Potential of dose optimisation in MRI-based PDR brachytherapy of cervix carcinoma

BACKGROUND AND PURPOSE: In this study on PDR treatment planning of utero-vaginal carcinoma, we analysed the dosimetry of traditional X-ray based plans as it presents on MR images. The potential gain of MRI-based dose optimisation was assessed. PATIENTS AND METHODS: Sixteen patients boosted with PDR brachytherapy after external beam therapy were included. The clinical X-ray based plans were projected on MR images. The GTV, HR-CTV and IR-CTV were retrospectively contoured, as well as the bladder, rectum and sigmoid colon. The dose in the critical organs and target coverage was investigated. In a second phase, the plans were manually optimised using the MR information. The objectives were to lower the dose in the critical organs (85Gy(alphabeta3) for bladder, 75Gy(alphabeta3) for rectum and sigmoid colon) and to increase the HR-CTV dose to D9085Gy(alphabeta10). RESULTS: In the X-ray based plans, D(2cc) in bladder and sigmoid colon exceeded the tolerance doses in 10/16 and 7/16 patients, respectively. Coverage of the IR-CTV with the 60Gy(alphabeta10) was acceptable. D90 of the HR-CTV was below 85Gy(alphabeta10) in 13 out of 16 patients. After optimisation, the dose constraints in the OAR were not exceeded anymore in any patient. The average D(2cc) dose reduction was 7+/-6Gy(alphabeta3) in the bladder and 7+/-4Gy(alphabeta3) in the sigmoid colon for those patients in which the dose constraint was initially exceeded. In addition, an average dose increase of 3Gy(alphabeta10) was accomplished in the HR-CTV. CONCLUSIONS: MRI-based dose optimisation can play an important role to reduce the dose delivered to the critical organs and to improve target coverage.     

Apparent coactivation due to interference of expression constructs with nuclear receptor expression

Transient cotransfection in COS-7 cells, a standard approach to demonstrate coactivation, was used to study the coactivation properties of NuRIP183, a new nuclear receptor interacting protein of 183 kDa, isolated by a yeast two-hybrid screening. Transfection with a NuRIP183 expression construct strongly increased the ligand-dependent response of reporter constructs for several nuclear receptors when compared to transfection with the empty expression vector. A more detailed study, however, revealed major changes in the expression level of the nuclear receptors in cotransfection experiments, indicating that the observed changes in receptor activity were not due to coactivation but to differences in receptor concentration caused by interference from the cotransfected expression constructs with the expression of the receptor. Such interference, which is inversely related to the length of the insert, was observed, not only in COS-7 cells but also in CV-1 and MCF-7 cells, using different transfection techniques (FuGENE-6 and calcium phosphate) and different expression vectors (pSG5, pcDNA1.1 and pIRESneo). These data cast some doubt on coactivation of nuclear receptors based on similar cotransfection experiments without measurement of receptor concentration. Moreover, it is recommended to limit the amounts of (co)transfected expression plasmid and to avoid the use of empty expression plasmid as a control. Finally, one should be aware of similar misleading results in other experimental set-ups based on cotransfection.     

Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations: a review

Hereditary sensory neuropathies (HSNs) are rare disorders characterized by progressive distal sensory loss, predominantly affecting the lower limbs. Foot ulcers, severe skin and bone infections, arthropathy, and amputations are frequent and feared complications. Occasionally, patients complain of spontaneous shooting or lancinating pain. Autonomic fibers can be affected to a variable degree. Patients with HSN can also have severe distal weakness, and some HSN variants have therefore been classified among the hereditary motor and sensory neuropathies (HMSNs). Molecular genetic studies of autosomal dominant inherited neuropathies with prominent sensory loss and ulceromutilating features have assigned the genetic loci for HMSN type 2B (Charcot-Marie-Tooth syndrome type 2B) and HSN type 1 to chromosomes 3q13-22 and 9q22.1-22.3, respectively. However, some families with HSN have been excluded for linkage to these loci, suggesting further genetic heterogeneity. Recently, disease-causing mutations in the SPTLC1 gene have been identified in patients with HSN type 1. In this review, we discuss the hallmark features associated with the distinct genetic subtypes of autosomal dominant inherited HSN and provide genotype-phenotype correlations.     

Early expression of thyroid hormone deiodinases and receptors in human fetal cerebral cortex

Thyroid hormones are known to be important for optimal development of the human central nervous system. Classically, maternal thyroid hormones have not been thought to have a major role in defining central nervous system development. However, recent epidemiological evidence has indicated that subtle deficiencies in circulating maternal thyroid hormones in the first trimester of pregnancy are associated with adverse neurodevelopment. We have used real time PCR to quantitate the expression of mRNAs encoding the thyroid receptor isoforms (TR alpha1, alpha2, beta1 and beta2) and thyronine deiodinase subtypes (5'-DI, 5'-DII and 5-DIII) in human fetal cerebral cortex from the first and second trimesters of pregnancy. Deiodinase subtype activities have also been determined in these tissues and compared to 'normal' adult human cerebral cortex. Iodothyronine deiodinase mRNAs were expressed in human fetal cerebral cortex from 7 to 8 weeks of gestation. The expression of 5'-DI mRNA was variable in fetal life but increased relative to adult cortex (P<0.05), whereas the activity of this enzyme was below the level of assay detection. 5'-DII mRNA and activity in fetal cerebral cortex was detectable from as early as 7-8 weeks but not significantly different from that in adult life except at 15-16 weeks when mRNA expression increased (P<0.05). Fetal cortex 5-DIII mRNA expression was present from the early first trimester but less abundant than in adult tissue (P<0.01) and 5-DIII activity appeared greater in fetal cortex (P<0.01) as compared to adults. Only TR alpha1 mRNA was more abundantly expressed in fetal cortex than adult tissues (P<0.01). In contrast, the TR isoforms (alpha2 and beta1) were expressed significantly less than in adult tissues (P<0.05). Only 26% of fetal cerebral cortex samples expressed TR beta 1. There is evidence that the developing fetal brain, as early as the first trimester, expresses TRs and exhibits the mechanisms of pre-receptor control of thyroid hormone supply.     

Evaluation of biophysical and clinical parameters of skin barrier function among hospital workers

The goal of this study was to evaluate biophysically and clinically the hand skin of nurses working in the operating room in comparison with the hand skin of a control group of female administrative employees. 19 nurses and 14 employees were included in this trial. Transepidermal water loss (TEWL) and stratum corneum (SC) hydration were evaluated on 4 different test sites - dominant and non-dominant pulse, and dominant and non-dominant hand dorsum. The clinical score Dermatology Life Quality Index (DLQI) and subjective evaluation of skin sensitivity were also recorded. In comparison with the control group, TEWL values among nurses were significantly higher on all test sites, while SC hydration was significantly lower on 3 of the 4 test sites. In addition, clinical score showed the presence of irritant contact dermatitis (ICD). DLQI reported a higher level of disability among the nurses group, while the subjective evaluation of skin sensitivity was identical in both groups. The results suggest the presence of skin barrier alterations and clinical signs of chronic ICD on the hands of nurses working in operating room units.     

Post-transplant Lymphoproliferative Disorders: Implications for Acquired Immunodeficiency Syndrome-Associated Malignancies

Post-transplant lymphoproliferative disorders (PTLDs) comprisea histologic spectrum, ranging from hyperplastic-appearing lesionsto frank non-Hodgkin's lymphoma or multiple myeloma histology.Multiple clones may coexist, each representing a discrete lymphomagenicevent, a situation that is unique to immunodeficiency states.The incidence varies from 1% in renal recipients to 5% in heartrecipients, but can be markedly increased by the use of anti-T-celltherapies or by T-cell depletion in bone marrow transplantation.PTLD continues to arise, even many years after transplantation,and late T-cell lymphomas have recently been recognized. PretransplantEpstein-Barr virus (EBV) seronegativity increases risk to ashigh as 30%–50%. PTLD has a highly variable clinical picture;certain patterns are, however, seen. Reversibility of PTLD withreduction in immunosuppressives has long been recognized. Predictingreversibility has been difficult. The presence or absence ofbcl-6 mutations has recently been identified as being of predictivevalue. Surgical resection can be curative. Cytotoxics, althoughproblematic, can also be curative. Long-term remission has beenachieved with anti CD21 and CD24 antibodies; efficacy has beenreported for interferon alfa and for rituximab. In vitro expandedEBV-specific T cells have been effective as treatment and asprophylaxis in the setting of bone marrow transplantation. EBVviral load measured in blood appears to associate with the emergenceof PTLD and may facilitate prophylactic studies. PTLD is a modelof immunodeficiency-related EBV lymphomagenesis. Pathogenetic,therapeutic, and prophylactic insights gained from the studyof PTLD are likely to be applicable to the acquired immunodeficiencysyndrome setting.