Insertion of a left ventricular assist device (LVAD) is an accepted therapy for advanced heart failure patients. However, the effects on end-organ perfusion, including cerebral autoregulation, are ...unclear in the presence of reduced pulsatility. Therefore, the objective of this study was to determine whether cerebral autoregulation is impaired in patients with continuous-flow (CF) LVADs.
Dynamic cerebral autoregulation was assessed in both time-domain (autoregulatory index) and frequency-domain (transfer function analysis) analyses in 9 CF-LVAD subjects, 5 pulsatile LVAD subjects and 10 healthy controls, by evaluating mean arterial pressure (MAP) and cerebral blood flow velocity (CBFV) during a sit-stand maneuver at 0.05 Hz (10-second sit, 10-second stand). The autoregulatory index was calculated as the percent change in mean CBFV per mm Hg change in MAP.
The magnitude of oscillation in MAP and CBFV was greater in subjects with pulsatile LVADs than either CF-LVADs or healthy controls (p = 0.065 for MAP, p = 0.004 for CBFV). The autoregulatory index and transfer function gain were similar among groups, indicating that dynamic cerebral autoregulation is preserved among patients with CF-LVADs.
Cerebral blood flow in patients with CF-LVADs is comparable to that of healthy controls across a range of blood pressures. Patients with pulsatile devices have greater oscillations in MAP and CBFV. However, dynamic cerebral autoregulation is preserved among subjects with either type of device. Thus, the reduction in pulsatility afforded by CF-LVADs does not impair normal autoregulatory processes.
The peritoneal cavity of mice is enriched for B-1 B cells, a lymphocyte subset that differs from conventional B-2 cells phenotypically, functionally, and developmentally. According to current ...paradigms, all peritoneal B-1 cells express Mac-1 whereas B-2 cells do not and thus these populations are often purified by FACS sorting or magnetic bead isolation based on B cell expression of Mac-1 or lack thereof. However, in the course of studying B220
+/Mac-1
− peritoneal B-2 cells, we discovered that this population is actually heterogeneous, with approximately 30–40% of these B220
+/Mac-1
− cells expressing the B-1 cell marker CD5. It was unclear whether this B220
+/CD5
+/Mac-1
− peritoneal B cell population represented aberrantly CD5 expressing B-2 cells or Mac-1
− B-1 cells. To address this issue we tested CD5
+/Mac-1
− peritoneal B cells for several traits that distinguish B-1 and B-2 cells. We found that CD5
+/Mac-1
− peritoneal B cells resembled CD5
+ B-1 cells and not B-2 cells in terms of expression of several additional surface markers (IgM, IgD, CD23, CD43, and CD80). Further, CD5
+/Mac-1
− peritoneal B cells expressed high levels of V
H11 and V
H12, two Ig variable genes that are expressed mainly by B-1 but not B-2 cells. In addition, CD5
+/Mac-1
− peritoneal B cells responded to PMA, a mitogen that stimulates B-1 cells but not B-2 cells, and not to anti-Ig, that stimulates B-2 cells but not B-1 cells. ELISPOT analyses of freshly isolated CD5
+/Mac-1
− peritoneal B cells revealed that they secreted IgM constitutively, like B-1 cells and unlike B-2 cells. These results indicate that CD5
+/Mac-1
− peritoneal B cells are a new subset of B-1 cells, here termed B-1c, and stress the importance of using multiple surface markers to identify and purify specific B cell populations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PALB2 has emerged as a breast cancer susceptibility gene. Mutations in PALB2 have been identified in almost all breast cancer populations studied to date, but the rarity of these mutations and lack ...of information regarding their penetrance makes genetic counseling for these families challenging. We studied BRCA1/2 -negative breast and/or ovarian cancer families to a) assess the contribution of PALB2 mutations in this series and b) identify clinical, pathological and family history characteristics that might make PALB2 screening more efficient.
The coding region of the PALB2 gene was analyzed in 175 probands with family histories of breast and/or ovarian cancer ascertained from a single Canadian institution in Eastern Ontario.
We identified 2 probands with PALB2 mutations that are known or strongly considered to be pathogenic and 3 probands with missense mutations that are possibly pathogenic. One of the identified truncating mutations c.3113G > A (p.Gly1000_Trp1038del - major product), has been previously described while the other four mutations c.3507_3508delTC (p.H1170Ffs*19), c.1846G > C (p.D616H), c.3418 T > G (p.W1140G), c.3287A > G (p.N1096S) have not been previously reported. Loss of heterozygosity was detected in two breast tumors from one c.3507_3508delTC mutation carrier but not in other available tumors from that family or in tumors from carriers of other mutations.
PALB2 mutation screening identifies a small, but significant number of mutations in BRCA1/2 -negative breast and/or ovarian cancer families. We show that mutations are more likely to be found in families with three or more breast cancers as well as other BRCA2-related cancers. In our cohort, both clearly pathogenic mutations were identified in premenopausal breast cancer cases (2/77, 2.6%). Testing should be preferentially offered to affected women from such families.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The recent discovery of CD4
+
T cells characterized by secretion of interleukin (IL)-17 (T
H
17 cells) and the naturally occurring regulatory FOXP3
+
CD4 T cell (nT
reg
) has had a major impact on ...our understanding of immune processes not readily explained by the T
H
1/T
H
2 paradigm. T
H
17 and nT
reg
cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis
1
,
2
. Our recent data and the work of others demonstrated that transforming growth factor-β (TGF-β) and IL-6 are responsible for the differentiation of naive mouse T cells into T
H
17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the T
H
17 phenotype
3
-
5
. A second pathway has been discovered in which a combination of TGF-β and IL-21 is capable of inducing differentiation of mouse T
H
17 cells in the absence of IL-6 (refs
6
-
8
). However, TGF-β and IL-6 are not capable of differentiating human T
H
17 cells
2
,
9
and it has been suggested that TGF-β may in fact suppress the generation of human T
H
17 cells
10
. Instead, it has been recently shown that the cytokines IL-1β, IL-6 and IL-23 are capable of driving IL-17 secretion in short-term CD4
+
T cell lines isolated from human peripheral blood
11
, although the factors required for differentiation of naive human CD4 to T
H
17 cells are still unknown. Here we confirm that whereas IL-1β and IL-6 induce IL-17A secretion from human central memory CD4
+
T cells, TGF-β and IL-21 uniquely promote the differentiation of human naive CD4
+
T cells into T
H
17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of T
H
17 cells in human inflammatory disease.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background and goal: RAD51D is a key player in DNA repair by homologous recombination (HR) and carriers of truncating RAD51D mutations have an increased risk for ovarian cancer (OC). ...However, the contribution of non-truncating RAD51D variants to cancer predisposition remains uncertain. We sought to fully characterize the previously described missense RAD51D variant c.620C>T;p.S207L in order to elucidate its role in OC.
Methods: A clinical panel screening was used to identify the RAD51D variant c.620C>T;p.S207L in two French Canadian (FC) kindred affected with familial High Grade Serous Cancer (HGSC) of the ovary or endometrium. High resolution melting, TaqMan genotyping and Sanger sequencing were used to genotype the p.S207L variant in a series of unselected cases of HGSC of the ovary and endometrium, breast, pancreas and colorectal cancer and healthy controls, all of a FC origin. Whole exome sequencing (WES) was performed to study the genetic signature characterizing RAD51D associated tumors. RAD51 foci formation and CRISPR-Cas9-stimulated and HR-mediated gene targeting assays were used to assess HR activity of RAD51D-S207L mutated CHO cells. HR activity in RAD51D-S207L mutated human cells was tested by a DR-GFP assay. The effect of RAD51D p.S207L on RAD51D-XRCC2 interactions was analyzed by co-immunoprecipitation and quantified in-vivo in a single cell colocalization assay. Sensitivity to PARP inhibitors (PARPi) was evaluated in a cell survival assay.
Results: Using deep sequencing and case-control genotyping studies, we showed that the missense RAD51D variant c.620C>T;p.S207L is over-represented in the French Canadian population affected by HGSC of the ovary (3.8% cases vs 0.002% controls; p < 0.0001).The frequency of the p.S207L variant did not differ from that of controls in breast, endometrial, pancreas and colorectal adenocarcinomas. A common haplotype shared by all the carriers suggested a founder origin for c.620C>T;p.S207L mutation. WES analysis of RAD51D tumor profiles revealed the presence of signature 3 which is known to be associated with HR defects. Functionally, we show that this mutation impairs HR by disrupting the RAD51D-XRCC2 interaction and confers PARP-inhibitor sensitivity to CHO cells.
Conclusions: This work identifies RAD51D p.S207L as the first bona fide pathogenic missense susceptibility allele for HGSC of the ovary and supports the use of targeted PARPi therapies in OC patients carrying missense RAD51D mutations.
Citation Format: Barbara Rivera, Massimo R. Di Iorio, Jessica Frankum, Javad Nadaf, Somayyeh Fahiminiya, Suzanna L. Arcand, David Burk, Damien Grapton, Eva Tomiak, Valerie Hastings, Nancy Hamel, Rabea Wagener, Olga Aleynikova, Sylvie Giroux, Fadi F. Hamdan, Alexandre Orthwein, George Zogopoulos, Francois Rousseau, Albert Berghuis, Diane M. Provencher, Guy A. Rouleau, Jacques L. Michaud, Anne-Marie Mes-Masson, Jacek Majewski, Susanne Bens, Reiner Siebert, Steven Narod, Mohammad Akbari, Chris J. Lord, Patricia N. Tonin, Alexandre Dionne-Laporte, William D. Foulkes. A functionally null RAD51D missense mutation is strongly associated with ovarian carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2479. doi:10.1158/1538-7445.AM2017-2479
Species invasions provide numerous unplanned and frequently, but imperfectly, replicated experiments that can be used to better understand the natural world. Classic studies by Darwin, Grinnell, ...Elton and others on these species-invasion experiments provided invaluable insights for ecology and evolutionary biology. Recent studies of invasions have resulted in additional insights, six of which we discuss here; these insights highlight the utility of using exotic species as ‘model organisms’. We also discuss a nascent hypothesis that might provide a more general, predictive understanding of invasions and community assembly. Finally, we emphasize how the study of invasions can help to inform our understanding of applied problems, such as extinction, ecosystem function and the response of species to climate change.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Oligonucleotide sequences selected from the 16S rRNA genes of various species of ammonia-oxidizing bacteria were evaluated as specific PCR amplification primers and probes. The specificities of ...primer pairs for eubacterial, Nitrosospira and Nitrosomonas rRNA genes were established with sequence databases, and the primer pairs were used to amplify DNA from laboratory cultures and environmental samples. Eubacterial rRNA genes amplified from samples of soil and activated sludge hybridized with an oligonucleotide probe specific for Nitrosospira spp., but not with a Nitrosomonas-specific probe. Lakewater and sediment samples were analysed using a nested PCR technique in which eubacterial rRNA genes were subjected to a secondary amplification with Nitrosomonas or Nitrosospira specific primers. Again, the presence of Nitrosospira DNA, but not Nitrosomonas DNA, was detected and this was confirmed by hybridization of the amplified DNA with an internal oligonucleotide probe. Enrichments of lakewater and sediment samples, incubated for two weeks in the presence of ammonium, produced nitrite and were found to contain DNA from both Nitrosospira and Nitrosomonas as determined by nested PCR amplification and probing of 16S rRNA genes. This demonstrates that Nitrosospira spp. are widespread in the environment. The implications of the detection of Nitrosomonas DNA only after enrichment culture are discussed.
Glyoxal is a significant atmospheric aldehyde formed from both anthropogenic aromatic compounds and biogenic isoprene emissions. The chemical behavior of glyoxal relevant to secondary organic aerosol ...(SOA) formation and analysis is examined in GC−MS, electrospray ionization (ESI)-MS, and particle chamber experiments. Glyoxal oligomers are shown to rapidly decompose to glyoxal in GC injection ports at temperatures ≥120 °C. Glyoxal dihydrate monomer is dehydrated at temperatures ≥140 °C during GC analysis but shows only oligomers (n ≤ 7) upon ESI-MS analysis. Thus both of these analytical techniques will cause artifacts in speciation of glyoxal in SOA. In particle chamber experiments, glyoxal (at ∼0.1 Torr) condensed via particle-phase reactions when relative humidity levels exceeded a threshold of ∼26%. Both the threshold humidity and particle growth rates (∼0.1 nm/min) are consistent with a recent study performed at glyoxal concentrations 4 orders of magnitude below those used here. This consistency suggests a mechanism where the surface water layer of solid-phase aerosol becomes saturated with glyoxal dihydrate monomer, triggering polymerization and the establishment of an organic phase.
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IJS, KILJ, NUK, PNG, UL, UM
B cell susceptibility to Fas-mediated apoptosis is downmodulated by engagement of IL-4 and sIg receptors. IL-4 produces Fas-resistance in both normal and tolerant B lymphocytes and has been ...associated with autoantibody production in mice expressing heterogeneous B cell receptors. To study the in vivo effects of IL-4 on autoreactive B cells in a more well-defined system, mice triply transgenic for IL-4, soluble HEL and anti-HEL B cell receptors were generated. Anti-HEL/sHEL/IL-4 triple transgenic mice matured normally but accumulated increasing amounts of serum anti-HEL antibodies over time, whereas anti-HEL/sHEL double transgenic mice lacked serum anti-HEL. Autoantibodies in triple transgenic mice were accompanied by gross evidence of renal pathology, characterized by both abnormal histology and marked proteinuria, along with microscopic evidence of immune complex-type hepatic damage. Proteinuria and histopathological changes were also observed in IL-4 transgenic control mice. These results suggest that IL-4 induced a breakdown in tolerance and autoreactive B cell activity manifested by the onset and accumulation of autoantibodies and the development of frank autoimmune disease.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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