To update the follow-up of the Euro-Lupus Nephritis Trial (ELNT), a randomised prospective trial comparing low-dose (LD) and high-dose (HD) intravenous (IV) cyclophosphamide (CY) followed by ...azathioprine (AZA) as treatment for proliferative lupus nephritis.
Data for survival and kidney function were prospectively collected during a 10-year period for the 90 patients randomised in the ELNT, except in 6 lost to follow-up.
Death, sustained doubling of serum creatinine and end-stage renal disease rates did not differ between the LD and HD group (5/44 (11%) vs 2/46 (4%), 6/44 (14%) vs 5/46 (11%) and 2/44 (5%) vs 4/46 (9%), respectively) nor did mean serum creatinine, 24 h proteinuria and damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. After 10 years of follow-up, the positive predictive value for a good outcome of an early drop in proteinuria in response to initial immunosuppressive therapy was confirmed.
The data confirm that a LD IVCY regimen followed by AZA-the "Euro-Lupus regimen"-achieves good clinical results in the very long term.
A MW 6.3 earthquake struck on April 6, 2009 the Abruzzi region (central Italy) producing vast damage in the L'Aquila town and surroundings. In this paper we present the location and geometry of the ...fault system as obtained by the analysis of main shock and aftershocks recorded by permanent and temporary networks. The distribution of aftershocks, 712 selected events with ML ≥ 2.3 and 20 with ML ≥ 4.0, defines a complex, 40 km long, NW trending extensional structure. The main shock fault segment extends for 15–18 km and dips at 45° to the SW, between 10 and 2 km depth. The extent of aftershocks coincides with the surface trace of the Paganica fault, a poorly known normal fault that, after the event, has been quoted to accommodate the extension of the area. We observe a migration of seismicity to the north on an echelon fault that can rupture in future large earthquakes.
BACKGROUND AND PURPOSE Several studies have demonstrated anti‐proliferative and pro‐apoptotic actions of cannabinoids on various tumours, together with their anti‐angiogenic properties. The ...non‐psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down‐regulates some pro‐angiogenic signals produced by glioma cells. As its anti‐angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis.
EXPERIMENTAL APPROACH Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability – through 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay and FACS analysis – and in vitro motility – both in a classical Boyden chamber test and in a wound‐healing assay. We next investigated CBD effects on different angiogenesis‐related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice.
KEY RESULTS CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down‐modulation of several angiogenesis‐related molecules.
CONCLUSIONS AND IMPLICATIONS This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy.
To cite this article:
Lenza MG, Lenza de O. MM, Dalstra M, Melsen B, Cattaneo PM: An analysis of different approaches to the assessment of upper airway morphology: a CBCT study Orthod Craniofac Res ...2010;13:96–105
Structured
Authors – Lenza MG, Lenza de O MM, Dalstra M, Melsen B, Cattaneo PM
Background – Upper airway morphology and respiration have been assigned an important role in the development of the craniofacial complex. Several studies advocate lateral cephalograms to evaluate the upper airway. Although this method has been widely used, a two‐dimensional projection of a three‐dimensional anatomical structure is questionable.
Objective – To correlate linear measurements (sagittal and transversal), cross‐sectional areas, and volumes of the upper airway determined on Cone Beam CT (CBCT) data sets.
Material and Methods – CBCT‐scans of 34 patients were used to perform a 3D evaluation of the upper airway. Linear sagittal measurements reproducing those usually performed on lateral cephalograms, linear transversal measurements, cross‐sectional areas, partial and total volumes (TV) were computed.
Results – The analysis showed a weak correlation (r < 0.8) between most of the linear measurements. The correlations between sagittal, transversal, and cross‐sectional area with partial volumes were weak, except for the lower part of the nasopharynx which was highly correlated (r > 0.9) with sagittal measurement and with area. The upper part of the velopharynx presented a good correlation (0.8 < r < 0.9) between area and volume. Good correlation between most transversal measurements and the corresponding areas was found. Minimal sagittal, minimal transversal, and minimal area were weakly correlated with TV.
Conclusions – Upper airway cannot be accurately expressed by single linear measurements as performed on cephalograms. The TV alone does not depict the morphology of the airway. A CBCT‐based 3D analysis gives a better picture of the anatomical characteristics of the upper airways and therefore can lead to an improvement of the diagnosis.
We present the first direct search for lepton flavour violating muon decay mediated by a new light particle X,
μ
+
→
e
+
X
,
X
→
γ
γ
. This search uses a dataset resulting from
7.5
×
10
14
stopped ...muons collected by the MEG experiment at the Paul Scherrer Institut in the period 2009–2013. No significant excess is found in the mass region 20–45 MeV/c
2
for lifetimes below 40 ps, and we set the most stringent branching ratio upper limits in the mass region of 20–40 MeV/c
2
, down to
O
(
10
-
11
)
at 90% confidence level.
Abstract Multilevel synchrotron radiation-based microtomography has been performed on a human jaw segment obtained at autopsy by cutting increasingly smaller samples from the original segment. The ...focus of this study lay on the microstructure of the interface between root, periodontal ligament (PDL) and alveolar bone in order to find an answer to the question why alveolar bone remodels during orthodontic loading, when the associated stress and strain levels calculated with finite element analyses are well below the established threshold levels for bone remodeling. While the inner surface of the alveolus appears to be rather smooth on the lower resolution scans, detailed scans of the root–PDL–bone interface reveal that on a microscopical scale it is actually quite rough and uneven with bony spiculae protruding into the PDL space. Any external (orthodontic) loading applied to the root, when transferred through the PDL to the alveolar bone, will cause stress concentrations in these spiculae, rather than be distributed over a “smooth surface”. As osteocyte lacunae are shown to be present in these spiculae, the local amplified stresses and strain can well be registered by the mechano-sensory network of osteocytes. In addition, a second stress amplification mechanism, due to the very presence of the lacunae themselves, is evidence that stresses and strains calculated with FE analyses, based on macroscopical scale models of teeth and their supporting structures, grossly underestimate the actual mechanical loading of alveolar bone at tissue level. It is therefore hypothesized that remodeling of alveolar bone is subject to the same biological regulatory process as remodeling in other bones.
Therapeutic drug monitoring (TDM) is a tool to personalize and optimize dosing by measuring the drug concentration and subsequently adjusting the dose to reach a target concentration or exposure. The ...evidence to support TDM is however often ranked as expert opinion. Limitations in study design and sample size have hampered definitive conclusions of the potential added value of TDM.
We aim to give expert opinion and discuss the main points and limitations of available data from antibiotic TDM trials and emphasize key elements for consideration in design of future clinical studies to quantify the benefits of TDM.
The sources were peer-reviewed publications, guidelines and expert opinions from the field of TDM.
This review focuses on key aspects of antimicrobial TDM study design: describing the rationale for a TDM study, assessing the exposure of a drug, assessing susceptibility of pathogens and selecting appropriate clinical endpoints. Moreover we provide guidance on appropriate study design.
This is an overview of different aspects relevant for the conduct of a TDM study. We believe that this paper will help researchers and clinicians to design and conduct high-quality TDM studies.
Recent investigations demonstrated a significant correlation between rectal dose-volume patterns and late rectal toxicity. The reduction of the DVH to a value expressing the probability of ...complication would be suitable. To fit different normal tissue complication probability (NTCP) models to clinical outcome on late rectal bleeding after external beam radiotherapy (RT) for prostate cancer.
Rectal dose-volume histograms of the rectum (DVH) and clinical records of 547 prostate cancer patients (pts) pooled from five institutions previously collected and analyzed were considered. All patients were treated in supine position with 3 or 4-field techniques: 123 patients received an ICRU dose between 64 and 70
Gy, 255 patients between 70 and 74
Gy and 169 patients between 74 and 79.2
Gy; 457/547 patients were treated with conformal RT and 203/547 underwent radical prostatectomy before RT. Minimum follow-up was 18 months. Patients were considered as bleeders if showing grade 2/3 late bleeding (slightly modified RTOG/EORTC scoring system) within 18 months after the end of RT. Four NTCP models were considered: (a) the Lyman model with DVH reduced to the equivalent uniform dose (LEUD, coincident with the classical Lyman–Kutcher–Burman, LKB, model), (b) logistic with DVH reduced to EUD (LOGEUD), (c) Poisson coupled to EUD reduction scheme and (d) relative seriality (RS). The parameters for the different models were fit to the patient data using a maximum likelihood analysis. The 68% confidence intervals (CI) of each parameter were also derived.
Forty six out of five hundred and forty seven patients experienced grade 2/3 late bleeding: 38/46 developed rectal bleeding within 18 months and were then considered as bleeders The risk of rectal bleeding can be well calculated with a ‘smooth’ function of EUD (with a seriality parameter
n equal to 0.23 (CI 0.05), best fit result). Using LEUD the relationship between EUD and NTCP can be described with a TD50 of 81.9
Gy (CI 1.8
Gy) and a steepness parameter
m of 0.19 (CI 0.01); when using LOGEUD, TD50 is 82.2
Gy and
k is 7.85. Best fit parameters for RS are
s=0.49, γ=1.69, TD50=83.1
Gy. Qualitative as well as quantitative comparisons (chi-squared statistics,
P=0.005) show that the models fit the observed complication rates very well. The results found in the overall population were substantially confirmed in the subgroup of radically treated patients (LEUD:
n=0.24
m=0.14 TD50=75.8
Gy). If considering just the grade 3 bleeders (
n=9) the best fit is found in correspondence of a
n-value around 0.06, suggesting that for severe bleeding the rectum is more serial.
Different NTCP models fit quite accurately the considered clinical data. The results are consistent with a rectum ‘less serial’ than previously reported investigations when considering grade 2 bleeding while a more serial behaviour was found for severe bleeding. EUD may be considered as a robust and simple parameter correlated with the risk of late rectal bleeding.
Epigenetic changes on DNA and chromatin are implicated in cell differentiation and organogenesis. For the heart, distinct histone methylation profiles were recently linked to stage-specific gene ...expression programs during cardiac differentiation in vitro. However, the enzymes catalyzing these modifications and the genes regulated by them remain poorly defined. We therefore decided to identify the epigenetic enzymes that are potentially involved in cardiomyogenesis by analyzing the expression profile of the 85 genes encoding the epigenetic-related proteins in mouse cardiomyocytes (CMs), and then study how they affect gene expression during differentiation and maturation of this cell type. We show here with gene expression screening of epigenetic enzymes that the highly expressed H3 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) drives a transitional pattern of di-methylation on H3 lysine 79 (H3K79) in CMs at different stages of differentiation in vitro and in vivo. Through a genome-wide chromatin-immunoprecipitation DNA-sequencing approach, we found H3K79me2 enriched at genes expressed during cardiac differentiation. Moreover, knockdown of Dot1L affected the expression of H3K79me2-enriched genes. Our results demonstrate that histone methylation, and in particular DOT1L-mediated H3K79me2 modification, drives cardiomyogenesis through the definition of a specific transcriptional landscape.
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