20 research outputs found
A re-appraisal of volume status and renal function impairment in chronic heart failure: combined effects of pre-renal failure and venous congestion on renal function
The association between cardiac failure and renal function impairment has gained wide recognition over the last decade. Both structural damage in the form of systemic atherosclerosis and (patho) physiological hemodynamic changes may explain this association. As regards hemodynamic factors, renal impairment in chronic heart failure is traditionally assumed to be mainly due to a decrease in cardiac output and a subsequent decrease in renal perfusion. This will lead to a decrease in glomerular filtration rate and a compensatory increase in tubular sodium retention. The latter is a physiological renal response aimed at retaining fluids in order to increase cardiac filling pressure and thus renal perfusion. In heart failure, however, larger increases in cardiac filling pressure are needed to restore renal perfusion and thus more volume retention. In this concept, in chronic heart failure, an equilibrium exists where a certain degree of congestion is the price to be paid to maintain adequate renal perfusion and function. Recently, this hypothesis was challenged by new studies, wherein it was found that the association between right-sided cardiac filling pressures and renal function is bimodal, with worse renal function at the highest filling pressures, reflecting a severely congested state. Renal hemodynamic studies suggest that congestion negatively affects renal function in particular in patients in whom renal perfusion is also compromised. Thus, an interplay between cardiac forward failure and backward failure is involved in the renal function impairment in the congestive state, presumably along with other factors. Only few data are available on the impact of intervention in volume status on the cardio-renal interaction. Sparse data in cardiac patients as well as evidence from cohorts with primary renal disease suggest that specific targeting of volume overload may be beneficial for long-term outcome, in spite of a certain further decrease in renal function, at least in the context of current treatment where possible reflex neurohumoral activation is ameliorated by the background treatment by blockers of the renin–angiotensin–aldosterone system
Selection of Salmonella enterica Serovar Typhi Genes Involved during Interaction with Human Macrophages by Screening of a Transposon Mutant Library
The human-adapted Salmonella enterica serovar Typhi (S. Typhi) causes a systemic infection known as typhoid fever. This disease relies on the ability of the bacterium to survive within macrophages. In order to identify genes involved during interaction with macrophages, a pool of approximately 105 transposon mutants of S. Typhi was subjected to three serial passages of 24 hours through human macrophages. Mutants recovered from infected macrophages (output) were compared to the initial pool (input) and those significantly underrepresented resulted in the identification of 130 genes encoding for cell membrane components, fimbriae, flagella, regulatory processes, pathogenesis, and many genes of unknown function. Defined deletions in 28 genes or gene clusters were created and mutants were evaluated in competitive and individual infection assays for uptake and intracellular survival during interaction with human macrophages. Overall, 26 mutants had defects in the competitive assay and 14 mutants had defects in the individual assay. Twelve mutants had defects in both assays, including acrA, exbDB, flhCD, fliC, gppA, mlc, pgtE, typA, waaQGP, SPI-4, STY1867-68, and STY2346. The complementation of several mutants by expression of plasmid-borne wild-type genes or gene clusters reversed defects, confirming that the phenotypic impairments within macrophages were gene-specific. In this study, 35 novel phenotypes of either uptake or intracellular survival in macrophages were associated with Salmonella genes. Moreover, these results reveal several genes encoding molecular mechanisms not previously known to be involved in systemic infection by human-adapted typhoidal Salmonella that will need to be elucidated
Using whole-genome sequences of the LG/J and SM/J inbred mouse strains to prioritize quantitative trait genes and nucleotides
Phase II trial of preoperative radiochemotherapy with concurrent bevacizumab, capecitabine and oxaliplatin in patients with locally advanced rectal cancer
Background: Preoperative radiochemotherapy (RCT) with 5-FU or capecitabine is the standard of care for patients with locally advanced rectal cancer (LARC). Preoperative RCT achieves pathological complete response rates (pCR) of 10-15%. We conducted a single arm phase II study to investigate the feasibility and efficacy of addition of bevacizumab and oxaliplatin to preoperative standard RCT with capecitabine.
Methods: Eligible patients had LARC (cT3-4; N0/1/2, M0/1) and were treated with preoperative RCT prior to planned surgery. Patients received conventionally fractionated radiotherapy (50.4 Gy in 1.8 Gy fractions) and simultaneous chemotherapy with capecitabine 825 mg/m2 bid (d1-14, d22-35) and oxaliplatin 50 mg/m2 (d1, d8, d22, d29). Bevacizumab 5 mg/kg was added on days 1, 15, and 29. The primary study objective was the pCR rate.
Results: 70 patients with LARC (cT3-4; N0/1, M0/1), ECOG < 2, were enrolled at 6 sites from 07/2008 through 02/2010 (median age 61 years [range 39–89], 68% male). At initial diagnosis, 84% of patients had clinical stage T3, 62% of patients had nodal involvement and 83% of patients were M0. Mean tumor distance from anal verge was 5.92 cm (± 3.68). 58 patients received the complete RCT (full dose RT and full dose of all chemotherapy). During preoperative treatment, grade 3 or 4 toxicities were experienced by 6 and 2 patients, respectively: grade 4 diarrhea and nausea in one patient (1.4%), respectively, grade 3 diarrhea in 2 patients (3%), grade 3 obstipation, anal abscess, anaphylactic reaction, leucopenia and neutropenia in one patient (1.4%), respectively. In total, 30 patients (46%) developed postoperative complications of any grade including one gastrointestinal perforation in one patient (2%), wound-healing problems in 7 patients (11%) and bleedings in 2 patients (3%). pCR was observed in 12/69 (17.4%) patients. Pathological downstaging (ypT < cT and ypN ≤ cN) was achieved in 31 of 69 patients (44.9%). All of the 66 operated patients had a R0 resection. 47 patients (68.1%) underwent sphincter preserving surgery.
Conclusions: The addition of bevacizumab and oxaliplatin to RCT with capecitabine was well tolerated and did not increase perioperative morbidity or mortality. However, the pCR rate was not improved in comparison to other trials that used capecitabine or capecitabine/oxaliplatin in preoperative radiochemotherapy
The Pcdp1 complex coordinates the activity of dynein isoforms to produce wild-type ciliary motility
The C1d projection of the central apparatus includes Pcdp1 and is required for ciliary motility. A combination of structural and functional studies shows that C1d is required for coordination of dynein activity on specific doublets and differentially affects the activity of both the outer and inner dynein arms
The CSC is required for complete radial spoke assembly and wild-type ciliary motility
Structural and functional analyses of artificial micro RNA (amiRNA) mutants reveal that the CSC plays a role not only in generating wild-type motility, but also in assembly of at least a subset of radial spokes. This study also produced the unexpected finding that, contrary to current belief, the radial spokes may not be homogeneous
Candidate genes for obesity revealed from a C57BL/6J x 129S1/SvImJ intercross.
OBJECTIVE: To identify the genes controlling body fat, we carried out a quantitative trait locus (QTL) analysis using C57BL/6J (B6) and 129S1/SvImJ (129) mice, which differ in obesity susceptibility after consuming an atherogenic diet. METHODS: Mice were fed chow until 8 weeks and an atherogenic diet from 8 to 16 weeks; body fatness was measured by X-ray absorptiometry in 528 (B6 x 129) F(2) at 8 and 16 weeks. A high-density genome scan was performed using 508 polymorphic markers. After identifying the genetic loci, we narrowed the QTL using comparative genomics and bioinformatics. RESULTS: The percentage of body fat was significantly linked to loci on chromosomes (Chr) 1 (22, 68 and 173 Mb), 4 (74 Mb), 5 (73 Mb), 7 (88 Mb), 8 (43 and 80 Mb), 9 (55 Mb), 11 (115 Mb) and 12 (32 Mb); three suggestive loci on Chrs 6 (76 Mb), 9 (30 Mb) and 16 (26 Mb) and two pairs of interacting loci (Chr 2 at 99.8 Mb with Chr 7; Chr 1 at 68 Mb with Chr 11). Comparative genomics narrowed the QTL intervals by 20-57% depending on the chromosome; in most cases, haplotype analysis further narrowed them by about 90%. CONCLUSIONS: Our analysis identified 15 QTL for percentage of body fat. We narrowed the QTL using comparative genomics and haplotype analysis and suggest several candidate genes: Apcs on Chr 1, Ppargc1a on Chr 5, Ucp1 on Chr 8, Angptl6 on Chr 9 and Lpin1 on Chr 12