Genetic and epigenetic characterization of a discordant kmt2a/aff1-rearranged infant monozygotic twin pair

The KMT2A/AFF1 rearrangement is associated with an unfavorable prognosis in infant acute lymphocytic leukemia (ALL). Discordant ALL in monozygotic twins is uncommon and represents an attractive resource to evaluate intrauterine environment–genetic interplay in ALL. Mutational and epigenetic profiles were characterized for a discordant KMT2A/AFF1-rearranged infant monozygotic twin pair and their parents, and they were compared to three independent KMT2A/AFF1-positive ALL infants, in which the DNA methylation and gene expression profiles were investigated. A de novo Q61H NRAS mutation was detected in the affected twin at diagnosis and backtracked in both twins at birth. The KMT2A/AFF1 rearrangement was absent at birth in both twins. Genetic analyses conducted at birth gave more insights into the timing of the mutation hit. We identified correlations between DNA methylation and gene expression changes for 32 genes in the three independent affected versus remitted patients. The strongest correlations were observed for the RAB32, PDK4, CXCL3, RANBP17, and MACROD2 genes. This epigenetic signature could be a putative target for the development of novel epigenetic-based therapies and could help in explaining the molecular mechanisms characterizing ALL infants with KMT2A/AFF1 fusions

Design, Fabrication, and Experimental Validation of Microfluidic Devices for the Investigation of Pore-Scale Phenomena in Underground Gas Storage Systems

The understanding of multiphase flow phenomena occurring in porous media at the pore scale is fundamental in a significant number of fields, from life science to geo and environmental engineering. However, because of the optical opacity and the geometrical complexity of natural porous media, detailed visual characterization is not possible or is limited and requires powerful and expensive imaging techniques. As a consequence, the understanding of micro-scale behavior is based on the interpretation of macro-scale parameters and indirect measurements. Microfluidic devices are transparent and synthetic tools that reproduce the porous network on a 2D plane, enabling the direct visualization of the fluid dynamics. Moreover, microfluidic patterns (also called micromodels) can be specifically designed according to research interests by tuning their geometrical features and surface properties. In this work we design, fabricate and test two different micromodels for the visualization and analysis of the gas-brine fluid flow, occurring during gas injection and withdrawal in underground storage systems. In particular, we compare two different designs: a regular grid and a real rock-like pattern reconstructed from a thin section of a sample of Hostun rock. We characterize the two media in terms of porosity, tortuosity and pore size distribution using the A* algorithm and CFD simulation. We fabricate PDMS-glass devices via soft lithography, and we perform preliminary air-water displacement tests at different capillary numbers to observe the impact of the design on the fluid dynamics. This preliminary work serves as a validation of design and fabrication procedures and opens the way to further investigations

Maternal but Not Paternal Association of Ambulatory Blood Pressure With Albumin Excretion in Young Offspring With Type 1 Diabetes

OBJECTIVE: Familial predisposition to hypertension has been associated with the development of diabetic nephropathy in adults, but there are limited data in adolescents. Our aim was to assess whether parental ambulatory blood pressure (ABP) was associated with ABP and albumin excretion in young offspring with type 1 diabetes. RESEARCH DESIGN AND METHODS: Twenty-four-hour ABP monitoring was performed in 509 young offspring (mean +/- SD age 15.8 +/- 2.3 years) with type 1 diabetes, 311 fathers, and 444 mothers. Systolic (SBP) and diastolic blood pressure (DBP) measurements during 24 h, daytime, and nighttime were calculated. Three early morning urinary albumin-to-creatinine ratios (ACRs), A1C, and anthropometric parameters were available for the offspring. RESULTS: All paternal ABP parameters, except for nighttime SBP, were independently related to the offspring's ABP (24-h SBP beta = 0.18, 24-h DBP beta = 0.22, daytime SBP beta = 0.25, daytime DBP beta = 0.23, and nighttime DBP beta = 0.18; all P < 0.01). Maternal 24-h DBP (beta = 0.19, P = 0.004), daytime DBP (beta = 0.09, P = 0.04), and nighttime SBP (beta = 0.24 P = 0.001) were related to the corresponding ABP parameter in the offspring. Significant associations were found between the offspring's logACR and maternal ABP. The association with 24-h DBP (beta = 0.16, P = 0.02), daytime DBP (beta = 0.16 P = 0.02), and nighttime DBP (beta = 0.15 P = 0.03) persisted even after adjustment for the offspring's ABP. Mothers of offspring with microalbuminuria had higher ABP than mothers of offspring without microalbuminuria (all P < 0.05). CONCLUSIONS: In this cohort, parental ABP significantly influenced offspring blood pressure, therefore confirming familial influences on this trait. In addition, maternal ABP, particularly DBP, was closely related to ACR in the offspring, suggesting a dominant effect of maternal genes or an effect of the intrauterine environment on microalbuminuria risk

Current trends on subtotal petrosectomy with cochlear implantation in recalcitrant chronic middle ear disorders

Objective. To establish the safety and effectiveness of subtotal petrosectomy with cochlear implantation in patients affected by chronic middle ear disorders to refractory to previous surgical treatments. Methods. A multicentre, retrospective study was conducted on patients affected by recalcitrant chronic middle ear disorders who underwent cochlear implantation in combi-nation with subtotal petrosectomy. Patients’ details were collected from databases of 11 Italian tertiary referral centres. Additionally, a review of the most updated literature was carried out. Results. 55 patients were included with a mean follow-up time of 44 months. Cholestea-toma was the most common middle ear recurrent pathology and 50.9% of patients had an open cavity. 80% of patients underwent a single stage surgery. One case of explantation for device failure was reported among the 7 patients with post-operative complications. Conclusions. Subtotal petrosectomy with cochlear implantation is a benchmark for management of patients with recalcitrant chronic middle ear disorders. A single stage procedure is the most recommended strategy. Optimal follow-up is still debated. Further studies are required to investigate the role of this surgery in paediatric patients

Determinants of urinary albumin excretion within the normal range in patients with type 2 diabetes: the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study

In contrast to microalbuminuric type 2 diabetic patients, the factors correlated with urinary albumin excretion are less well known in normoalbuminuric patients. This may be important because even within the normoalbuminuric range, higher rates of albuminuria are known to be associated with higher renal and cardiovascular risk. At the time of screening for the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) Study, the urinary albumin/creatinine ratio (UACR) was 0.44 mg/mmol in 4,449 type 2 diabetic patients. The independent correlates of UACR were analysed. Independent correlates of UACR during baseline were (in descending order): night-time systolic BP (r (s) = 0.19); HbA(1c) (r (s) = 0.18); mean 24 h systolic BP (r (s) = 0.16); fasting blood glucose (r (s) = 0.16); night-time diastolic BP (r (s) = 0.12); office systolic BP, sitting (r (s) = 0.11), standing (r (s) = 0.10); estimated GFR (r (s) = 0.10); heart rate, sitting (r (s) = 0.10); haemoglobin (r (s) = -0.10); triacylglycerol (r (s) = 0.09); and uric acid (r (s) = -0.08; all p a parts per thousand currency signaEuro parts per thousand 0.001). Significantly higher albumin excretion rates were found for the following categorical variables: higher waist circumference (more marked in men); presence of the metabolic syndrome; smoking (difference more marked in males); female sex; antihypertensive treatment; use of amlodipine; insulin treatment; family history of diabetes; and family history of cardiovascular disease (more marked in women). Although observational correlations do not prove causality, in normoalbuminuric type 2 diabetic patients the albumin excretion rate is correlated with many factors that are potentially susceptible to intervention. ClinicalTrials.gov ID no.: NCT00185159 This study was sponsored by Daichii-Sankyo.Nephrolog

Inducible Overexpression of sFlt-1 in Podocytes Ameliorates Glomerulopathy in Diabetic Mice

OBJECTIVE—Podocyte-specific, doxycycline (DOX)-inducible overexpression of soluble vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1) in adult mice was used to investigate the role of the VEGF-A/VEGF receptor (VEGFR) system in diabetic glomerulopathy

The surgical pathology laboratory in Mwanza, Tanzania: A survey on the reproducibility of diagnoses after the first years of autonomous activity

Background: In 2000, an Italian non-governmental organisation (NGO) began a 9-year project to establish a surgical pathology laboratory at the Bugando Medical Centre (BMC) in Mwanza, Tanzania, a country with a low Human Development Index (HDI), and as of 2009, the laboratory was operating autonomously. The present survey aims to evaluate the reproducibility of histological and cytological diagnoses assigned in the laboratory's early years of autonomous activity. We selected a random sample of 196 histological and cytological diagnoses issued in 2010-2011 at the BMC surgical pathology laboratory. The corresponding samples were sent to Italy for review by Italian senior pathologists, who were blinded to the local results. Samples were classified into four diagnostic categories: malignant, benign, inflammatory, and suspicious. The two-observer kappa-statistic for categorised (qualitative) data was then calculated to measure diagnostic concordance between the local Tanzanian pathologists and Italian senior pathologists. The k-Cohen was calculated for concordance in the overall study sample. Concordance and discordance rates were also stratified by subset: general adult, paediatric/adolescent, and lymphoproliferative histopathological diagnoses; fluid and fine needle aspiration (FNA) cytological diagnoses; and PAP tests. Discordance was also categorised by the corresponding hypothetical clinical implications: high, intermediate, and not significant. Results: Overall concordance was 85.2% (167 of 196 diagnoses), with a k-Cohen of 0.7691 (P = 0.0000). Very high concordance was observed in the subsets of adult general pathological diagnoses (90%) and paediatric/adolescent pathological diagnoses (91.18%). Concordance in the subset of PAP tests was 75%, and for fluid/FNA cytological diagnoses it was 56.52%. Concordance among 12 histological subtypes of lymphoma was 75.86%, with substantial discordance observed in the diagnosis of Burkitt lymphoma (five cases diagnosed by Italian pathologists versus 2 by local pathologists). The overall proportion of discordance with high hypothetical clinical implications was 6.1% (12 diagnoses). Conclusion: This blind review of diagnoses assigned in Tanzania, a country with low HDI, and in Italy, a country with a very high HDI, seemed to be a sensitive and effective method to identify areas of potential error and may represent a reference point for future, more detailed quality control processes or audits of surgical pathology services located in limited-resource regions