Aims
To investigate whether small nerve fibre degeneration detected using corneal confocal microscopy is associated with cardiac autonomic neuropathy in people with Type 1 diabetes.
Methods
...Thirty‐six people with Type 1 diabetes and 20 age‐ and sex‐matched healthy control subjects were enrolled. Tests to determine heart rate response to deep‐breathing (expiratory‐to‐inspiratory ratio), heart rate response to lying‐to‐stand test (30:15 ratio) and blood pressure response to standing were performed to detect cardiac autonomic neuropathy. Corneal confocal microscopy was performed to assess: corneal nerve density and corneal nerve beadings; branching pattern; and nerve fibre tortuosity.
Results
Compared with control participants, participants with Type 1 diabetes had fewer (mean ± sd 45.4 ± 20.2 vs 92.0 ± 22.7 fibres/mm2; P < 0.001) and more tortuous corneal nerve fibres (20 participants with Type 1 diabetes vs four control participants had nerve tortuosity grade 2/3; P = 0.022) and fewer beadings (mean ± sd 15.1 ± 3.5 vs 20.6 ± 5.0; P < 0.001). Of the participants with Type 1 diabetes, 11 met the criteria for the diagnosis of cardiac autonomic neuropathy. Corneal nerve density was significantly lower in participants with cardiac autonomic neuropathy than in those without (mean ± sd 32.8 ± 16.4 vs 51.7 ± 18.9 fibres/mm2; P = 0.008). This difference remained significant after adjustment for age (P = 0.02), gender (P = 0.04), disease duration (P = 0.005), insulin requirement (P = 0.02) and neuropathy disability score (P = 0.04).
Conclusion
This study suggests that corneal confocal microscopy could represent a new and non‐invasive tool to investigate cardiac autonomic neuropathy in people with Type 1 diabetes. Larger studies are required to define the role of corneal confocal microscopy in the assessment of cardiac autonomic neuropathy.
What's new?
Cardiac autonomic neuropathy is one of the most overlooked but life‐threatening complications of diabetes mellitus.
It is possible to improve impaired cardiac autonomic function, especially in the earlier stages of cardiac autonomic neuropathy but, unfortunately, tests currently available for the investigation of cardiac autonomic neuropathy are invasive and/or inaccurate, difficult to perform and time‐consuming. New techniques that allow easier screening for cardiac autonomic neuropathy are therefore required.
We show, for the first time, that corneal confocal microscopy can be an effective tool for the clinical diagnosis of cardiac autonomic neuropathy.
Abstract
This paper presents the experimental investigation results from the modalities of variation of the hydraulic conductivity scaling law for a confined aquifer, varying the porous medium that ...constitutes it. In four subsequent stages, different confined aquifers were built up, each with a different typological configuration of a porous medium. For each of the aquifers considered, various hydraulic conductivity (
K
) measurements were performed by slug tests. The effective porosity (
n
e
) was set as a scale parameter, therefore the scaling laws
K = K(n
e
)
, already determined and reported in previous studies, were taken into consideration for each of the four artificial aquifers considered. The same variation law of
K
vs
n
e
was also determined by means of some of the well-known empirical and semi-empirical relationships. The latter are based on the particle size distribution and are suitable for application to the porous media considered here, which can be classified as coarse sand. The comparison between the different scaling laws mentioned above allowed us to discuss, through graphical analysis, the reliability of the models considered here. This will facilitate researchers and practitioners working in the field, in the methodological choice of the most appropriate model that should be used for this type of porous media.
The mdm2 oncogene product, MDM2, is an ubiquitin protein ligase that inhibits the transcriptional activity of the tumor suppressor p53 and promotes its degradation. About 50% of all human cancers ...present mutations or deletions in the TP53 gene. In the remaining half of all human neoplasias that express the wild-type protein, aberrations of p53 regulators, such as MDM2, account for p53 inhibition. For this reason, designing small-molecule inhibitors of the p53-MDM2 protein-protein interaction is a promising strategy for the treatment of cancers retaining wild-type p53. The development of inhibitors has been challenging. Although many small-molecule MDM2 inhibitors have shown potent in vitro activity, only a limited number of compounds have demonstrated to possess acceptable pharmacokinetic properties for in vivo evaluation. To date, the most studied chemotypes have been cis-imidazolines (such as nutlins), benzodiazepines, and spiro-oxindoles. The cis-imidazolines were the first discovered potent and selective small-molecule inhibitors of the p53-MDM2 interaction and they continue to show therapeutic potential. This review will focus on recent molecular modeling approaches (molecular dynamics, pharmacophore-based, molecular docking, structure-based design) used with the aim to better understand the behavior of these proteins and to discover new small-molecule inhibitors of the p53-MDM2 protein-protein interaction for the treatment of cancer.
Recent developments of the nuclear emulsion technology led to the production of films with nanometric silver halide grains suitable to track low energy nuclear recoils with submicrometric length. ...This improvement opens the way to a directional Dark Matter detection, thus providing an innovative and complementary approach to the on-going WIMP searches. An important background source for these searches is represented by neutron-induced nuclear recoils that can mimic the WIMP signal. In this paper we provide an estimation of the contribution to this background from the intrinsic radioactive contamination of nuclear emulsions. We also report the neutron-induced background as a function of the read-out threshold, by using a GEANT4 simulation of the nuclear emulsion, showing that it amounts to about 0.06 per year per kilogram, fully compatible with the design of a 10 kg × year exposure.
Aims
C‐peptide secretion is currently the only available clinical biomarker to measure residual β‐cell function in type 1 diabetes. However, the natural history of C‐peptide decline after diagnosis ...can vary considerably dependent upon several variables. We investigated the shape of C‐peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, haemoglobin A1c (HbA1c) levels and insulin dose.
Methods
We analysed data from 3929 type 1 diabetes patients recruited from seven European centres representing all age groups at disease onset (childhood, adolescence and adulthood). The influence of the age at onset on β‐cell function was investigated in a longitudinal analysis at diagnosis and up to 5‐years follow‐up.
Results
Fasting C‐peptide (FCP) data at diagnosis were available in 3668 patients stratified according to age at diagnosis in four groups (<5 years, n = 344; >5 years < 10 years, n = 668; >10 years < 18 years, n = 991; >18 years, n = 1655). FCP levels were positively correlated with age (p < 0.001); the subsequent decline in FCP over time was log‐linear with a greater decline rate in younger age groups (p < 0.0001).
Conclusions
This study reveals a positive correlation between age at diagnosis of type 1 diabetes and FCP with a more rapid decline of β‐cell function in the very young patients. These data can inform the design of clinical trials using C‐peptide values as an end‐point for the effect of a given treatment.
► Use of a vast battery of biomarkers in Hediste diversicolor exposed to Benzoapyrene. ► Elevated sensibility of biomarkers targeting coelomocytes cells. ► BaP caused significant changes at ...cytological and genotoxical level. ► H.diversicolor as potential bioindicator for organic contamination.
The aim of this study was to develop a preliminary characterization of the biological responses of Hediste diversicolor to polycyclic aromatic hydrocarbons (PAHs) under controlled laboratory conditions. In order to test the effects of PAH exposure, a battery of biomarkers was applied to the polychaetes by exposing them to sublethal concentrations of benzoapyrene (0.1 and 0.5mgL−1) for 10d under laboratory conditions. The battery of biomarkers tested included oxidative stress biomarkers (glutathione content, enzymatic activities of catalase, glutathione S-transferases, glutathione reductase, glutathione peroxidases), total oxyradical scavenging capacity (TOSC) toward peroxyl and hydroxyl radicals and activity of acyl CoA oxidase (AOX) as a marker of peroxisome proliferation measured in the entire body; lipofuscin and neutral lipid accumulations and levels of Ca2+-ATPase activity analyzed in the intestinal epithelium; lysosomal membrane stability and genotoxic effects measured as DNA strand breaks and frequency of micronuclei in coelomocytes. Chemical analyses were also carried out to verify the polychaete’s benzoapyrene (BaP) bioaccumulation levels after the exposure period. The results obtained indicate that BaP caused significant changes in most of the parameters measured in H. diversicolor. Biological responses to the organic compound were particularly significant for the biomarkers measured in the intestinal epithelium and in coelomocytes, emphasizing that these tissues were more affected during our experimental conditions. Considering the key trophic role of this benthic species in estuarine and coastal ecosystems, this study confirmed that H. diversicolor is an appropriate bioindicator of organic contamination.
Body weight-related insulin resistance probably plays a role in progression to type 1 diabetes, but has an uncertain impact following diagnosis. In this study, we investigated whether BMI measured at ...diagnosis was an independent predictor of C-peptide decline 1-year post-diagnosis.
Multicentre longitudinal study carried out at diagnosis and up to 1-year follow-up.
Data on C-peptide were collected from seven diabetes centres in Europe. Patients were grouped according to age at diagnosis (<5 years, n=126; >5 years <10 years, n=295; >10 years <18 years, n=421; >18 years, n=410). Linear regression was used to investigate whether BMI was an independent predictor of change in fasting C-peptide over 1 year. Models were additionally adjusted for baseline insulin dose and HbA1c.
In individuals diagnosed between 0 and 5 years, 5 and 10 years and those diagnosed >18 years, we found no association between BMI and C-peptide decline. In patients aged 10-18 years, higher BMI at baseline was associated with a greater decline in fasting C-peptide over 1 year with a decrease (β 95% CI; P value) of 0.025 (0.010, 0.041) nM/kg per m(2) higher baseline BMI (P=0.001). This association remained significant after adjusting for gender and differences in HbA1c and insulin dose (β=0.026, 95% CI=0.0097, 0.042; P=0.002).
These observations indicate that increased body weight and increased insulin demand are associated with more rapid disease progression after diagnosis of type 1 diabetes in an age group 10-18 years. This should be considered in studies of β-cell function in type 1 diabetes.
The effect of sintering atmosphere on the optical and structural properties of Cerium doped sol–gel silica was investigated. Two sets of xerogels with Ce concentration from 0 to 10
mol% were prepared ...and densified in different conditions. The effect of a post-densification rapid thermal treatment was also considered. Optical absorption measurements evidenced that in oxidizing conditions Cerium is preferably incorporated inside the silica matrix as Ce
4+ while the trivalent state is favoured by reducing conditions. Transmission electron microscopy images show rare-earth clusters formation whose nature was investigated by means of Raman, EDS and microdiffraction measurements. In order to evaluate the efficiency of the glasses as scintillating materials radio-luminescence measurements were carried out. A numerical fit of RL spectra showed the presence of two components peaking at 2.7 and 3.1
eV. After RTT, the relative intensity of the 3.1
eV component increases with Ce concentration.
Background
The aim of the study was to investigate the different B‐cell responses after a glucagon stimulation test (GST) versus mixed meal tolerance test (MMTT).
Methods
We conducted GST and MMTT in ...10 healthy people (aged 25‐40 years) and measured C‐peptide, gastric inhibitory peptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) at different time points after the administration of 1 mg i.v. glucagon for GST or a liquid mixed meal for MMTT.
Results
The GST stimulated C‐peptide showed a mean increase of 147.1%, whereas the mean increase of MMTT stimulated C‐peptide was 99.82% (Δincrease = 47.2%). Maximum C‐peptide level reached with the MMTT was greater than that obtained with the GST (C‐pept max MMTT = 2.35 nmol/L vs C‐pep max GST = 1.9 nmol/L). A positive and linear correlation was found between the GST incremental area under the curve C‐peptide and the MMTT incremental area under the curve C‐peptide (r = 0.618, P = .05). After GST, there was no increment of GIP and glucagon like peptide‐1 levels compared to baseline levels. A positive and linear correlation between GIP and C‐peptide levels was observed only for the MMTT (r = 0.922, P = .008) indicating that in the GST, the C‐peptide response is independent of the incretin axis response.
Conclusions
Although the 2 stimulation tests may elicit a similar response in C‐peptide secretion, B‐cell response to MMTT depends on a functionally normal incretin axis. These results may have implications when investigating the B‐cell response in people with diabetes and for studies in which stimulated C‐peptide secretion is used as primary or secondary outcome for response to therapy.
PDF
