A tissue-bioengineering strategy for modeling rare human kidney diseases in vivo.

The lack of animal models for some human diseases precludes our understanding of disease mechanisms and our ability to test prospective therapies in vivo. Generation of kidney organoids from Tuberous Sclerosis Complex (TSC) patient-derived-hiPSCs allows us to recapitulate a rare kidney tumor called angiomyolipoma (AML). Organoids derived from TSC2-/- hiPSCs but not from isogenic TSC2+/- or TSC2+/+ hiPSCs share a common transcriptional signature and a myomelanocytic cell phenotype with kidney AMLs, and develop epithelial cysts, replicating two major TSC-associated kidney lesions driven by genetic mechanisms that cannot be consistently recapitulated with transgenic mice. Transplantation of multiple TSC2-/- renal organoids into the kidneys of immunodeficient rats allows us to model AML in vivo for the study of tumor mechanisms, and to test the efficacy of rapamycin-loaded nanoparticles as an approach to rapidly ablate AMLs. Collectively, our experimental approaches represent an innovative and scalable tissue-bioengineering strategy for modeling rare kidney disease in vivo.

Glucose-6-Phosphate dehydrogenase deficiency incidence in a Hispanic population.

Glucose-6-phosphate dehydrogenase deficiency (D-G6PD) is a common erythroenzymopathy that needs to be addressed as an important public health issue. Proper population monitoring is needed to anticipate clinical complications. A joint venture between Genomi-k (a Mexican company focused on newborn screening) and several university researchers conducted a retrospetive study for D-G6PD based on 156,152 newborn screening reports belonging to the Mexican population comprising a period of 10 years. We identified 540 male newborns affected with this deficiency, representing an incidence of 6.78 cases per 1,000 newborn males. A single double mutation of G202A:A376G was detected in 97.22% of cases. In regions where there is an absence of a national centralized health data for D-G6PD, information from a non-probabilistic large population sample can be used as a national incidence subrogate.

Clinical and cytogenetic characterization of a patient with tetrasomy 18p / Caracterización clínica y citogenética de un paciente con tetrasomía 18p

The 18p tetrasomy is a structural chromosomal abnormality with the presence of an extra isochromosome 18p, caused by a nondisjunction failure during maternal meiosis II. This additional i(18p) occurs in 1 of 180,000 live-born children worldwide, affecting males and females equally. It is characterized by craniofacial dysmorphisms; ears, nose and throat (ENT) abnormalities; musculoskeletal alterations; and global development delay. We aim to present the clinical and cytogenetic findings of a 3-year-10-month-old Latin American male with i(18p), to support the gene dosage effects, comparing his features with the ones reported in literature. This patient was product of the second pregnancy of a 39-year-old woman and the first son of a 49-year-old man. His main clinical features were microcephaly, facial dysmorphism, generalized hypotonia, and developmental delay. A blood sample of the patient was required to perform a GTG-banded karyotype and a fluorescence in situ hybridization (FISH) for chromosome 18 short arm. In addition, an SNP microarray analysis was carried out to detect genomic imbalances. Cytogenetic analysis revealed the presence of a metacentric supernumerary marker chromosome. The FISH study confirmed the origin of the marker chromosome by showing two signals for the 18p subtelomere and an intermediate signal for the 18 centromere. The microarray analysis showed a copy number gain of 18,385 Mb within the 18p.Tetrasomy tends to be a result of de novo events. The presence of the patient's isochromosome could be explained by advanced maternal age as it is known that this factor has high influence in isochromosome formation. Despite that there were no genes associated with the i(18p)'s clinical manifestations, these features are negatively correlated with dosage effects of the entire short arm. Physical and language therapy was recommended to the patient; the family received medical orientation, and awareness in family planning was raised.

La tetrasomía 18p es una anormalidad cromosómica estructural con la presencia de un isocromosoma extra 18p, causado por una no disyunción durante la meiosis materna II. Este adicional i(18p) ocurre en 1 de 180.000 niños nacidos vivos en todo el mundo, y afecta a hombres y mujeres por igual. Se caracteriza por dismorfias craneofaciales; anomalías en oídos, nariz y garganta (ENT); alteraciones musculoesqueléticas y del desarrollo global. Nuestro objetivo es presentar los hallazgos clínicos y citogenéticos de un varón latinoamericano de 3 años y 10 meses de edad con i(18p), para explicar los efectos de dosificación génica, comparando sus características con las reportadas en la literatura. Este paciente es producto del segundo embarazo de una mujer de 39 años y el primer hijo de un hombre de 49 años. Sus principales características clínicas fueron microcefalia, dismorfia facial, hipotonía generalizada y retraso global en el desarrollo. Se requirió una muestra de sangre del paciente para realizar un cariotipo con bandas GTG y una hibridación fluorescente in situ (FISH) para el análisis del brazo corto del cromosoma 18. Además, se llevó a cabo un análisis de microarreglos para detectar desequilibrios genómicos. El análisis citogenético reveló la presencia de un cromosoma supernumerario metacéntrico. Mientras que el estudio FISH confirma el origen del cromosoma marcador al mostrar dos señales para subtelómeros 18p y una señal intermedia para el centrómero 18. El análisis de microarreglos mostró una ganancia en el número de copias de 18,385 Mb dentro de la región 18p.La tetrasomía tiende a ser el resultado de eventos de novo. El isocromosoma del paciente podría explicarse por la edad materna avanzada, ya que se sabe que tiene una gran influencia en su formación. A pesar de que no hay genes asociados con las manifestaciones clínicas de i(18p), estas características están negativamente correlacionadas con los efectos de dosificación de todo el brazo corto. Se le recomendó terapia física y de lenguaje al paciente, la familia recibió orientación médica y se concientiza sobre la planificación familiar.

Towards an open grapevine information system.

Viticulture, like other fields of agriculture, is currently facing important challenges that will be addressed only through sustained, dedicated and coordinated research. Although the methods used in biology have evolved tremendously in recent years and now involve the routine production of large data sets of varied nature, in many domains of study, including grapevine research, there is a need to improve the findability, accessibility, interoperability and reusability (FAIR-ness) of these data. Considering the heterogeneous nature of the data produced, the transnational nature of the scientific community and the experience gained elsewhere, we have formed an open working group, in the framework of the International Grapevine Genome Program (www.vitaceae.org), to construct a coordinated federation of information systems holding grapevine data distributed around the world, providing an integrated set of interfaces supporting advanced data modeling, rich semantic integration and the next generation of data mining tools. To achieve this goal, it will be critical to develop, implement and adopt appropriate standards for data annotation and formatting. The development of this system, the GrapeIS, linking genotypes to phenotypes, and scientific research to agronomical and oeneological data, should provide new insights into grape biology, and allow the development of new varieties to meet the challenges of biotic and abiotic stress, environmental change, and consumer demand.

Risk allelic load in Th2 and Th3 cytokines genes as biomarker of susceptibility to HPV-16 positive cervical cancer: a case control study.

BACKGROUND: Alterations in the host cellular immune response allow persistent infections with High-Risk Human Papillomavirus (HR-HPV) and development of premalignant cervical lesions and cervical cancer (CC). Variations of immunosuppressive cytokine levels in cervix are associated with the natural history of CC. To assess the potential role of genetic host immunity and cytokines serum levels in the risk of developing CC, we conducted a case-control study paired by age. METHODS: Peripheral blood samples from patients with CC (n = 200) and hospital controls (n = 200), were used to evaluate nine biallelic SNPs of six cytokine genes of the adaptive immune system by allelic discrimination and cytokines serum levels by ELISA. RESULTS: After analyzing the SNP association by multivariate logistic regression adjusted by age, CC history and smoking history, three Th2 cytokines (IL-4, IL-6 and IL-10) and one Th3 (TGFB1) cytokine were significantly associated with CC. Individuals with at least one copy of the following risk alleles: T of SNP (-590C > T IL-4), C of SNP (-573G > C IL-6), A of SNP (-592C > A IL-10), T of SNP (-819C > T IL-10) and T of SNP (-509C > T TGFB1), had an adjusted odds ratio (OR) of 2.08 (95 % CI 1.475-2.934, p = 0.0001), an OR of 1.70 (95 % CI 1.208-2.404, p = 0.002), an OR of 1.87 (95 % CI 1.332-2.630, p = 0.0001), an OR of 1.67 (95 % CI 1.192-2.353, p = 0.003) and an OR of 1.91 (95 % CI 1.354-2.701, p = 0.0001), respectively, for CC. The burden of carrying two or more of these risk alleles was found to have an additive effect on the risk of CC (p trend = 0.0001). Finally, the serum levels of Th2 and Th3 cytokines were higher in CC cases than the controls; whereas IFNG levels, a Th1 cytokine, were higher in controls than CC cases. CONCLUSION: The significant associations of five SNPs with CC indicate that these polymorphisms are potential candidates for predicting the risk of development of CC, representing a risk allelic load for CC and can be used as a biomarker of susceptibility to this disease.

Brachytherapy versus radical hysterectomy after external beam chemoradiation with gemcitabine plus cisplatin: a randomized, phase III study in IB2-IIB cervical cancer patients.

BACKGROUND: The aim of the present study was to demonstrate that radical hysterectomy (RH) leads to improved survival outcomes in FIGO stage IB2-IIB cervical cancer when compared with standard brachytherapy (BCT) after identical external beam chemoradiation (EBRT-CT). PATIENTS AND METHODS: EBRT-CT treatment consisted of six courses of cisplatin at 40 mg/m² and gemcitabine at 125 mg/m² per week concurrent with 50.4 Gy of radiation. In the BCT arm, EBRT-CT was followed by BCT to reach a point A dose of 85 Gy, whereas in the experimental arm, a type III RH with bilateral pelvic lymph node dissection and para-aortic lymph node sampling (RH) was carried out within 4-6 weeks after EBRT-CT. RESULTS: Between May 2004 and June 2009, 211 patients were enrolled (BCT, 100 and RH, 111). At a median follow-up time of 36 months (3-80), progression-free survival (PFS) and overall survival (OS) rates were similar in both the arms. PFS rates were 74.8% and 71.7% in the BCT and RH arms [HR 0.6516 (95% confidence interval (CI) 0.3504-1.2116)], P = 0.186. OS rates were 76.3% in the BCT versus 74.5% in the surgical arm [HR 0.6981 (95% CI 0.3106-1.3439)], P = 0.236. No differences were observed in the pattern of local and systemic failures. CONCLUSIONS: This study failed to demonstrate that RH after EBRT-CT is superior to standard BCT.

Late recurrence of cervical cancer: a report of 16 cases.

PURPOSE: To analyze the clinical characteristics and outcome of cervical cancer patients presenting late recurrence. MATERIALS AND METHODS: The medical records of 16 patients who were treated between 1974 and 1999 at the Institution and whose cancer recurred after a five-year disease-free interval were reviewed. RESULTS: Mean time from initial therapy to recurrence was 162.5 months (60-360 mean). Smear abnormalities, atypical genital bleeding, abdominal and lumbar pain, and respiratory findings were the most common symptoms and signs associated with late recurrence. Fourteen patients were diagnosed by physical examination. Three of the six patients with local recurrence who were re-irradiated developed a vesico-vaginal fistula. At a median follow-up time of 12.5 months (4-38 mean), 12 patients were alive and the median survival time was 30 months. CONCLUSIONS: Cervical cancer patients surviving free of disease after the fifth year post-treatment are still at risk for relapse and in most of them, the recurrence is suspected by clinical examination alone.

The intersection between cell wall disassembly, ripening, and fruit susceptibility to Botrytis cinerea.

Fruit ripening is characterized by processes that modify texture and flavor but also by a dramatic increase in susceptibility to necrotrophic pathogens, such as Botrytis cinerea. Disassembly of the major structural polysaccharides of the cell wall (CW) is a significant process associated with ripening and contributes to fruit softening. In tomato, polygalacturonase (PG) and expansin (Exp) are among the CW proteins that cooperatively participate in ripening-associated CW disassembly. To determine whether endogenous CW disassembly influences the ripening-regulated increase in necrotropic pathogen susceptibility, B. cinerea susceptibility was assessed in transgenic fruit with suppressed polygalacturonase (LePG) and expansin (LeExp1) expression. Suppression of either LePG or LeExp1 alone did not reduce susceptibility but simultaneous suppression of both dramatically reduced the susceptibility of ripening fruit to B. cinerea, as measured by fungal biomass accumulation and by macerating lesion development. These results demonstrate that altering endogenous plant CW disassembly during ripening influences the course of infection by B. cinerea, perhaps by changing the structure or the accessibility of CW substrates to pathogen CW-degrading enzymes. Recognition of the role of ripening-associated CW metabolism in postharvest pathogen susceptibility may be useful in the design and development of strategies to limit pathogen losses during fruit storage, handling, and distribution.

Intraductal papillary or mucinous tumors (IPMT) of the pancreas: report of a case series and review of the literature.

OBJECTIVE: Despite a better understanding of these conditions, intraductal papillary or mucinous tumors (IPMT) of the pancreas still present difficulty relating to the predictive factors of malignancy and the risk of relapse after surgical resection. The aim of this study was to report on our experience and to compare it to previously published cases. METHODS: We studied retrospectively 26 patients (mean age 60.3 yr) presenting with IPMT. Of the 26 patients, 19 had surgical resection and seven did not. The main clinical feature was acute pancreatitis occurring in 38% of the patients. Segmental pancreatectomy was performed in all the cases. At pathological assessment of resection margins, tumor resection was considered as complete in 17 cases. Margins exhibited benign mucinous involvement, and resection was considered to be incomplete in one multifocal case and in one case with diffuse spread of the tumor. RESULTS: A total of 11 tumors were benign and five were malignant. Carcinomas were invasive in four cases (two invading the pancreatic parenchyma, one the duodenum, and one the peripancreatic nodes) and in situ in one case. Malignancy was not diagnosed preoperatively except when invasion was evident (duodenal spread). Although main pancreatic duct type and obstructive jaundice appeared as suggestive features for the risk of malignancy, no reliable preoperative predictive factors for malignancy could be identified as regarding to clinical parameters, biological examinations, carcinoembryonic antigen or CA19-9 levels in serum or in pure pancreatic juice, imaging, and cytological methods. Within 40.8 months mean follow-up after surgery (range 2-96 months), three patients (16%), two with malignant and one with benign tumor, had tumor relapse after respectively 7, 27, and 14 months. Margins were positive without malignant features in the two malignant cases and negative in the other case. Tumor relapse was malignant with diffuse spreading in the three cases, and the patients died within 34 months after surgical resection. CONCLUSIONS: Our series and the review of the literature indicate that preoperative indicators of malignancy in IPMT are still lacking. Concerning resection margins, complete tumor resection is usually possible by segmental pancreatectomy. Malignant relapses are not exceptional. Incomplete resection and diffuse or multifocal tumor represent poor prognostic factors. Total pancreatectomy should be considered in such cases.

Epidemiology of Mango Malformation in Guerrero, México, with Traditional and Integrated Management.

The temporal progress of malformation (MM) of mango (Mangifera indica) was studied from 1993 to 1995 with three management technologies applied to commercial plantations in North Guerrero, Mexico. Management influenced shoot production and thus determined the dynamics of epidemics. Environmental factors also affected disease incidence, particularly through an apparent effect on inoculum dispersal. In general, integrated management (IM), consisting of pruning, acaricide, and fungicide sprays, resulted in slower rates of epidemic development, lower levels of initial and final disease, and lesser areas under the disease progress curves. In the first cycle, IM increased yield per tree by 51% in relation to high technology (HT) and 74% in relation to lower traditional technology (LT), representing a benefit-cost rate of 2.8 and 3.3, respectively. Change of malformation incidence was correlated positively with the number of macroconidia of Fusarium sp. trapped in the canopy (r = 0.90, P = 0.0001) and wind speed (r = 0.83, P = 0.0001); both variables lagged over a 4-month period. The greatest change in malformation occurred during the main vegetative flush, which occurred 3 to 6 months after picking the fruit (May). The accumulated proportion of diseased shoots was correlated with the following variables measured over a 1-week period: average maximum daily temperature (r = -0.68, P = 0. 01), average temperature per hour (r = -0.59, P = 0.04), average number of hours with relative humidity ≥60% (r = -0.82, P = 0.001), and wind speed (r = 0.94, P = 0.0001). In general, the greatest spore density was found during the rainy season, with a morning periodicity showing the highest correlation with wind speed (r = 0.812, P = 0.0001). F. subglutinans was isolated consistently from diseased (86%) and asymptomatic (5%) vegetative and flowering shoots.

Total therapeutic paracentesis (TTP) with and without intravenous albumin in the treatment of cirrhotic tense ascites: a randomized controlled trial.

We studied 35 cirrhotic patients with tense ascites assigned at random into two groups: Group I consisted of 17 patients treated by total therapeutic paracentesis (TTP) (6-15 l) plus i.v. albumin (5 g/l of fluid) and Group II consisted of 18 patients treated by TTP (5.5-15.5 l) without albumin. On 19 patients we performed a sequential assessment of cardiac output (CO), plasma renin activity (PRA) and plasma aldosterone (PA). Both groups were similar in age, sex, and etiology of cirrhosis. CO, PRA and PA values were expressed as mean changes occurring in relation to their respective baseline values. CO changes after TTP (l/min): Group I: 2.5 after 6 h and 2.2 after 12 h; Group II: 2.2 after 6 h and -0.4 after 12 h, (p < 0.05 comparing values after 12 h between the two groups). PRA changes after TTP (ng/dl/h): Group I: -7.4 after 1 h, -7.8 after 6 h and -3.2 after 24 h; Group II: -2.4 after 1 h, -0.8 after 6 h and 3.9 after 24 h (p < 0.05 comparing values between both groups after 6 and 24 h). PA changes after TTP (ng/dl): Group I: -50.5 after 1 h, -36.7 after 6 h and -34.6 after 24 h; Group II: -18.2 after 1 h, -2.2 after 6 h and 20 after 24 h, (p < 0.05 comparing values between both groups after 1 and 6 h). Complications were minimal in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)