Citations

Nephron number may be an important determinant of kidney health but has been difficult to study in living humans. We evaluated 1638 living kidney donors at Mayo Clinic (MN and AZ sites) and Cleveland Clinic. We obtained cortical volumes of both kidneys from predonation computed tomography scans. At the time of kidney transplant, we obtained and analyzed the sections of a biopsy specimen of the cortex to determine the density of both nonsclerotic and globally sclerotic glomeruli; the total number of glomeruli was estimated from cortical volume×glomerular density. Donors 18–29 years old had a mean 990,661 nonsclerotic glomeruli and 16,614 globally sclerotic glomeruli per kidney, which progressively decreased to 520,410 nonsclerotic glomeruli per kidney and increased to 141,714 globally sclerotic glomeruli per kidney in donors 70–75 years old. Between the youngest and oldest age groups, the number of nonsclerotic glomeruli decreased by 48%, whereas cortical volume decreased by only 16% and the proportion of globally sclerotic glomeruli on biopsy increased by only 15%. Clinical characteristics that independently associated with fewer nonsclerotic glomeruli were older age, shorter height, family history of ESRD, higher serum uric acid level, and lower measured GFR. The incomplete representation of nephron loss with aging by either increased glomerulosclerosis or by cortical volume decline is consistent with atrophy and reabsorption of globally sclerotic glomeruli and hypertrophy of remaining nephrons. In conclusion, lower nephron number in healthy adults associates with characteristics reflective of both lower nephron endowment at birth and subsequent loss of nephrons.

Abstract Purpose: Ovarian cancer has a high recurrence and mortality rate. A barrier to improved outcomes includes a lack of accurate models for preclinical testing of novel therapeutics. Experimental Design: Clinically relevant, patient-derived tumorgraft models were generated from sequential patients and the first 168 engrafted models are described. Fresh ovarian, primary peritoneal, and fallopian tube carcinomas were collected at the time of debulking surgery and injected intraperitoneally into severe combined immunodeficient mice. Results: Tumorgrafts demonstrated a 74% engraftment rate with microscopic fidelity of primary tumor characteristics. Low-passage tumorgrafts also showed comparable genomic aberrations with the corresponding primary tumor and exhibit gene set enrichment of multiple ovarian cancer molecular subtypes, similar to patient tumors. Importantly, each of these tumorgraft models is annotated with clinical data and for those that have been tested, response to platinum chemotherapy correlates with the source patient. Conclusions: Presented herein is the largest known living tumor bank of patient-derived, ovarian tumorgraft models that can be applied to the development of personalized cancer treatment. Clin Cancer Res; 20(5); 1288–97. ©2014 AACR.

Recent clinical and experimental evidence has challenged the traditional concept of the venous system as a “passive” element in the genesis and evolution of intracranial vascular malformations. The authors review the clinical and experimental evidence linking the venous system and its anomalies to the genesis of various intracranial vascular malformations, including dural arteriovenous fistulas, cavernous malformations, parenchymal arteriovenous malformations, and capillary telangiectasia. They also describe the potential significance of different associations of these vascular anomalies.

A subset of proteins that transit the endosomal system are directed into the intralumenal vesicles of multivesicular bodies (MVBs). MVB formation is critical for a variety of cellular functions including receptor down-regulation, viral budding, antigen presentation, and the generation of lysosome-related organelles. Entry of transmembrane proteins into the intralumenal vesicles of a MVB is a highly regulated process that is positively modulated by covalent modification of cargoes with ubiquitin. To identify additional MVB sorting signals, we examined the previously described ubiquitination-independent MVB cargo Sna3. Although Sna3 ubiquitination is not essential, Sna3 MVB sorting is positively modulated by its ubiquitination. Examination of MVB sorting determinants within a form of Sna3 lacking all lysine residues identified two critical regions: an amino-terminal tyrosine-containing region and a carboxyl-terminal PPAY motif. This PPAY motif interacts with the WW domains of the ubiquitin ligase Rsp5, and mutations in either the WW or, surprisingly, the HECT domains of Rsp5 negatively impacted MVB targeting of lysine-minus Sna3. These data indicate that Rsp5 function is required for MVB targeting of Sna3 in a capacity beyond cargo ubiquitination. These results uncover a series of determinants impacting Sna3 MVB sorting, including unexpected roles for Rsp5.

Objective. To determine the usefulness of measurements of the vaginal opening and amount of hymenal tissue present inferiorly and laterally in the diagnosis of vaginal penetration. Methods. The transhymenal diameters and the amount of tissue present between the hymenal edge and vestibule inferiorly at 6 o’clock and laterally at 3 o’clock and 9 o’clock were measured from photographs of 189 prepubertal children with a validated history of digital or penile penetration and 197 children who denied previous sexual abuse. Statistical analyses were conducted to compare the mean values and hymenal symmetry between groups as well as to determine the sensitivity and specificity of various cutoff points. Results. Comparison of the mean diameters demonstrated that children with a penetration history had a significantly larger transverse opening than nonabused children when examined in the knee-chest position (5.6 vs 4.6 mm). However, there was extensive overlap in measurements between the 2 groups. No significant differences were noted between groups in the size of the vertical diameter, the amount of tissue present inferiorly or laterally, or the symmetry of the hymen in either position. Children with previous penetration were more likely than nonabused children to have a horizontal opening measuring >6.5 mm in the knee-chest position, but the sensitivity and specificity of this test were low (29% and 86%, respectively). Higher values had better specificity but very low sensitivity. Less than 1.0 mm of hymenal tissue was detected at 6 o’clock only in those with a history of penetration (100% specificity), but the sensitivity was low (1%–2%). Conclusion. Most hymenal measurements lack adequate sensitivity or specificity to be used to confirm previous penetration. Less than 1.0 mm of hymenal tissue at 6 o’clock was detected only in victims of abuse, but the usefulness of this test is limited by the rarity of this finding.