A randomised feasibility study of serial magnetic resonance imaging to reduce treatment times in Charcot neuroarthropathy in people with diabetes (CADOM): A protocol

Background Charcot neuroarthropathy is a complication of peripheral neuropathy associated with diabetes which most frequently affects the lower limb. It can cause fractures and dislocations within the foot, which may progress to deformity and ulceration. Recommended treatment is immobilisation and offloading, with a below knee non-removable cast or boot. Duration of treatment varies from six months to more than one year. Small observational studies suggest that repeated assessment with Magnetic Resonance Imaging improves decision making about when to stop treatment, but this has not been tested in clinical trials. This study aims to explore the feasibility of using serial Magnetic Resonance Imaging without contrast in the monitoring of Charcot neuroarthropathy to reduce duration of immobilisation of the foot. A nested qualitative study aims to explore participants’ lived experience of Charcot neuroarthropathy and of taking part in the feasibility study. Methods We will undertake a two arm, open study, and randomise 60 people with a suspected or confirmed diagnosis of Charcot neuroarthropathy from five NHS, secondary care multidisciplinary Diabetic Foot Clinics across England. Participants will be randomised 1:1 to receive Magnetic Resonance Imaging at baseline and remission up to 12 months, with repeated foot temperature measurements and x-rays (standard care plus), or standard care plus with additional three-monthly Magnetic Resonance Imaging until remission up to 12 months (intervention). Time to confirmed remission of Charcot neuroarthropathy with off-loading treatment (days) and its variance will be used to inform sample size in a full-scale trial. We will look for opportunities to improve the protocols for monitoring techniques and the clinical, patient centred, and health economic measures used in a future study. For the nested qualitative study, we will invite a purposive sample of 10-14 people able to offer maximally varying experiences from the feasibility study to take part in semi-structured interviews to be analysed using thematic analysis. Discussion The study will inform the decision whether to proceed to a full-scale trial. It will also allow deeper understanding of the lived experience of Charcot neuroarthropathy, and factors that contribute to engagement in management and contribute to the development of more effective patient centred strategies. Trial registration ISRCTN, ISRCTN, 74101606. Registered on 6 November 2017, http://www.isrctn.com/ISRCTN74101606?q=CADom&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10&searchType=basic-searc

Dynamic epigenetic regulation of the microRNA-200 family mediates epithelial and mesenchymal transitions in human tumorigenesis

Epithelial-mesenchymal (EMT) and mesenchymal-epithelial (MET) transitions occur in the development of human tumorigenesis and are part of the natural history of the process to adapt to the changing microenvironment. In this setting, the miR-200 family is recognized as a master regulator of the epithelial phenotype by targeting ZEB1 and ZEB2, two important transcriptional repressors of the cell adherence (E-cadherin) and polarity (CRB3 and LGL2) genes. Recently, the putative DNA methylation associated inactivation of various miR-200 members has been described in cancer. Herein, we show that the miR-200ba429 and miR-200c141 transcripts undergo a dynamic epigenetic regulation linked to EMT or MET phenotypes in tumor progression. The 5′-CpG islands of both miR-200 loci were found unmethylated and coupled to the expression of the corresponding miRNAs in human cancer cell lines with epithelial features, such as low levels of ZEB1/ZEB2 and high expression of E-cadherin, CRB3 and LGL2, while CpG island hypermethylation-associated silencing was observed in transformed cells with mesenchymal characteristics. The recovery of miR-200ba429 and miR-200c141 expression by stable transfection in the hypermethylated cells restored the epithelial markers and inhibited migration in cell culture and tumoral growth and metastasis formation in nude mice. We also discovered, using both cell culture and animal models, that the miR-200 epigenetic silencing is not an static and fixed process but it can be shifted to hypermethylated or unmethylated 5′-CpG island status corresponding to the EMT and MET phenotypes, respectively. In fact, careful laser microdissection in human primary colorectal tumorigenesis unveiled that in normal colon mucosa crypts (epithelia) and stroma (mesenchyma) already are unmethylated and methylated at these loci, respectively; and that the colorectal tumors undergo selective miR-200 hypermethylation of their epithelial component. These findings indicate that the epigenetic silencing plasticity of the miR-200 family contributes to the evolving and adapting phenotypes of human tumors

Tracing the Evolution of Temperature in Near Fermi Energy Heavy Ion Collisions

The kinetic energy variation of emitted light clusters has been employed as a clock to explore the time evolution of the temperature for thermalizing composite systems produced in the reactions of 26A, 35A and 47A MeV $^{64}$Zn with $^{58}$Ni, $^{92}$Mo and $^{197}$Au. For each system investigated, the double isotope ratio temperature curve exhibits a high maximum apparent temperature, in the range of 10-25 MeV, at high ejectile velocity. These maximum values increase with increasing projectile energy and decrease with increasing target mass. The time at which the maximum in the temperature curve is reached ranges from 80 to 130 fm/c after contact. For each different target, the subsequent cooling curves for all three projectile energies are quite similar. Temperatures comparable to those of limiting temperature systematics are reached 30 to 40 fm/c after the times corresponding to the maxima, at a time when AMD-V transport model calculations predict entry into the final evaporative or fragmentation stage of de-excitation of the hot composite systems. Evidence for the establishment of thermal and chemical equilibrium is discussed.Comment: 9 pages, 5 figure

Evidence of Critical Behavior in the Disassembly of Nuclei with A ~ 36

A wide variety of observables indicate that maximal fluctuations in the disassembly of hot nuclei with A ~ 36 occur at an excitation energy of 5.6 +- 0.5 MeV/u and temperature of 8.3 +- 0.5 MeV. Associated with this point of maximal fluctuations are a number of quantitative indicators of apparent critical behavior. The associated caloric curve does not appear to show a flattening such as that seen for heavier systems. This suggests that, in contrast to similar signals seen for liquid-gas transitions in heavier nuclei, the observed behavior in these very light nuclei is associated with a transition much closer to the critical point.Comment: v2: Major changes, new model calculations, new figure

Critical Behavior in Light Nuclear Systems: Experimental Aspects

An extensive experimental survey of the features of the disassembly of a small quasi-projectile system with $A \sim$ 36, produced in the reactions of 47 MeV/nucleon $^{40}$Ar + $^{27}$Al, $^{48}$Ti and $^{58}$Ni, has been carried out. Nuclei in the excitation energy range of 1-9 MeV/u have been investigated employing a new method to reconstruct the quasi-projectile source. At an excitation energy $\sim$ 5.6 MeV/nucleon many observables indicate the presence of maximal fluctuations in the de-excitation processes. The fragment topological structure shows that the rank sorted fragments obey Zipf's law at the point of largest fluctuations providing another indication of a liquid gas phase transition. The caloric curve for this system shows a monotonic increase of temperature with excitation energy and no apparent plateau. The temperature at the point of maximal fluctuations is $8.3 \pm 0.5$ MeV. Taking this temperature as the critical temperature and employing the caloric curve information we have extracted the critical exponents $\beta$, $\gamma$ and $\sigma$ from the data. Their values are also consistent with the values of the universality class of the liquid gas phase transition. Taken together, this body of evidence strongly suggests a phase change in an equilibrated mesoscopic system at, or extremely close to, the critical point.Comment: Physical Review C, in press; some discussions about the validity of excitation energy in peripheral collisions have been added; 24 pages and 32 figures; longer abstract in the preprin

Towards the critical behavior for the light nuclei by NIMROD detector

The critical behavior for the light nuclei with A$\sim 36$ has been investigated experimentally by the NIMROD multi-detectors. The wide variety of observables indicate the critical point has been reached in the disassembly of hot nuclei at an excitation energy of 5.6$\pm$0.5 MeV/u.Comment: 4 pages, 2 figures; Proceeding of 18th Nuclear Physics Division Conference of the Euro. Phys. Society (NPDC18) "Phase transitions in strongly interacting matter", Prague, 23.8.-29.8. 2004. To be published in Nuclear Physics

Properties of the Initial Participant Matter Interaction Zone in Near Fermi-Energy Heavy Ion Collisions

The sizes, temperatures and free neutron to proton ratios of the initial interaction zones produced in the collisions of 40 MeV/nucleon $^{40}$Ar + $^{112}$Sn and 55 MeV/nucleon$^{27}$Al + $^{124}$Sn are derived using total detected neutron plus charged particle multiplicity as a measure of the impact parameter range and number of participant nucleons. The size of the initial interaction zone, determined from a coalescence model analysis, increases significantly with decreasing impact parameter. The temperatures and free neutron to proton ratios in the interaction zones are relatively similar for different impact parameter ranges and evolve in a similar fashion.Comment: 7 pages, 8 figure

A Ghoshal-like Test of Equilibration in Near-Fermi-Energy Heavy Ion Collisions

Calorimetric and coalescence techniques have been employed to probe equilibration for hot nuclei produced in heavy ion collisions of 35 to 55 MeV/u projectiles with medium mass targets. Entrance channel mass asymmetries and energies were selected in order that very hot composite nuclei of similar mass and excitation would remain after early stage pre-equilibrium particle emission. Inter-comparison of the properties and de-excitation patterns for these different systems provides evidence for the production of hot nuclei with decay patterns relatively independent of the specific entrance channel.Comment: 7 pages, 2 figure

Non Thermal Irreversible Electroporation: Novel Technology for Vascular Smooth Muscle Cells Ablation

Non thermal Irreversible electroporation (NTIRE) is a new tissue ablation method that induces selective damage only to the cell membrane while sparing all other tissue components. Our group has recently showed that NTIRE attenuated neointimal formation in rodent model. The goal of this study was to determine optimal values of NTIRE for vascular smooth muscle cell (VSMC) ablation.33 Sprague-Dawley rats were used to compare NTIRE protocols. Each animal had NTIRE applied to its left common carotid artery using a custom-made electrodes. The right carotid artery was used as control. Electric pulses of 100 microseconds were used. Eight IRE protocols were compared: 1-4) 10 pulses at a frequency of 10 Hz with electric fields of 3500, 1750, 875 and 437.5 V/cm and 5-8) 45 and 90 pulses at a frequency of 1 Hz with electric fields of 1750 and 875 V/cm. Animals were euthanized after one week. Histological analysis included VSMC counting and morphometry of 152 sections. Selective slides were stained with elastic Van Gieson and Masson trichrome to evaluate extra-cellular structures. The most efficient protocols were 10 pulses of 3500 V/cm at a frequency of 10 Hz and 90 pulses of 1750 V/cm at a frequency of 1 Hz, with ablation efficiency of 89+/-16% and 94+/-9% respectively. Extra-cellular structures were not damaged and the endothelial layer recovered completely.NTIRE is a promising, efficient and simple novel technology for VMSC ablation. It enables ablation within seconds without causing damage to extra-cellular structures, thus preserving the arterial scaffold and enabling endothelial regeneration. This study provides scientific information for future anti-restenosis experiments utilizing NTIRE