MicroRNA analysis of childhood atopic dermatitis reveals a role for miR-451a.

BACKGROUND: MicroRNAs (miRNAs), important regulators of gene expression, have been implicated in a variety of disorders. The expression pattern of miRNAs in paediatric atopic dermatitis (AD) has not been well studied. OBJECTIVES: We sought to investigate miRNA expression profiles in different blood compartments of infants with AD. METHODS: Small RNA and analysis with the HTG EdgeSeq system were performed to identify differentially expressed miRNAs in peripheral blood mononuclear cells (PBMCs) and plasma of infants with AD vs. age-matched healthy controls, with reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) used for validation and measurement of miRNA targets. Logistic regression models with area under the receiving operating characteristic estimation was used to evaluate the diagnostic potential of chosen miRNAs for AD. RESULTS: RNA sequencing was performed to access miRNA expression profiles in paediatric AD. We identified 10 differentially expressed miRNAs in PBMCs and eight dysregulated miRNAs in plasma of infants with AD compared with controls. Upregulated miRNAs in PBMCs included miRNAs known to be involved in inflammation: miR-223-3p, miR-126-5p and miR-143-3p. Differential expression of only one miRNA, miR-451a, was observed in both PBMCs and plasma of children with AD. Dysregulation of three miRNAs (miR-451a, miR-143-3p and miR-223-3p) was validated in larger numbers of samples and miR-451a was identified as a predictive biomarker for the early diagnosis of the disease. Experimentally verified targets of miR-451a, interleukin 6 receptor (IL6R) and proteasome subunit beta type-8 (PSMB8), were increased in patients with AD, negatively correlated with miR-451a levels and upregulated following inhibition of miR-451a in PBMCs. CONCLUSIONS: In infants with AD, a distinct peripheral blood miRNA signature is seen, highlighting the systemic effects of the disease. miR-451a is uniquely expressed in different blood compartments of patients with AD and may serve as a promising novel biomarker for the early diagnosis of AD.

The implementation of Tomorrow's Doctors.

BACKGROUND: In 1993 the General Medical Council published its recommendations on undergraduate medical education. AIM: To study the implementation of these recommendations in UK medical schools by means of informal visitations. METHODS: Teams consisting of 3-5 members visited the 25 UK medical schools in a 3-year period commencing in early 1995. RESULTS: Substantial changes have occurred in undergraduate medical education since the publication of Tomorrow's Doctors. Of the 13 principal recommendations, 3 had been implemented in most medical schools and a further 8 substantially implemented by the majority. However, progress in health promotion and the development of appropriate assessment schemes has been slower. CONCLUSIONS: Informal visits have served a useful purpose in monitoring the implementation of the General Medical Council's recommendations on undergraduate medical education. In addition, they have encouraged dialogue with the medical schools and allowed the identification of examples of good practice including the establishment by most schools of medical education units.

Targeted intra-operative radiotherapy (Targit): an innovative method of treatment for early breast cancer.

INTRODUCTION: We believe that conservative treatment of early breast cancer may not require radiotherapy that encompasses the whole breast. We present here the clinico-pathological basis for this view, as well as a novel therapeutic approach that allows intra-operative radiotherapy to be safely and accurately delivered to the target tissues in a standard operating theatre. THE RATIONALE: Whole-organ analysis of mastectomy specimens reveals that 80% of occult cancer foci are situated remote from the index quadrant. In contrast, over 90% of local recurrences after breast conservative therapy occur near the original tumour, even when radiotherapy is not given. Therefore, the remote occult cancer foci may be clinically irrelevant and radiotherapy to the index quadrant alone might be sufficient. A NOVEL TECHNIQUE: The Photon Radiosurgery System (PRS) is an ingenious portable electron-beam driven device that can typically deliver intra-operative doses of 5-20 Gy, respectively, to 1 cm and 0.2 cm from the tumour bed over about 22 min. The pliable breast tissue--the target--wraps around the source, providing perfect conformal radiotherapy. Being soft X-rays, the dose attenuates rapidly (alpha approximately 1/r3), reducing distant damage. RESULTS: In our pilot study of 25 patients (age 30-80 years, T = 0.42-4.0 cm), we replaced the routine post-operative tumour bed boost with targeted intra-operative radiotherapy. There have been no major complications and no patient has developed local recurrence, although the median follow-up time is short, at 24 months. CONCLUSION: It is safe and feasible to deliver targeted intraoperative radiotherapy (Targit) for early breast cancer. We have begun a randomised trial--the first of its kind--comparing Targit with conventional six-week course of radiotherapy. If proven equivalent in terms of local recurrence and cosmesis, it could eliminate the need for the usual six-week course of post-operative radiotherapy.

Monte Carlo simulation of a miniature, radiosurgery x-ray tube using the ITS 3.0 coupled electron-photon transport code.

A miniature, interstitial x-ray generator has recently been developed and is currently undergoing clinical trials for the treatment of brain tumors. The maximum photon energy from this x-ray tube is 50 keV, although most of the initial testing has been carried out at 40 keV. Dose rates of up to 2 Gy/min in a water phantom at a distance of 10 mm from the tube tip are produced. In this paper we describe the modeling and simulation of x-ray production from this device using the ITS 3.0 Monte Carlo code. Verification of the simulation of x-ray production in the device was carried out by comparing predictions of spatial photon distribution, energy spectrum, and dose versus depth in water with experimentally obtained measurements. Agreement between the simulated results and experimental measurements was fairly good when comparing the angular distribution of photons emitted from the x-ray tube and very good when comparing dose rate versus depth in a water phantom. Discrepancies observed when comparing the calculated and measured estimates of characteristic line radiation were reduced by incorporation of a modification to the ITS code. Possible causes of the remaining discrepancy in bremsstrahlung intensity are discussed.

A new miniature x-ray source for interstitial radiosurgery: device description.

A device that generates low-energy x rays at the tip of a needle-like probe was developed for stereotactic interstitial radiosurgery. Electrons from a small thermionic gun are accelerated to a final energy of up to 40 keV and directed along a 3 mm outside diameter drift tube to a thin Au target, where the beam size is approximately 0.3 mm. All high-voltage electronics are in the probe housing, connected by low-voltage cable to a battery-operated control box. X-ray output, which is nearly isotropic, consists of a bremsstrahlung spectrum and several lines between 7 and 14 keV, with characteristic radiation contributing 15% of the total energy output. To date, 14 patients with metastatic brain tumors have been treated with this device.

A new miniature x-ray device for interstitial radiosurgery: dosimetry.

A miniature, battery operated 40 kV x-ray device has been developed for the interstitial treatment of small tumors ( < 3 cm diam) in humans. X rays are emitted from the tip of a 10 cm long, 3 mm diameter probe that is stereotactically inserted into the tumor. The beam, characterized by half-value layer (HVL), spectrum analysis, and isodose contours, behaves essentially as a point isotropic source with an effective energy of 20 keV at a depth of 10 mm in water. The absolute output from the device was measured using a parallel plate ionization chamber, modified with a platinum aperture. The dose rate in water determined from these chamber measurements was found to be nominally 150 cGy/min at a distance of 10 mm for a beam current of 40 microA and voltage of 40 kV. The dose in water falls off approximately as the third power of the distance. To date, 14 patients have been treated with this device in a phase I clinical trial.