Success of umbilical cord blood transplantation (UCBT) has been limited by a high rate of graft failure and delayed hematological recovery. It has been postulated that MSCs have ...hematopoiesis-supportive properties. Therefore, to overcome the limitation of UCBT, third-party UCB-derived MSCs were co-transplanted in recipients receiving unrelated UCBT. Seven patients received UCB and third-party UCB-MSCs. Hematopoietic recovery and transplantation outcomes were compared with historic controls. There was no acute toxicity associated with the infusion of MSCs. The median day to neutrophil engraftment was 19 days in patients, as compared with 24 days in controls (P=0.03). The median day of platelet engraftment was 47 days and 57 days in patients and controls, respectively (P=0.26). In addition, there was no engraftment failure in the MSC group. The incidence of acute and chronic GVHD was comparable between the two groups. However, veno-occlusive disease and TRM did not occur in the MSC group. Third-party UCB-MSCs infusion was safe and feasible. MSCs may also enhance the engraftment of UCBT and prevent rejection. In addition, MSCs may have a role in decreasing TRM. Randomized, controlled trials are required to confirm these results and longer follow-up will determine the effects of MSCs on the risk of relapse.
Hyposmia in Alzheimer's disease (AD) is a typical early symptom according to numerous previous clinical studies. Although amyloid-β (Aβ), which is one of the toxic factors upregulated early in AD, ...has been identified in many studies, even in the peripheral areas of the olfactory system, the pathology involving olfactory sensory neurons (OSNs) remains poorly understood.
Here, we focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also confirmed histologically the pathological changes in 3-month-old 5xFAD mouse models, which recapitulates AD pathology. We introduced a numeric scale histologically to compare physiological phenomenon and local tissue lesions regardless of the anatomical plane.
We observed the odorant group that the 5xFAD mice showed reduced responses to odorants. These also did not physiologically activate OSNs that propagate their axons to the ventral olfactory bulb. Interestingly, the amount of accumulated amyloid-β (Aβ) was high in the OSNs located in the olfactory epithelial ectoturbinate and the ventral olfactory bulb glomeruli. We also observed irreversible damage to the ectoturbinate of the olfactory epithelium by measuring the impaired neuronal turnover ratio from the basal cells to the matured OSNs.
Our results showed that partial and asymmetrical accumulation of Aβ coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely associated with peripheral OSN's loss could be a leading cause of AD-related hyposmia, a characteristic of early AD.
OBJECTIVE: To determine the diagnostic accuracy of the Xpert® MTB/RIF assay using samples obtained through bronchoscopy in patients with suspected pulmonary tuberculosis (PTB).DESIGN: We ...retrospectively reviewed the records of patients with suspected PTB for whom the Xpert MTB/RIF
assay was performed on bronchoscopy specimens. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the diagnosis of active PTB were calculated for acid-fast bacilli (AFB) smear microscopy and the Xpert assay using culture of Mycobacterium
tuberculosis from sputum or bronchoscopy specimens as a reference standard.RESULTS: A total of 132 patients were included in the final analysis. Of these, 38 had culture-confirmed PTB. The sensitivity of the Xpert assay using bronchial washing or bronchoalveolar lavage (BAL) fluid
for the diagnosis of PTB was 81.6%, and specificity was 100%. The PPV and NPV were 100% and 92.1%, respectively. The sensitivity and specificity of AFB smear microscopy were respectively 13.2% and 98.8%.CONCLUSION: The Xpert assay on bronchoscopy specimens provided an accurate diagnosis
of PTB in patients who had a negative AFB smear or who could not produce sputum.
Geographic atrophy (GA), an untreatable advanced form of age-related macular degeneration, results from retinal pigmented epithelium (RPE) cell degeneration. Here we show that the microRNA ...(miRNA)-processing enzyme DICER1 is reduced in the RPE of humans with GA, and that conditional ablation of Dicer1, but not seven other miRNA-processing enzymes, induces RPE degeneration in mice. DICER1 knockdown induces accumulation of Alu RNA in human RPE cells and Alu-like B1 and B2 RNAs in mouse RPE. Alu RNA is increased in the RPE of humans with GA, and this pathogenic RNA induces human RPE cytotoxicity and RPE degeneration in mice. Antisense oligonucleotides targeting Alu/B1/B2 RNAs prevent DICER1 depletion-induced RPE degeneration despite global miRNA downregulation. DICER1 degrades Alu RNA, and this digested Alu RNA cannot induce RPE degeneration in mice. These findings reveal a miRNA-independent cell survival function for DICER1 involving retrotransposon transcript degradation, show that Alu RNA can directly cause human pathology, and identify new targets for a major cause of blindness.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
Specific guidelines for initial dosing of warfarin in ischaemic stroke patients have not been developed. Therefore, we have developed an age‐ and weight‐adjusted warfarin initiation ...nomogram (AW‐WIN) for ischaemic stroke patients and then evaluated the efficacy and safety of AW‐WIN compared with physician‐determined warfarin dosing (PDWD).
Methods
The age‐ and weight‐adjusted warfarin initiation nomogram was administered to 104 acute ischaemic stroke patients between January 2008 and February 2009. A historical control group (PDWD) of 96 patients was selected from comparable patients who were discharged with warfarin during the previous year. Time‐to‐therapeutic international normalized ratios (INRs) and the incidence of excessive anticoagulation were compared in the AW‐WIN and PDWD groups.
Results
The general characteristics, risk factors, and stroke mechanism of the AW‐WIN and PDWD groups did not differ significantly. The mean time to INR ≥ 2.0 was significantly shorter in the AW‐WIN than in the PDWD group (4.9 ± 0.7 vs. 6.2 ± 0.8 days, P = 0.0008). After adjustment for potential confounding variables, the AW‐WIN group reached target INR faster than the PDWD group (hazard ratio, 1.76; 95% confidence interval, 1.26–2.45; P = 0.001). The time‐to‐therapeutic INR ≥1.7 was shorter (P = 0.0002), the proportion of patients with therapeutic INR (2–3) at 5 days was higher (P = 0.002), and the rate of excessive anticoagulation of ≥3.5 INR during hospitalization was lower (P = 0.024) in the AW‐WIN than in the PDWD group.
Conclusions
AW‐WIN reduces the time to target INR and the risk of excessive anticoagulation. AW‐WIN may be an efficient and safe method of anticoagulation during the acute phase of ischaemic stroke.
Melanins are a family of heterogeneous polymeric pigments that provide ultraviolet (UV) light protection, structural support, coloration, and free radical scavenging. Formed by oxidative ...oligomerization of catecholic small molecules, the physical properties of melanins are influenced by covalent and noncovalent disorder. We report the use of tyrosine-containing tripeptides as tunable precursors for polymeric pigments. In these structures, phenols are presented in a (supra-)molecular context dictated by the positions of the amino acids in the peptide sequence. Oxidative polymerization can be tuned in a sequence-dependent manner, resulting in peptide sequence–encoded properties such as UV absorbance, morphology, coloration, and electrochemical properties over a considerable range. Short peptides have low barriers to application and can be easily scaled, suggesting near-term applications in cosmetics and biomedicine.
Promoter hypermethylation is an important pathway for repression of gene transcription in cancer cells. We analyzed aberrant DNA methylation at four genes in primary tumors from 95 head and neck ...cancer patients and then used the presence of this methylation as a marker for cancer cell detection in serum DNA. These four genes were tested by methylation-specific PCR and included: p16 (CDKN2A), O6-methylguanine-DNA-methyltransferase, glutathione S-transferase P1, and death-associated protein kinase (DAP-kinase). Fifty-five % (52 of 95) of the primary tumors displayed promoter hypermethylation in at least one of the genes studied: 27% (26/95) at p16, 33% (31 of 95) at O6-methylguanine-DNA-methyltransferase; and 18% (17 of 92) at DAP-kinase. No promoter hypermethylation was observed at the glutathione S-transferase P1 gene promoter. We detected a statistically significant correlation between the presence of DAP-kinase gene promoter hypermethylation and lymph node involvement (P = 0.014) and advanced disease stage (P = 0.016). In 50 patients with paired serum available for epigenetic analysis, the same methylation pattern was detected in the corresponding serum DNA of 21 (42%) cases. Among the patients with methylated serum DNA, 5 developed distant metastasis compared with the occurrence of metastasis in only 1 patient negative for serum promoter hypermethylation (P = 0.056). Promoter hypermethylation of key genes in critical pathways is common in head and neck cancer and represents a promising serum marker for monitoring affected patients.
The COHERENT experiment is well poised to test sub-GeV dark matter models using detectors sensitive to coherent elastic neutrino-nucleus scattering (CEvNS) in the π+ decay-at-rest (π-DAR) neutrino ...beam produced by the Spallation Neutron Source. We show a planned 750-kg single-phase liquid argon scintillation detector would place leading limits on scalar light dark matter models for dark matter particles produced through vector and leptophobic portals in the absence of other effects beyond the standard model. The characteristic timing profile of a π-DAR beam allows a unique opportunity for constraining systematic uncertainties on the standard model background using a time window where dark matter signal is not expected, enhancing expected sensitivity. Additionally, we discuss future prospects which show that an on-axis CEvNS detector would probe the thermal abundance for a scalar dark matter candidate for all couplings α′ ≤ 1 for 15 MeV dark matter with just 1.0 tonne-yr of exposure with increased exposure testing a wider range of dark matter masses and spins.
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