Citations

AbstractBackgroundIt is not known whether preclinical cognitive decline is associated with fibrillar β‐amyloid (Aβ) deposition irrespective of apolipoprotein E (APOE) ε4 status.MethodsFrom a prospective observational study of 623 cognitively normal individuals, we identified all subjects who showed preclinical decline of at least 2 standard deviations beyond the decline of the entire group in memory or executive function. Fourteen decliners were matched by APOE ε4 gene dose, age, sex, and education with 14 nondecliners. Dynamic Pittsburgh compound B (PiB) positron emission tomography (PET) scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest were used to characterize and compare cerebral‐to‐cerebellar PiB distribution volume ratios (DVRs), reflecting fibrillar Aβ burden.ResultsAt P < .005 (uncorrected), decliners had significantly greater DVRs in comparison to nondecliners.ConclusionsAsymptomatic longitudinal neuropsychological decline is associated with subsequent increased fibrillar amyloid deposition, even when controlling for APOE ε4 genotype.

AbstractBackgroundIt is unclear whether self‐ or informant‐based subjective cognition better distinguishes emotional factors from early‐stage Alzheimer's disease (AD).MethodsHealthy members (n = 447) of the Arizona apolipoprotein E (APOE) cohort and their informants completed the self and informant paired Multidimensional Assessment of Neurodegenerative Symptoms questionnaire (MANS).ResultsDecline on the MANS was endorsed by 30.6% of members and 26.2% of informants. Self‐ and informant‐based decliners had higher scores of psychological distress and slightly lower cognitive scores than nondecliners. Over the next 6.7 years, 20 developed mild cognitive impairment (MCI). Converters were older at entry than nonconverters (63.8 [7.0] vs 58.8 [7.3] years, P = .003), 85% were APOE ε4 carriers (P < .0001), and they self‐endorsed decline earlier than informants (58.9 [39.2] vs 28.0 [40.4] months before MCI; P = .002).ConclusionsSelf‐ and informant‐based subjective decline correlated with greater psychological distress and slightly lower cognitive performance. Those with incident MCI generally self‐endorsed decline earlier than informants.

Background and Study Aims. Endoscopic placement of self-expanding metal stents (SEMSs) is indicated for palliation of inoperable malignant biliary obstruction. A fully covered biliary SEMS (WallFlex Biliary RX Boston Scientific, Natick, USA) was assessed for palliation of extrahepatic malignant biliary obstruction.Patients and Methods. 58 patients were included in this prospective, multicenter series conducted under an FDA-approved IDE. Main outcome measurements included (1) absence of stent occlusion within six months or until death, whichever occurred first and (2) technical success, need for reintervention, bilirubin levels, stent patency, time to stent occlusion, and adverse events.Results. Technical success was achieved in 98% (57/58), with demonstrated acute removability in two patients. Adequate clinical palliation until completion of followup was achievedin 98% (54/55) ofevaluablepatients, with 1 reintervention due to stent obstruction after 142 days. Mean total bilirubin decreased from 8.9 mg/dL to 1.2 mg/dL at 1 month. Device-related adverse events were limited and included 2 cases of cholecystitis. One stent migrated following radiation therapy.Conclusions. The WallFlex Biliary fully covered stent yielded technically successful placement with uncomplicated acute removal where required, appropriate reduction in bilirubin levels, and low rates of stent migration and occlusion. This SEMS allows successful palliation of malignant extrahepatic biliary obstruction.

Blood-brain barrier (BBB) dysfunction in acute liver failure (ALF) results in increased BBB permeability that often precludes the patients from obtaining a life-saving liver transplantation. It remains controversial whether matrix metalloproteinase-9 (MMP-9) from the injured liver contributes to the deregulation of BBB function in ALF. We selectively upregulated a physiologic inhibitor of MMP-9 (TIMP-1) with a single intracerebroventricular injection of TIMP-1 cDNA plasmids at 48 and 72 hours, or with pegylated-TIMP-1 protein. Acute liver failure was induced with tumor necrosis factor-α and D-(+)-galactosamine in mice. Permeability of BBB was assessed with sodium fluorescein (NaF) extravasation. We found a significant increase in TIMP-1 within the central nervous system (CNS) after the administration of TIMP-1 cDNA plasmids and that increased TIMP-1 within the CNS resulted in an attenuation of BBB permeability, a reduction in activation of epidermal growth factor receptor and p38 mitogen-activated protein kinase signals, and a restoration of the tight junction protein occludin in mice with experimental ALF. Pegylated TIMP-1 provided similar protection against BBB permeability in mice with ALF. Our results provided a proof of principle that MMP-9 contributes to the BBB dysfunction in ALF and suggests a potential therapeutic role of TIMP-1 in ALF.

This study concerns the development and preliminary experimental verification of a topological sensitivity–based platform for the material characterization of tissue anomalies exposed by vibroacoustography-type imaging techniques. Vibroacoustography (VA) is a high-resolution imaging method that has been applied to the detection of pathological changes in soft tissues. Although the data provided by this method is related to the mechanical properties of tissue, the viscoelastic parameters of the object cannot be estimated by this imaging method itself. Topological sensitivity (TS) method is a data processing methodology that can be used to estimate the viscoelastic parameters of an object from vibration data. In this study, the concept of topological sensitivity is applied to interpret the vibroacoustography measurements for the purpose of lesion characterization. In the proposed approach, the topological sensitivity function, which signifies the variation of a given cost functional when an infinitesimal inclusion with trial material parameters is placed at the location of a point force, is formulated in terms of the adjoint field. The effectiveness of the resulting formula as a material indicator for lesion characterization is demonstrated by estimating the relative elastic parameters of a well-controlled neoprene sphere embedded in a tissue-mimicking phantom specimen.

A 66-year-old male patient presented with nausea, abdominal pain, occasional rectal bleeding, progressive dysgeusia, onicodystrophy, and alopecia. Endoscopic exam and biopsies revealed severe atrophy and diffuse marked edema of mucosa of stomach and duodenum. No evidence of polyps was found in any portion of the gastrointestinal tract. The diagnosis of Cronkhite–Canada syndrome (CCS) was rendered. The patient symptoms resolved completely after initiation of steroid treatment. This additional case of CCS illustrates how the diagnosis of CCS does not require the presence of polyps but is defined by the appreciation of the diffuse marked edema and atrophy of the gastrointestinal mucosa.

HE4, also known as WFDC2, is a useful biomarker for ovarian cancer when either used alone or in combination with CA125. HE4 is also overexpressed in endometrial cancer (EC), but its function in cancer cells is not clear. In this study, we investigate the role of HE4 in EC progression. An HE4-overexpression system was established by cloning the HE4 prototypic mRNA variant (HE4-V0) into a eukaryotic expression vector. Following transfection, stable clones in two EC cell lines were selected. The effects of HE4 overexpression on cell growth and function were measured with the use of cell proliferation assay, matrigel invasion, and soft agar gel colony formation assays. HE4-induced cancer cell proliferation in vivo was examined in a mouse xenograft model. HE4 overexpression significantly enhanced EC cell proliferation, matrigel invasion, and colony formation in soft agar. Moreover, HE4 overexpression promoted tumor growth in the mouse xenograft model. HE4 overexpression enhanced several malignant phenotypes in cell culture and in a mouse model. These results are consistent with our previous observation that high levels of serum HE4 closely correlate with the stage, myometrial invasion and tumor size in patients with EC. This study provides evidence that HE4 overexpression directly impacts tumor progression in endometrial cancer.

Na+/H+exchanger 3 (NHE3) provides one of the major Na+absorptive pathways of the intestine and kidney in mammals, and recent studies of aquatic vertebrates (teleosts and elasmobranchs) have demonstrated that NHE3 is expressed in the gill and plays important roles in ion and acid-base regulation. To understand the role of NHE3 in elasmobranch osmoregulatory organs, we analyzed renal and intestinal expressions and localizations of NHE3 in a marine elasmobranch, Japanese banded houndshark ( Triakis scyllium). mRNA for Triakis NHE3 was most highly expressed in the gill, kidney, spiral intestine, and rectum. The kidney and intestine expressed a transcriptional isoform of NHE3 (NHE3k/i), which has a different amino terminus compared with that of NHE3 isolated from the gill (NHE3g), suggesting that NHE3k/i and NHE3g arise from a single gene by alternative promoter usage. Immunohistochemical analyses of the Triakis kidney demonstrated that NHE3k/i is expressed in the apical membrane of a part of the proximal and late distal tubules in the sinus zone. In the bundle zone of the kidney, NHE3k/i was expressed in the apical membrane of the early distal tubules known as the diluting segment. In the spiral intestine and rectum, NHE3k/i was localized toward the apical membrane of the epithelial cells. The transcriptional levels of NHE3k/i were increased in the kidney when Triakis was acclimated in 130% seawater, whereas those in the spiral intestine were increased in fish acclimated in diluted seawater. These results suggest that NHE3 is involved in renal Na+reabsorption, urine acidification, and intestinal Na+absorption in elasmobranchs.

Abstract In shotgun proteomics, database search algorithms rely on fragmentation models to predict fragment ions that should be observed for a given peptide sequence. The most widely used strategy (Naive model) is oversimplified, cleaving all peptide bonds with equal probability to produce fragments of all charges below that of the precursor ion. More accurate models, based on fragmentation simulation, are too computationally intensive for on-the-fly use in database search algorithms. We have created an ordinal-regression-based model called Basophile that takes fragment size and basic residue distribution into account when determining the charge retention during CID/higher-energy collision induced dissociation (HCD) of charged peptides. This model improves the accuracy of predictions by reducing the number of unnecessary fragments that are routinely predicted for highly-charged precursors. Basophile increased the identification rates by 26% (on average) over the Naive model, when analyzing triply-charged precursors from ion trap data. Basophile achieves simplicity and speed by solving the prediction problem with an ordinal regression equation, which can be incorporated into any database search software for shotgun proteomic identification.