The Proximal Tubule and Albuminuria: Really DICKSON, Landon E; WAGNER, Mark C; SANDOVAL, Ruben M ...
Journal of the American Society of Nephrology,
03/2014, Letnik:
25, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Recent data highlight the role of the proximal tubule (PT) in reabsorbing, processing, and transcytosing urinary albumin from the glomerular filtrate. Innovative techniques and approaches have ...provided exciting insights into these processes, and numerous investigators have shown that selective PT cell defects lead to significant albuminuria, even reaching nephrotic range in animal models. Thus, the mechanisms of albumin reabsorption and transcytosis are undergoing intense study. Working in concert with megalin and cubilin, a nonselective multireceptor complex that predominantly directs proteins for lysosomal degradation, the neonatal Fc receptor (FcRn) located at the brush border of the apical membrane has been implicated as the "receptor" mediating albumin transcytosis. The FcRn pathway facilitates reabsorption and mediates transcytosis by its pH-dependent binding affinity in endosomal compartments. This also allows for selective albumin sorting within the PT cell. This reclamation pathway minimizes urinary losses and catabolism of albumin, thus prolonging its serum half-life. It may also serve as a molecular sorter to preserve and reclaim normal albumin while allowing "altered" albumin to be catabolized via lysosomal pathways. Here, we critically review the data supporting this novel mechanism.
Marine stickleback fish have colonized and adapted to thousands of streams and lakes formed since the last ice age, providing an exceptional opportunity to characterize genomic mechanisms underlying ...repeated ecological adaptation in nature. Here we develop a high-quality reference genome assembly for threespine sticklebacks. By sequencing the genomes of twenty additional individuals from a global set of marine and freshwater populations, we identify a genome-wide set of loci that are consistently associated with marine-freshwater divergence. Our results indicate that reuse of globally shared standing genetic variation, including chromosomal inversions, has an important role in repeated evolution of distinct marine and freshwater sticklebacks, and in the maintenance of divergent ecotypes during early stages of reproductive isolation. Both coding and regulatory changes occur in the set of loci underlying marine-freshwater evolution, but regulatory changes appear to predominate in this well known example of repeated adaptive evolution in nature.
BackgroundReactivation of hepatitis B virus (HBV) replication is a well-recognised complication in patients receiving disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA). ...Limited data exist on HBV reactivation among patients with RA treated with janus kinase (JAK) inhibitors. The objective of the current study was to assess HBV reactivation in clinical trials of baricitinib, an oral selective JAK1 and JAK2 inhibitor in RA.MethodsData were integrated from four completed Phase 3 trials and one ongoing long-term extension (data up to 1 April 2017) in patients naïve to DMARDs or who had inadequate response (IR) to DMARDs including methotrexate (MTX)-IR and/or other conventional synthetic DMARD (csDMARD)-IR, or tumour necrosis factor inhibitors-IR. Within the clinical programme, baricitinib-treated patients may have received concomitant csDMARDs including MTX, or previous treatment with active comparators including MTX or adalimumab + MTX. At screening, all patients were tested for HBV surface antigen (HBsAg), core antibody (HBcAb) and surface antibody (HBsAb). Patients were excluded if they had (1) HBsAg+, (2) HBcAb+/HBsAb− (in Japan, could enrol if HBV DNA−) or (3) HBsAb+ and HBV DNA+. HBV DNA monitoring, following randomisation in the originating Phase 3 studies, was performed in Japan for patients with HBcAb+ and/or HBsAb+ at screening, and was later instituted globally for HBcAb+ patients in accordance with evolving guidance for HBV monitoring and management with immunomodulatory therapy.ResultsIn total, 2890 patients received at least one dose of baricitinib in Phase 3 (6993 patient-years exposure). Of 215 patients with baseline serology suggestive of prior HBV infection (HbcAb+) who received a post-baseline DNA test, 32 (14.9%) were HBV DNA+ at some point following treatment initiation; 8 of 215 patients (3.7%) had a single quantifiable result (≥29 IU/mL). Of these eight patients, four met the definition of reactivation of HBV (HBV DNA level ≥100 IU/mL); baricitinib was permanently discontinued in four patients, and temporarily interrupted in two patients. No patient developed clinical evidence of hepatitis and in five of eight patients, antiviral therapy was not used.ConclusionHBV reactivation can occur among RA patients treated with DMARDs, including baricitinib, with prior HBV exposure. Our data suggest that such patients should be monitored for HBV DNA during treatment and might be treated safely with the use of antiviral therapy as needed. The risk of HBV reactivation in patients with HBsAg treated with baricitinib is unknown.
This report presents systematic empirical annotation of transcript products from 399 annotated protein-coding loci across the 1% of the human genome targeted by the Encyclopedia of DNA elements ...(ENCODE) pilot project using a combination of 5' rapid amplification of cDNA ends (RACE) and high-density resolution tiling arrays. We identified previously unannotated and often tissue- or cell-line-specific transcribed fragments (RACEfrags), both 5' distal to the annotated 5' terminus and internal to the annotated gene bounds for the vast majority (81.5%) of the tested genes. Half of the distal RACEfrags span large segments of genomic sequences away from the main portion of the coding transcript and often overlap with the upstream-annotated gene(s). Notably, at least 20% of the resultant novel transcripts have changes in their open reading frames (ORFs), most of them fusing ORFs of adjacent transcripts. A significant fraction of distal RACEfrags show expression levels comparable to those of known exons of the same locus, suggesting that they are not part of very minority splice forms. These results have significant implications concerning (1) our current understanding of the architecture of protein-coding genes; (2) our views on locations of regulatory regions in the genome; and (3) the interpretation of sequence polymorphisms mapping to regions hitherto considered to be "noncoding," ultimately relating to the identification of disease-related sequence alterations.
Straight leg elevation to rule out pelvic injury Bolt, Caroline; O’Keeffe, Francis; Finnegan, Pete ...
Injury,
February 2018, 2018-Feb, 2018-02-00, 20180201, Letnik:
49, Številka:
2
Journal Article
Recenzirano
Pelvic x-ray is frequently used as a screening tool during initial assessment of injured patients. However routine use in the awake and alert blunt trauma patient may be questioned due to low yield. ...We propose a clinical tool that may avoid unnecessary imaging by examining whether the ability to straight leg raise, without pain, can rule out pelvic injury.
We conducted a prospective cohort study with the exposure variables of ability to straight leg raise and presence of pain on doing so, and presence of pelvic fracture on x-ray as the primary outcome variable.
Of the 328 participants, 35 had pelvic fractures, and of these 32 were either unable to straight leg raise, or had pain on doing so, with a sensitivity of 91.43% (95% CI: 76.94–98.2%) and a negative predictive value of 98.57% (95% CI: 95.88–99.70%). The 3 participants with a pelvic fracture who could straight leg raise with no pain, all had a GCS of less than 15, and therefore, among the sub-group of patients with GCS15, a 100% sensitivity and 100% negative predictive value for straight leg raise with no pain to rule out pelvic fracture was demonstrated.
Among awake, alert patients, painless straight leg raise can exclude pelvic fractures and be incorporated into initial examination during reception and resuscitation of injured patients.
Large-scale genetic screens in zebrafish have identified thousands of mutations in hundreds of essential genes. The genetic mapping of these mutations is necessary to link DNA sequences to the gene ...functions defined by mutant phenotypes. Here, we report two advances that will accelerate the mapping of zebrafish mutations: (1) The construction of a first generation single nucleotide polymorphism (SNP) map of the zebrafish genome comprising 2035 SNPs and 178 small insertions/deletions, and (2) the development of a method for mapping mutations in which hundreds of SNPs can be scored in parallel with an oligonucleotide microarray. We have demonstrated the utility of the microarray technique in crosses with haploid and diploid embryos by mapping two known mutations to their previously identified locations. We have also used this approach to localize four previously unmapped mutations. We expect that mapping with SNPs and oligonucleotide microarrays will accelerate the molecular analysis of zebrafish mutations.
Variability of allozymes (1170 individuals, 47 populations) and chloroplast DNA (692 individuals, 29 populations) was examined in native European and introduced North American populations of ...Epipactis helleborine (Orchidaceae). At the species level, the percentage of allozyme loci that were polymorphic (P99) was 67%, with a mean of 2.11 alleles (A) per locus, and an expected heterozygosity (Hexp) of 0.294. At the population level, mean P99= 56%, mean A = 1.81, and mean Hexp= 0.231. Although field observations suggest that self-pollination occurs frequently, populations had a genetic structure consistent with Hardy-Weinberg expectations and random mating (mean FIS= 0.002). There was significant deviation from panmixia associated with population differentiation (mean FST= 0.206). The distribution of two chloroplast haplotypes showed that 15 of the 29 populations were polymorphic. Using both nuclear and organelle FSTestimates, a pollen to seed flow ratio of 1.43 :1 was calculated. This is very low compared with published estimates for other plant groups, consistent with the high dispersability of orchid seeds. Finally, there was no evidence for a genetic bottleneck associated with the introduction of E. helleborine to North America.
PDF
