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41.
A new procedure was developed and applied to study immunoglobulin free light chains (FLC) in saliva of healthy subjects and patients with multiple sclerosis (MS). The procedure was based on a Western blot analysis for detection and semiquantitative evaluation of monomeric and dimeric FLCs. The FLC indices accounting for the total FLC levels and for the monomer/dimer ratios of κ and λ FLC were calculated, and the cut‐off values of the FLC indices were determined to distinguish healthy state from MS disease. The obtained FLC index values were statistically different in the saliva of three groups: active MS patients, MS patients in remission and healthy subjects groups. Our FLC monomer–dimer analysis allowed differentiation between healthy state and active MS with specificity of 100% and a sensitivity of 88·5%. The developed technique may serve as a new non‐invasive complementary tool to evaluate the disease state by differentiating active MS from remission with sensitivity of 89% and specificity of 80%.  相似文献   
42.
Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin‐induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double‐transgenic (DTG) mice with doxycycline‐inducible overexpression of human FGF2 (SPC‐rtTA;TRE‐hFGF2) or single‐transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or day 7. In addition, wild‐type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline‐induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGFβ1‐induced expression of alpha smooth muscle actin (αSMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad‐dependent gene expression, FGF2 inhibited TGFβ1‐induced stress fiber formation and serum response factor‐dependent gene expression. FGF2 inhibition of stress fiber formation and αSMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin‐induced pulmonary fibrosis in vivo and reverses TGFβ1‐induced collagen and αSMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.  相似文献   
43.

Objectives

The study investigated the association between plasma homocysteine, folate and vitamin B12 with 5,10 methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), thymidylate synthase (TYMS 2R → 3R) and methionine synthase (MTR A2756G) polymorphisms and methotrexate (MTX) treatment and toxicity in Tunisian Rheumatoid arthritis (RA) patients.

Methods

A total of 185 patients with RA were included. Homocysteine (Hcy) was assessed by fluorescence polarization immunoassay, and folate and vitamin B12 were measured by chemiluminescence immunoassays. The genetic polymorphisms were analyzed by PCR or PCR-RFLP. Hyperhomocysteinemia (HHC) was considered for Hcy?>?15 µmol/L.

Results

MTHFR C677T polymorphism was associated with HHC in RA patients (multi-adjusted OR, 95% CI 2.18, [1.07–4.57]; p?=?0.031). No association was detected with the remaining polymorphisms. Plasma Hcy, folate, and vitamin B12 did not differ according to each polymorphism, or with MTX treatment or toxicity. However, HHC was more prevalent in patients with than those without MTX toxicity (32.7 vs. 16.7%; p?=?0.035).

Conclusions

The MTHFR 677TT genotype is an independent risk factor for HHC in Tunisians RA patients. HHC could be a useful marker of MTX toxicity in RA patients.
  相似文献   
44.

Background

Traditionally, the clinical training of health professionals has been located in central academic hospitals. This is changing. As academic institutions explore ways to produce a health workforce that meets the needs of both the health system and the communities it serves, the placement of students in these communities is becoming increasingly common. While there is a growing literature on the student experience at such distributed sites, we know less about how the presence of students influences the site itself. We therefore set out to elicit insights from key role-players at a number of distributed health service-based training sites about the contribution that students make and the influence their presence has on that site.

Methods

This interpretivist study analysed qualitative data generated during twenty-four semi-structured interviews with facility managers, clinical supervisors and other clinicians working at eight distributed sites. A sampling grid was used to select sites that proportionally represented location, level of care and mix of health professions students. Transcribed data were subjected to thematic analysis. Following an iterative process, initial analyses and code lists were discussed and compared between team members after which the data were coded systematically across the entire data set.

Results

The clustering and categorising of codes led to the generation of three over-arching themes: influence on the facility (culturally and materially); on patient care and community (contribution to service; improved patient outcomes); and on supervisors (enriched work experience, attitude towards teaching role). A subsequent stratified analysis of emergent events identified some consequences of taking clinical training to distributed sites. These consequences occurred when certain conditions were present. Further critical reflection pointed to a set of caveats that modulated the nature of these conditions, emphasising the complexity inherent in this context.

Conclusions

The move towards training health professions students at distributed sites potentially offers many affordances for the facilities where the training takes places, for those responsible for student supervision, and for the patients and communities that these facilities serve. In establishing and maintaining relationships with the facilities, academic institutions will need to be mindful of the conditions and caveats that can influence these affordances.
  相似文献   
45.
The development of the reprogramming technology led to generation of induced Pluripotent Stem Cells (iPSC) from a variety of somatic cells. Ever since, fast growing knowledge of different efficient protocols enabled the differentiation of these iPSCs into different cells types utilized for disease modeling. Indeed, iPSC-derived cells have been increasingly used for investigating molecular and cellular pathophysiological mechanisms underlying inherited diseases. However, a major barrier in the field of iPSC-based disease modeling relies on discriminating between the effects of the causative mutation and the genetic background of these cells. In the past decade, researchers have made great improvement in genome editing techniques, with one of the latest being CRISPR/Cas9. Using a single non-sequence specific protein combined with a small guiding RNA molecule, this state-of-the-art approach enables modifications of genes with high efficiency and accuracy. By so doing, this technique enables the generation of isogenic controls or isogenic mutated cell lines in order to focus on the pathologies caused by a specific mutation. In this article, we review the latest studies combining iPSC and CRISPR/Cas9 technologies for the investigation of the molecular and cellular mechanisms underlying inherited diseases including immunological, metabolic, hematological, neurodegenerative and cardiac diseases.  相似文献   
46.
Pleistocene residential sites with multiple contemporaneous human burials are extremely rare in the Americas. We report mitochondrial genomic variation in the first multiple mitochondrial genomes from a single prehistoric population: two infant burials (USR1 and USR2) from a common interment at the Upward Sun River Site in central Alaska dating to ∼11,500 cal B.P. Using a targeted capture method and next-generation sequencing, we determined that the USR1 infant possessed variants that define mitochondrial lineage C1b, whereas the USR2 genome falls at the root of lineage B2, allowing us to refine younger coalescence age estimates for these two clades. C1b and B2 are rare to absent in modern populations of northern North America. Documentation of these lineages at this location in the Late Pleistocene provides evidence for the extent of mitochondrial diversity in early Beringian populations, which supports the expectations of the Beringian Standstill Model.The colonization of the Western Hemisphere has been of interest to scholars since 1590, when Jose de Acosta postulated a northeast Asian origin of the indigenous populations of the Americas (1). Both the archaeological (2, 3) and genetic (410) records consistently indicate a primary entry point from Asia to the Americas via the Bering Land Bridge, sometime during the Late Pleistocene. However, there are unfortunate lacunae in both records. The archaeological record indicates a relatively late (<14–16 kya), rapid colonization event following the Last Glacial Maximum. This temporal scale supports the clear northeastward geographical expansion of late Upper Paleolithic (Diuktai) populations from southern and central Siberia to Beringia after 16 kya (5). However, archaeological evidence is accumulating that shows people had penetrated parts of North and South America before 13,250 cal B.P., the earliest date associated with Clovis, the first widespread cultural tradition in North America (25, 11).The genetic record is equally problematic. Continental scale analyses of genetic variation rely heavily on Central and South American population data, as well as data from Arctic populations (69, 12, 13). Few data exist for North American populations south of the Arctic. Recent surveys of contemporary genetic variation in the Americas are consistent with a period of population isolation during which the distinctive composition of Native American genomes differentiated from ancestral Asian genomes, followed by a rapid colonization; this scenario has been deemed the “Beringian Standstill Model” (6, 7, 10). How early the Native American gene pool diverged remains uncertain, but estimates of up to 30 kya have been postulated (5, 6, 10, 12, 14, 15). Most geneticists argue for at least a several thousand-year period of isolation and genetic differentiation in Beringia before a southward dispersal, despite the absence of supporting archaeological evidence (2, 4, 5, 10). Recently, Raghavan et al. (15), using genome-wide low-coverage data, suggested the dates of this isolation began no earlier than 23 kya and lasted no longer than 8,000 y (15).Ancient DNA (aDNA) samples from early inhabitants of the Americas would be important for linking the modern genetic and archaeological records (16), but few exist. The Mal’ta child from South Central Siberia indicates an early origin (>24 kya) of some signal of Native American ancestry (9), but although a few Pleistocene-aged remains have been recovered in central North America (below the Laurentide Ice Sheet) or along the Northwest Coast, no similarly aged Beringian human remains have previously been available for genetic comparison. Very few Late Pleistocene (>10,000 cal B.P.) individuals have yielded mitochondrial genetic (mtDNA) data, although we highlight the seven sites with ancient human remains dating to >8,000-y-old that have been characterized for mtDNA lineages: Hoyo Negro, Mexico (17); Anzick, MT (18); Kennewick, WA (19); On-Your-Knees Cave, AK; Wizard’s Beach, NV; Hourglass Cave, CO; and, indirectly through coprolite analysis, Paisley Cave, OR (the last four are reviewed in ref. 20) (Fig. 1).Open in a separate windowFig. 1.Geographic map of reported Native American populations with >40% C1 or B2 haplogroup frequencies, as well as locations of archaeological sites discussed. The locations of the Upward Sun River site, as well as the seven previously reported archaeological sites dated at >8,000 y B.P. with successfully genotyped human mitochondrial DNA lineages, are listed on the map (with reported haplotypes). Reported populations of ≥20 individuals with ≥40% C1 (yellow) or B2 (blue) are shown. Populations and frequencies specific to this figure (referenced by numbers 1–50) are available in the SI Materials and Methods.In 2011 Potter et al. (21) reported on the discovery of a cremated 3-y-old child from a residential feature at Upward Sun River (USR) in eastern Beringia dating to 11,500 cal B.P. Additional excavation at this deeply stratified and well-dated site (22) recently yielded two additional infant burials (Fig. 1) (USR1 and USR2) (23). A series of radiocarbon ages securely date the three individuals between 11,600 and 11,270 cal B.P. (23). Based on dental and osteological aging methods, USR1 represents a late preterm fetus, and USR2 likely died within the first 6 wk of life (23). The proximity of these three burials, their context within the same feature, and radiocarbon analyses presented in Potter et al. (23) strongly suggest that all three burials represent nearly contemporaneous events, and that the three individuals were members of a single population.We attempted to extract and sequence the mitochondrial genomes from these three Late Pleistocene burials. From burnt bone fragments of the cremated infant and well-preserved samples of the petrous portion of the parietal bone, DNA was extracted using a silica-based method and attempts were made to Sanger sequence three overlapping fragments of the mitochondrial hypervariable region 1 (HVR1). From USR1 and USR2, all three HVR1 fragments were successfully amplified, and from the cremated infant only one fragment amplified, albeit inconsistently. DNA samples and applicable blank controls from USR1 and USR2 were converted to Ion Torrent Ion Plus Fragment libraries with laboratory-unique barcodes. We targeted the mitochondrial genomes by hybridization capture (24) and sequenced the libraries on two P1 chips with an Ion Proton System (Life Technologies). This is one of the first examples of the Ion Torrent technology applied to aDNA.  相似文献   
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