in groups of people who are vulnerable to infections and who have immunological system depletions.