Acute interstitial nephritis with acetaminophen and alcohol intoxication

Drug-induced acute interstitial nephritis (AIN) represents a growing cause of renal failure in current medical practice. While antimicrobials and non-steroidal anti-inflammatory drugs are typically associated with drug-induced AIN, few reports have been made on the involvement of other analgesics. We report our experience in managing a 17-year-old female with AIN and subsequent renal injury following an acetaminophen overdose in conjunction with acute alcohol intoxication. It is well established that acetaminophen metabolism, particularly at high doses, produces reactive metabolites that may induce renal and hepatic toxicity. It is also plausible however, that such reactive species could instead alter renal peptide immunogenicity, thereby inducing AIN. In the following report, we review a possible mechanism for the acetaminophen-induced AIN observed in our patient and also discuss the potential involvement of acute alcohol ingestion in disease onset. The objective of our report is to increase awareness of healthcare professionals to the potential involvement of these commonly used agents in AIN pathogenesis

Serum Galactose-Deficient IgA1 Level Is Not Associated with Proteinuria in Children with IgA Nephropathy

Introduction. Percentage of galactose-deficient IgA1 (Gd-IgA1) relative to total IgA in serum was recently reported to correlate with proteinuria at time of sampling and during follow-up for pediatric and adult patients with IgA nephropathy. We sought to determine whether this association exists in another cohort of pediatric patients with IgA nephropathy. Methods. Subjects were younger than 18 years at entry. Blood samples were collected on one or more occasions for determination of serum total IgA and Gd-IgA1. Gd-IgA1 was expressed as serum level and percent of total IgA. Urinary protein/creatinine ratio was calculated for random specimens. Spearman's correlation coefficients assessed the relationship between study variables. Results. The cohort had 29 Caucasians and 11 African-Americans with a male : female ratio of 1.9 : 1. Mean age at diagnosis was 11.7 ± 3.7 years. No statistically significant correlation was identified between serum total IgA, Gd-IgA1, or percent Gd-IgA1 versus urinary protein/creatinine ratio determined contemporaneously with biopsy or between average serum Gd-IgA1 or average percent Gd-IgA1 and time-average urinary protein/creatinine ratio. Conclusion. The magnitude of proteinuria in this cohort of pediatric patients with IgA nephropathy was influenced by factors other than Gd-IgA1 level, consistent with the proposed multi-hit pathogenetic pathways for this renal disease

Crustal structure across the Grand Banks–Newfoundland Basin Continental Margin – II. Results from a seismic reflection profile

Author Posting. © Blackwell, 2006. This is the author's version of the work. It is posted here by permission of Blackwell for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 167 (2006): 157-170, doi:10.1111/j.1365-246X.2006.02989.x.New multi-channel seismic (MCS) reflection data were collected over a 565km transect covering the non-volcanic rifted margin of the central eastern Grand Banks and the Newfoundland Basin in the northwestern Atlantic. Three major crustal zones are interpreted from west to east over the seaward 350-km of the profile: (1) continental crust; (2) transitional basement; (3) oceanic crust. Continental crust thins over a wide zone (~160 km) by forming a large rift basin (Carson Basin) and seaward fault block, together with a series of smaller fault blocks eastward beneath the Salar and Newfoundland basins. Analysis of selected previous reflection profiles (Lithoprobe 85-4, 85-2 and Conrad NB-1) indicates that prominent landward-dipping reflections observed under the continental slope are a regional phenomenon. They define the landward edge of a deep serpentinized mantle layer, which underlies both extended continental crust and transitional basement. The 80-km-wide transitional basement is defined landward by a basement high that may consist of serpentinized peridotite and seaward by a pair of basement highs of unknown crustal origin. Flat and unreflective transitional basement most likely is exhumed, serpentinized mantle, although our results do not exclude the possibility of anomalously thinned oceanic crust. A Moho reflection below interpreted oceanic crust is first observed landward of magnetic anomaly M4, 230 km from the shelf break. Extrapolation of ages from chron M0 to the edge of interpreted oceanic crust suggests that the onset of seafloor spreading was ~138Ma (Valanginian) in the south (southern Newfoundland Basin) to ~125Ma (Barremian-Aptian boundary) in the north (Flemish Cap), comparable to those proposed for the conjugate margins.This work was funded by NSF grants OCE-9819053 and OCE-0326714 to Woods Hole Oceanographic Institution, NSERC (Canada) and the Danish Research Council. B. Tucholke also acknowledges support from the Henry Bryant Bigelow Chair in Oceanography at Woods Hole Oceanographic Institution

Crustal structure across the Grand Banks–Newfoundland Basin Continental Margin – I. Results from a seismic refraction profile

Author Posting. © Blackwell, 2006. This is the author's version of the work. It is posted here by permission of Blackwell for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 167 (2006): 127-156, doi:10.1111/j.1365-246X.2006.02988.x.A P-wave velocity model along a 565-km-long profile across the Grand Banks/Newfoundland basin rifted margin is presented. Continental crust ~36-kmthick beneath the Grand Banks is divided into upper (5.8-6.25 km/s), middle (6.3- 6.53 km/s) and lower crust (6.77-6.9 km/s), consistent with velocity structure of Avalon zone Appalachian crust. Syn-rift sediment sequences 6-7-km thick occur in two primary layers within the Jeanne d’Arc and the Carson basins (~3 km/s in upper layer; ~5 km/s in lower layer). Abrupt crustal thinning (Moho dip ~ 35º) beneath the Carson basin and more gradual thinning seaward forms a 170-km-wide zone of rifted continental crust. Within this zone, lower and middle continental crust thin preferentially seaward until they are completely removed, while very thin (<3 km) upper crust continues ~60 km farther seaward. Adjacent to the continental crust, high velocity gradients (0.5-1.5 s-1) define an 80-km-wide zone of transitional basement that can be interpreted as exhumed, serpentinized mantle or anomalously thin oceanic crust, based on its velocity model alone. We prefer the exhumed-mantle interpretation after considering the non-reflective character of the basement and the low amplitude of associated magnetic anomalies, which are atypical of oceanic crust. Beneath both the transitional basement and thin (<6 km) continental crust, a 200-kmwide zone with reduced mantle velocities (7.6-7.9 km/s) is observed, which is interpreted as partially (<10%) serpentinized mantle. Seaward of the transitional basement, 2- to 6-km-thick crust with layer 2 (4.5-6.3 km/s) and layer 3 (6.3-7.2 km/s) velocities is interpreted as oceanic crust. Comparison of our crustal model with profile IAM-9 across the Iberia Abyssal Plain on the conjugate Iberia margin suggests asymmetrical continental breakup in which a wider zone of extended continental crust has been left on the Newfoundland side.This research was supported by National Science Foundation (NSF) grants OCE-9819053 and OCE-0326714, by the National Sciences and Engineering Research Council of Canada (NSERC), and by the Danish National Research Foundation. B. Tucholke also acknowledges support from the Henry Bryant Bigelow Chair in Oceanography from Woods Hole Oceanographic Institution

The TolC Protein of Legionella pneumophila Plays a Major Role in Multi-Drug Resistance and the Early Steps of Host Invasion

Pneumonia associated with Iegionnaires's disease is initiated in humans after inhalation of contaminated aerosols. In the environment, Legionella pneumophila is thought to survive and multiply as an intracellular parasite within free-living amoeba. In the genome of L. pneumophila Lens, we identified a unique gene, tolC, encoding a protein that is highly homologous to the outer membrane protein TolC of Escherichia coli. Deletion of tolC by allelic exchange in L. pneumophila caused increased sensitivity to various drugs. The complementation of the tolC mutation in trans restored drug resistance, indicating that TolC is involved in multi-drug efflux machinery. In addition, deletion of tolC caused a significant attenuation of virulence towards both amoebae and macrophages. Thus, the TolC protein appears to play a crucial role in virulence which could be mediated by its involvement in efflux pump mechanisms. These findings will be helpful in unraveling the pathogenic mechanisms of L. pneumophila as well as in developing new therapeutic agents affecting the efflux of toxic compounds

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Structural Analysis of a Repetitive Protein Sequence Motif in Strepsirrhine Primate Amelogenin

Strepsirrhines are members of a primate suborder that has a distinctive set of features associated with the development of the dentition. Amelogenin (AMEL), the better known of the enamel matrix proteins, forms 90% of the secreted organic matrix during amelogenesis. Although AMEL has been sequenced in numerous mammalian lineages, the only reported strepsirrhine AMEL sequences are those of the ring-tailed lemur and galago, which contain a set of additional proline-rich tandem repeats absent in all other primates species analyzed to date, but present in some non-primate mammals. Here, we first determined that these repeats are present in AMEL from three additional lemur species and thus are likely to be widespread throughout this group. To evaluate the functional relevance of these repeats in strepsirrhines, we engineered a mutated murine amelogenin sequence containing a similar proline-rich sequence to that of Lemur catta. In the monomeric form, the MQP insertions had no influence on the secondary structure or refolding properties, whereas in the assembled form, the insertions increased the hydrodynamic radii. We speculate that increased AMEL nanosphere size may influence enamel formation in strepsirrhine primates

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment