Citations

AbstractThe neurotransmitter dopamine (DA) is known to be involved in a multitude of physiological processes. We investigated sexually dimorphic effects of disruptions in DA homeostasis and its relationship to senescence using three different Drosophila melanogaster mutants namely Catsup (Catsup26) with elevated DA levels, and pale (ple2), Punch (PuZ22) with depleted DA levels. In all genotypes including controls, DA levels were significantly lower in old (45–50‐day‐old) flies compared with young (3–5‐day‐old) in both sexes. Interestingly, females had lower DA content than males at young age whereas this difference was not observed in old age, suggesting that males had a larger decline in DA levels with age. Females, in general, were longer lived compared with males in all genotypes except ple2 mutants with depleted DA levels. This phenotype was abolished in the ple2 rescue flies. Interestingly, females also demonstrated marked age‐related decline in circadian locomotor activity compared with males. Old Catsup26 males with elevated DA levels accumulated significantly lower levels of lipid peroxidation product 4‐hydroxy 2‐nonenal (4‐HNE) compared with age‐matched wild type, ple2 and PuZ22 mutant males. In Catsup26 revertant lines this phenomenon was absent. We also observed a sexually dimorphic response in the expression levels of key stress and aging associated and/or related transcription factor genes across genotypes with elevated or depleted DA levels which was reverted to wild type levels in specific rescue lines. Taken together, our results reveal a novel sexually dimorphic involvement of DA in senescence characteristics of D. melanogaster.

ABSTRACTIntroductionPolyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial.MethodsWe assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7Ionis) and its subscores and correlation with disability and health scores.ResultsThe mNIS+7Ionis sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests.ConclusionsSpecially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7Ionis, broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901–911, 2017

ABSTRACTIntroductionUltrasound is increasingly used as an adjunct in the diagnosis of neuromuscular disease by measuring muscle thickness and echointensity (EI). Reproducibility is limited because of variations in scanning technique and proprietary algorithms that alter EI values.MethodsWe developed a standardized scanning protocol and a portable machine without any postimaging processing. Ten subjects underwent scanning of 6 muscles by 3 sonographers on 2 separate days. One of the sonographers repeated the protocol with 4 different machine/transducer combinations. Gray‐scale values were measured from each image with the use of a region of interest (ROI) box.ResultsCombined intraclass correlation coefficients were 0.92 (intra‐rater), 0.88 (inter‐rater), and 0.96 (inter‐system). The biceps had the highest variability (coefficient of variance [COV] 12.7%), and the medial gastrocnemius had the lowest variability (COV 7.4%).ConclusionsWe demonstrate excellent reliability of a reproducible ultrasound system for gray‐scale analysis of muscle that has potential applicability as a screening tool for neuromuscular disease. Muscle Nerve 56: 408–412, 2017

Background: Mitral valve (MV) repair is preferred over replacement in clinical guidelines and is an important determinant of the indication for surgery in degenerative mitral regurgitation. However, the level of evidence supporting current recommendations is low, and recent data cast doubts on its validity in the current era. Accordingly, the aim of the present study was to analyze very long-term outcome after MV repair and replacement for degenerative mitral regurgitation with a flail leaflet. Methods: MIDA (Mitral Regurgitation International Database) is a multicenter registry enrolling patients with degenerative mitral regurgitation with a flail leaflet in 6 tertiary European and US centers. We analyzed the outcome after MV repair (n=1709) and replacement (n=213) overall, by propensity score matching, and by inverse probability-of-treatment weighting. Results: At baseline, patients undergoing MV repair were younger, had more comorbidities, and were more likely to present with a posterior leaflet prolapse than those undergoing MV replacement. After propensity score matching and inverse probability-of-treatment weighting, the 2 treatments groups were balanced, and absolute standardized differences were usually <10%, indicating adequate match. Operative mortality (defined as a death occurring within 30 days from surgery or during the same hospitalization) was lower after MV repair than after replacement in both the entire population (1.3% versus 4.7%; P <0.001) and the propensity-matched population (0.2% versus 4.4%; P <0.001). During a mean follow-up of 9.2 years, 552 deaths were observed, of which 207 were of cardiovascular origin. Twenty-year survival was better after MV repair than after MV replacement in both the entire population (46% versus 23%; P <0.001) and the matched population (41% versus 24%; P <0.001). Similar superiority of MV repair was obtained in patient subsets on the basis of age, sex, or any stratification criteria (all P <0.001). MV repair was also associated with reduced incidence of reoperations and valve-related complications. Conclusions: Among patients with degenerative mitral regurgitation with a flail leaflet referred to mitral surgery, MV repair was associated with lower operative mortality, better long-term survival, and fewer valve-related complications compared with MV replacement.

The most common causes of chronic cholestatic liver disease are primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Both disease processes are characterized by a destruction of intrahepatic and/or extrahepatic biliary ducts. The etiology is not entirely clear; however, there is an underlying autoimmune component contributing to both disease processes. Although PBC and PSC are often diagnosed and managed in the outpatient setting, in some instances, a patient may have jaundice, fatigue, and pruritus requiring evaluation and determination of the cholestatic cause. Patients with PSC should be monitored for evidence of cholangiocarcinoma, colon cancer, and gallbladder polyps as they are at an increased risk of malignant neoplasms. Liver transplant has the potential for improving quality of life, although disease recurrence is a risk.

ABSTRACT The widespread dissemination of carbapenem-resistant Acinetobacter spp. has created significant therapeutic challenges. At present, rapid molecular diagnostics (RMDs) that can identify this phenotype are not commercially available. Two RMD platforms, PCR combined with electrospray ionization mass spectrometry (PCR/ESI-MS) and molecular beacons (MB), for detecting genes conferring resistance/susceptibility to carbapenems in Acinetobacter spp. were evaluated. An archived collection of 200 clinical Acinetobacter sp. isolates was tested. Predictive values for susceptibility and resistance were estimated as a function of susceptibility prevalence and were based on the absence or presence of beta-lactamase ( bla ) NDM, VIM, IMP, KPC, and OXA carbapenemase genes (e.g., bla OXA-23 , bla OXA-24/40 , and bla OXA-58 found in this study) against the reference standard of MIC determinations. According to the interpretation of MICs, 49% ( n = 98) of the isolates were carbapenem resistant (as defined by either resistance or intermediate resistance to imipenem). The susceptibility sensitivities (95% confidence interval [CI]) for imipenem were 82% (74%, 89%) and 92% (85%, 97%) for PCR/ESI-MS and MB, respectively. Resistance sensitivities (95% CI) for imipenem were 95% (88%, 98%) and 88% (80%, 94%) for PCR/ESI-MS and MB, respectively. PRIMERS III establishes that RMDs can discriminate between carbapenem resistance and susceptibility in Acinetobacter spp. In the context of a known prevalence of resistance, SPVs and RPVs can inform clinicians regarding the best choice for empiric antimicrobial therapy against this multidrug-resistant pathogen.

Introduction: Racial and ethnic groups are under-represented among research subjects who assent to brain donation in Alzheimer disease research studies. There has been little research on this important topic. Although there are some studies that have investigated the barriers to brain donation among African American study volunteers, there is no known research on the factors that influence whether or not Asians or Latinos are willing to donate their brains for research. Methods: African American, Caucasian, Asian, and Latino research volunteers were surveyed at 15 Alzheimer Disease Centers to identify predictors of willingness to assent to brain donation. Results: Positive predictors included older age, Latino ethnicity, understanding of how the brain is used by researchers, and understanding of what participants need to do to ensure that their brain will be donated. Negative predictors included African/African American race, belief that the body should remain whole at burial, and concern that researchers might not be respectful of the body during autopsy. Discussion: The predictive factors identified in this study may be useful for researchers seeking to increase participation of diverse ethnic groups in brain donation.

Abstract We have investigated the distribution of PDGFR-a and -b in the stroma of normal breast tissue, ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) by immunohistochemistry. Both receptors were expressed by fibroblasts of normal breast tissue. While the PDGFRb remained high during cancer progression, the PDGFRa was lost in most of the DCIS samples and not detectable in IDC. The patient group with PDGFRa(low)/PDGFRb(high) fibroblasts had the highest risk for local recurrences or metastasis. The characteristic loss of stromal PDGFRa expression was also observed in the PyMT mouse breast cancer model. In vitro co-culture experiments confirmed a tumor cell-induced differentiation of fibroblasts, resulting in a fibroblast population marked by PDGFRa(low)/PDGFRb(high) expression. We could identify the interaction of Jagged-1 expressed by the tumor cells with Notch-2 expressed on the fibroblasts, as an essential activator of TGFb signaling in fibroblasts. Gene expression analysis and reporter-gene assays of sorted cells from co-cultures revealed, that fibroblasts switch from a more anti-tumorigenic signaling (expression of BMPs and Wnt antagonists) towards a pro-tumorigenic signaling (expression of BMP inhibitors, TGFb and Wnt ligands). Co-cultured tumor cells show an increased migratory activity and the induction of a mesenchymal phenotype. Inhibition of Notch or TGF signaling in fibroblasts could block these phenotypes. To investigate the impact of fibroblasts on the progression of DCIS to IDC, a DCIS xenograft model was used. Co-injection of MCF10.DCIS cells with human breast fibroblasts, expressing both PDGFRs, into the mouse mammary fat pad resulted in an earlier tumor take with faster tumor growth. The corresponding co-injection experiments with fibroblast and tumor cells, that were depleted of Notch2 respectively Jagged-1 expression by CRISPR/CAS technology is currently ongoing. Collectively the study identifies a potentially druggable paracrine cross-talk between epithelial and stromal cells, which promotes DCIS progression and involves a Notch mediated up-regulation of TGFb signaling. The study also suggests that loss of PDGFRa marks a subset of fibroblasts with specific tumor-promoting activities. Citation Format: Carina Strell, Janna Paulsson, Artur Mezheyeuski, Shao-Bo Jin, Pernilla Roswall, Johanna Andrea, Oliver Frings, Fredrick Warnberg, Hemming Johansson, Karin Jirstrom, Kristian Pietras, Per Hall, Urban Lendahl, Christer Betsholtz, Derek C. Radisky, Arne Ostman. Cell-contact dependent epithelial-stromal cross talk, including a modulation of stromal PDGFR expression, drives the progression of early-stage breast cancer lesions. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B41.