Skin manifestations of inborn errors of NF-κB.

More than 400 single gene defects have been identified as inborn errors of immunity, including many arising from genes encoding proteins that affect NF-κB activity. We summarise the skin phenotypes in this subset of disorders and provide an overview of pathogenic mechanisms. NF-κB acts cell-intrinsically in basal epithelial cells during differentiation of skin appendages, influences keratinocyte proliferation and survival, and both responses to and amplification of inflammation, particularly TNF. Skin phenotypes include ectodermal dysplasia, reduction and hyperproliferation of keratinocytes, and aberrant recruitment of inflammatory cells, which often occur in combination. Phenotypes conferred by these rare monogenic syndromes often resemble those observed with more common defects. This includes oral and perineal ulceration and pustular skin disease as occurs with Behcet's disease, hyperkeratosis with microabscess formation similar to psoriasis, and atopic dermatitis. Thus, these genotype-phenotype relations provide diagnostic clues for this subset of IEIs, and also provide insights into mechanisms of more common forms of skin disease.

Implementation and experimental results of 4D tumor tracking using robotic couch.

PURPOSE: This study presents the implementation and experimental results of a novel technique for 4D tumor tracking using a commercially available and commonly used treatment couch and evaluates the tumor tracking accuracy in clinical settings. METHODS: Commercially available couch is capable of positioning the patient accurately; however, currently there is no provision for compensating physiological movement using the treatment couch in real-time. In this paper, a real-time couch tracking control technique is presented together with experimental results in tumor motion compensation in four dimensions (superior-inferior, lateral, anterior-posterior, and time). To implement real-time couch motion for tracking, a novel control system for the treatment couch was developed. The primary functional requirements for this novel technique were: (a) the treatment couch should maintain all previous∕normal features for patient setup and positioning, (b) the new control system should be used as a parallel system when tumor tracking would be deployed, and (c) tracking could be performed in a single direction and∕or concurrently in all three directions of the couch motion (longitudinal, lateral, and vertical). To the authors' best knowledge, the implementation of such technique to a regular treatment couch for tumor tracking has not been reported so far. To evaluate the performance of the tracking couch, we investigated the mechanical characteristics of the system such as system positioning resolution, repeatability, accuracy, and tracking performance. Performance of the tracking system was evaluated using dosimetric test as an endpoint. To investigate the accuracy of real-time tracking in the clinical setting, the existing clinical treatment couch was replaced with our experimental couch and the linear accelerator was used to deliver 3D conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) treatment plans with and without tracking. The results of radiation dose distribution from these two sets of experiments were compared and presented here. RESULTS: The mechanical accuracies were 0.12, 0.14, and 0.18 mm in X, Y, and Z directions. The repeatability of the desired motion was within ±0.2 mm. The differences of central axis dose between the 3D-CRT stationary plan and two tracking plans with different motion trajectories were 0.21% and 1.19%. The absolute dose differences of both 3D tracking plans comparing to the stationary plan were 1.09% and 1.20%. Comparing the stationary IMRT plan with the tracking IMRT plan, it was observed that the central axis dose difference was -0.87% and the absolute difference of both IMRT plans was 0.55%. CONCLUSIONS: The experimental results revealed that the treatment couch could be successfully used for real-time tumor tracking with a high level of accuracy. It was demonstrated that 4D tumor tracking was feasible using existing couch with implementation of appropriate tracking methodology and with modifications in the control system.

Antinociceptive and anti-inflammatory activity of hydroalcoholic extracts and fractions from Erythrina mulungu

Erythrina mulungu Mart. ex Benth., Fabaceae, popularly known as mulungu, is used for the treatment of insomnia and disorders of the central nervous system. This study examined the antinociceptive effects of the hydroalcoholic extracts (HAE), the ethyl acetate and chloroformic fractions from E. mulungu in four experimental models of nociception using laboratory mice. The extracts and fractions were administered orally to mice at doses of 100 mg/kg. Inhibition of abdominal contractions were observed for all the extracts and fractions tested, as compared to controls. All extracts and fractions from E. mulungu reduced the nociception activity produced by formalin in the 2nd phase. In the hot plate test no significant effect was observed for any extract or fraction. In the peritonitis test induced by Zymosan, all of the tested extracts and the chloroformic fraction, except for the ethyl acetate phase, reduced cell migration of the peritoneal cavity. We concluded that E. mulungu shows antinociceptive effects, which are independent of the opioid system.

Variation of clinical target volume definition in three-dimensional conformal radiation therapy for prostate cancer.

PURPOSE: Currently, three-dimensional conformal radiation therapy (3D-CRT) planning relies on the interpretation of computed tomography (CT) axial images for defining the clinical target volume (CTV). This study investigates the variation among multiple observers to define the CTV used in 3D-CRT for prostate cancer. METHODS AND MATERIALS: Seven observers independently delineated the CTVs (prostate +/- seminal vesicles [SV]) from the CT simulation data of 10 prostate cancer patients undergoing 3D-CRT. Six patients underwent CT simulation without the use of contrast material and serve as a control group. The other 4 had urethral and bladder opacification with contrast medium. To determine interobserver variation, we evaluated the derived volume, the maximum dimensions, and the isocenter for each examination of CTV. We assessed the reliability in the CTVs among the observers by correlating the variation for each class of measurements. This was estimated by intraclass correlation coefficient (ICC), with 1.00 defining absolute correlation. RESULTS: For the prostate volumes, the ICC was 0.80 (95% confidence interval [CI]: 0.56-0.96). This changed to 0.92 (95% CI: 0.75-0.99) with the use of contrast material. Similarly, the maximal prostatic dimensions were reliable and improved. There was poor agreement in defining the SV. For this structure, the ICC never exceeded 0.28. The reliability of the isocenter was excellent, with the ICC exceeding 0.83 and 0.90 for the prostate +/- SV, respectively. CONCLUSIONS: In 3D-CRT for prostate cancer, there was excellent agreement among multiple observers to define the prostate target volume but poor agreement to define the SV. The use of urethral and bladder contrast improved the reliability of localizing the prostate. For all CTVs, the isocenter was very reliable and should be used to compare the variation in 3D dosimetry among multiple observers.

A dosimetry system for 192IR interstitial breast implants performed at the time of lumpectomy.

PURPOSE: 192Ir interstitial breast implants performed at the time of lumpectomy present a unique problem because they cannot be preplanned, and yet they are expected to produce a treatment dose rate (TDR) from 0.3 to 0.5 Gy/h using sources already procured. The purpose of this work is to describe a system of dosimetry that works within these constraints and has been used to perform more than 600 such implants. METHODS AND MATERIALS: The underlying principle is to fix the ribbon spacing, the interplaner separation, and the linear activity (1 mCi/cm) so that the TDR will depend only on the area (L x W) implanted. The ribbons are spaced 1.5 cm and 2.0 cm apart in single plane and double implants, respectively. Idealized implants were used to study the TDR as a function of the implant dimensions, and to study the effects of varying the ribbon spacing and interplanar separation. Volume-dose histograms were generated to study the homogeneity of dose. RESULTS: The TDRs of single plane implants range from 0.3 Gy/h for small 4 x 4 cm2 implants to 0.4 Gy/h for large 10 x 10 cm2 implants. The TDRs for double plane implants are similar for the same range of dimensions. CONCLUSIONS: Implants with a TDR between 0.3 and 0.5 Gy/h can be performed for a wide range of geometries without preplanning using fixed ribbons spacings of 1.5 and 2.0 cm for single and double plane implants, respectively, and a linear activity of 1 mCi/cm.

High frequency and error-prone DNA recombination in ataxia telangiectasia cell lines.

The only specific DNA repair defect found in ataxia telangiectasia (A-T) cells is mis-repair of cleaved DNA. In this report we measured DNA recombination, given its role in DNA repair and genetic instability. Using plasmids containing selectable reporter genes, we found a higher frequency of both chromosomal recombination (>100 times) and extra-chromosomal recombination (27 times) in SV40-transformed A-T cell lines compared with in an SV40-transformed normal fibroblast cell line. Southern analysis of single A-T colonies exhibiting post-integration recombination revealed that 24/27 had undergone aberrant rearrangements; recombination in normal fibroblast colonies was achieved by gene conversion in 8/11 clones and 10/11 clones showed unchanged copies of the plasmid. Using co-transfection of two integrating plasmids, each containing a separate deletion in the xgprt reporter gene, the 27 times difference in extra-chromosomal recombination was found when the plasmids were cleaved at a distance from the reporter gene. When the plasmids were cleaved within the reporter gene, the co-transfection frequency was reduced in A-T, but was increased in normal cells. We conclude that A-T cell lines have not only a high frequency chromosomal and extra-chromosomal recombination, but also exhibit error-prone recombination of cleaved DNA.