Magnetic resonance guided focused ultrasound surgery - a novel treatment for uterine fibroids

Uterine fibroids are the most common tumour of the reproductive tract in women of reproductive age. Although they are benign tumours that are often asymptomatic, they may cause debilitating symptoms in many women, such as abnormal uterine bleeding, abdominal pain, increased abdominal girth, urinary frequency, constipation, pregnancy loss, dyspareunia, and in some cases infertility. Several approaches are available for the treatment of uterine fibroids. These include pharmacologic options, such as hormonal therapies and gonadotropinreleasing hormone agonists; surgical approaches, such as hysterectomy, myomectomy; myolysis, laparoscopic uterine artery occlusion, uterine artery embolisation and magnetic resonance imaging-guided focused ultrasound surgery. The choice of approach may be dictated by factors such as the patient’s desire to become pregnant in the future, the importance of uterine preservation, symptom severity, and tumour characteristics. There is however, no widely agreed therapeutic strategy. There is a widespread view that hysterectomy is overused in the UK; the Chief Medical Officer in his annual report ‘On the state of public health’ in 2005, highlighted that hysterectomy in younger women is associated with complications, hospital stays, procedure-related interference with normal life and is costly. In addition he outlined the need to reduce the number of hysterectomies. This, along with the change in cultural attitudes amongst patients, who are becoming increasingly reluctant to undergo these conventional invasive procedures, has increased the need for new treatment options. Ideally new treatment options for uterine fibroids would be minimally invasive, have long-term data demonstrating efficacy and safety, have minimal or no incidence of fibroid recurrence, be easy to perform, preserve fertility, and be cost effective. New treatment approaches are under investigation, with the goals of being effective, safe, and less invasive. MRgFUS is a non-invasive thermo-ablative hybrid technique which uses both MR and ultrasound to destroy tumours. It is an outpatient procedure, which avoids the need for an anaesthetic, has a short recovery period, and is uterine sparing. The main objective of this work was to set out the rationale for using Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS) for the treatment of uterine fibroids. In order to achieve this aim, four main bodies of work are necessary; 1) Identifying patient selection criteria and investigating mitigating techniques to increase the pool of women for whom this treatment can be offered. 2) Investigating a method designed to overcome the problem of safely treating women with abdominal scars for whom this treatment can cause potential morbidity. 3) Investigating the potentiality of using MRgFUS to prolong the tumour shrinkage effect of GnRH analogue injections. 4) Investigating the safety of MRgFUS in treating symptomatic women who wish to preserve fertility. Results: the first aim of this project was to identify patient selection criteria and to investigate methods to widen the selection criteria. In our retrospective review it was found that 74% of women presenting were deemed technically suitable to proceed with treatment and several mitigating techniques that solved current technical difficulties were identified and allowed for less restrictive MRgFUS selection criteria for treatment of symptomatic uterine fibroids. These less restrictive criteria are expected to expand the pool of patients for whom MRgFUS is a viable treatment option for uterine fibroid symptoms. The second aim was to identify a method of overcoming the problem of treating women with previous abdominal scars safely. We identified a unique method of highlighting the scar by painting it with a paramagnetic iron oxide material which clearly outlined the scar on MR scanning allowing complete avoidance of the scar using MR guidance. In this small pilot study, all women were treated safely with no skin burns. The third aim of this project looked at the potentiality of prolonging the shrinkage effect of GnRH analogues by following a course of 3 injections with MRgFUS treatment. In this prospective study of fifty women, there was a 50% reduction in the mean symptoms severity score at 6 months which was maintained for 24 months post treatment. There was an average reduction in target fibroid volume which was maintained for 24 months. The final aim of the project was to investigate the safety of using MRgFUS as a treatment option for those women who wished to preserve their fertility. In this multicentre international study, One hundred and sixteen women were recruited from five centres. There were sixty four reported pregnancies in Sixty one women, with 30 completed deliveries. There were no reported cases of uterine rupture, premature labour, abnormal placentation or placental abruption. Conclusion: There is a growing body of data from clinical trials and more than four years of clinical experience to validate the safety and efficacy of MRgFUS for the treatment of uterine fibroids. MRgFUS is a totally non-invasive outpatient procedure that is not associated with the typical surgical risks of bleeding, infection and has minimal recovery time. Additionally, the procedure allows women to address their symptoms whilst preserving the uterus. Consequently, MRgFUS is an alternative treatment option for suitable patients who have refused other interventions due to concerns about lost productivity, risks of surgical complications or future fertility

The Demand for Military Spending in Egypt

Egypt plays a pivotal role in the security of the Middle East as the doorway to Europe and its military expenditure reflects its involvement in the machinations of such an unstable region, showing considerable variation over the last forty years. These characteristics make it a particularly interesting case study of the determinants of military spending. This paper presents such a study, estimating an econometric model of the Egyptian demand for military spending, taking into account important strategic and political factors. Both economic and strategic factors are found to play a role in determining military burden, with clear positive effects of lagged military burden, suggesting some sort of institutional inertia, plus negative output and net imports effects. The main strategic effect is the impact of Israel’s military burden, with no effect for that of the Jordanian and Syrian allies, but the results also suggest that simple arms race relationships are not an adequate representation of the relevant strategic factors.Egypt, demand for military expenditure, political determinants, strategic determinants

O6-Methylguanosine leads to position-dependent effects on ribosome speed and fidelity

Nucleic acids are under constant assault from endogenous and environmental agents that alter their physical and chemical properties. O6-methylation of guanosine (m(6)G) is particularly notable for its high mutagenicity, pairing with T, during DNA replication. Yet, while m(6)G accumulates in both DNA and RNA, little is known about its effects on RNA. Here, we investigate the effects of m(6)G on the decoding process, using a reconstituted bacterial translation system. m(6)G at the first and third position of the codon decreases the accuracy of tRNA selection. The ribosome readily incorporates near-cognate aminoacyl-tRNAs (aa-tRNAs) by forming m(6)G-uridine codon-anticodon pairs. Surprisingly, the introduction of m(6)G to the second position of the codon does not promote miscoding, but instead slows the observed rates of peptide-bond formation by \u3e1000-fold for cognate aa-tRNAs without altering the rates for near-cognate aa-tRNAs. These in vitro observations were recapitulated in eukaryotic extracts and HEK293 cells. Interestingly, the analogous modification N6-methyladenosine (m(6)A) at the second position has only a minimal effect on tRNA selection, suggesting that the effects on tRNA selection seen with m(6)G are due to altered geometry of the base pair. Given that the m6G:U base pair is predicted to be nearly indistinguishable from a Watson-Crick base pair, our data suggest that the decoding center of the ribosome is extremely sensitive to changes at the second position. Our data, apart from highlighting the deleterious effects that these adducts pose to cellular fitness, shed new insight into decoding and the process by which the ribosome recognizes codon-anticodon pairs

Ribosomes Left in the Dust: Diverse Strategies for Peptide-Mediated Translation Stalling

In two recent papers, Arenz et al. (2014a) and Bischoff et al. (2014) provide structural insights into drug-induced, peptide-mediated stalling of the ribosome

Uncomplicated term vaginal delivery following magnetic resonance-guided focused ultrasound surgery for uterine fibroids.

A 35 year-old para 1+0 underwent MRgFUS per study protocol for multiple uterine fibroids, the largest of which measured 5 cm. She conceived 10 months following the procedure. The patient was induced at 41+6 weeks and underwent a normal vaginal delivery

3-hydroxykynurenine suppresses CD4+ T-cell proliferation, induces T-regulatory-cell development, and prolongs corneal allograft survival

Copyright © 2011 Association for Research in Vision and Ophthalmology. This article is available open access through the publisher’s website at the link below.Purpose. IDO (indoleamine 2,3-dioxygenase) modulates the immune response by depletion of the essential amino acid tryptophan, and IDO overexpression has been shown to prolong corneal allograft survival. This study was conducted to examine the effect of kynurenines, the products of tryptophan breakdown and known to act directly on T lymphocytes, on corneal graft survival. Methods. The effects of kynurenines on T-cell proliferation and death, T-regulatory-cell development, and dendritic cell function, phenotype, and viability were analyzed in vitro. The effect of topical and systemic administration of 3-hydroxykynurenine (3HK) on orthotopic murine corneal allograft survival was examined. Results. T-lymphocyte proliferation was inhibited by two of the four different kynurenines: 3HK and 3-hydroxyanthranilic acid (3HAA). This effect was accompanied by significant T-cell death. Neither 3HK nor 3HAA altered dendritic cell function, nor did they induce apoptosis or pathogenicity to corneal endothelial cells. Administration of systemic and topical 3HK to mice receiving a fully mismatched corneal graft resulted in significant prolongation of graft survival (median survival of control grafts, 12 days; of treated, 19 and 15 days, respectively; P < 0.0003). While systemic administration of 3HK was associated with a significant depletion of CD4+ T, CD8+ T, and B lymphocytes in peripheral blood, no depletion was found after topical administration. Conclusions. The production of kynurenines, in particular 3HK and 3HAA, may be one mechanism (in addition to tryptophan depletion) by which IDO prolongs graft survival. These molecules have potential as specific agents for preventing allograft rejection in patients at high rejection risk.Fight for Sight and the Wellcome Trust

Study on regional differences in soil-water characteristics and their relevance to aquaculture productivity and fish disease

A total of 45 ponds used for fish polyculture were investigated in three zones of Bangladesh to identify the differences among the zones in respect to aqua-ecology, culture practices, fish productivity and health management. Four hundred and fifty fish from three zones were clinically examined by naked eye and histopathology. Out of total number of fish examined, 45 fish from Dhaka zones were examined for parasites and bacteria in addition to histopathology. Faded and haemorrhagic gill, skin, fin, scale loss and lesions were observed during fish examination. Aeromonas spp. Pseudomonas spp. and Streptococcus spp. were isolated respectively from 56%, 46% and 39% affected fish. Among the five water quality parameters analyzed, the highest average hardness and alkalinity respectively were recorded in Rajshahi (156 ppm and 142 ppm) followed by Dhaka (146 ppm and 132 ppm) and Chittagong (81 ppm and 90 ppm). The highest average pH was recorded in Mymensingh (7.52) followed by Rajshahi (7.13) and Chittagong (7.05). Water holding capacity of soil in Rajshahi zone was poor compared to other zones and farmers were found to be reluctant to fish farming

A Parallel G Quadruplex-Binding Protein Regulates the Boundaries of DNA Elimination Events of \u3ci\u3eTetrahymena thermophila\u3c/i\u3e

Guanine (G)-rich DNA readily forms four-stranded quadruplexes in vitro, but evidence for their participation in genome regulation is limited. We have identified a quadruplex-binding protein, Lia3, that controls the boundaries of germline-limited, internal eliminated sequences (IESs) of Tetrahymena thermophila. Differentiation of this ciliate’s somatic genome requires excision of thousands of IESs, targeted for removal by small-RNA-directed heterochromatin formation. In cells lacking LIA3 (ΔLIA3), the excision of IESs bounded by specific G-rich polypurine tracts was impaired and imprecise, whereas the removal of IESs without such controlling sequences was unaffected. We found that oligonucleotides containing these polypurine tracts formed parallel G-quadruplex structures that are specifically bound by Lia3. The discovery that Lia3 binds G-quadruplex DNA and controls the accuracy of DNA elimination at loci with specific G-tracts uncovers an unrecognized potential of quadruplex structures to regulate chromosome organization. Author Summary Non-canonical DNA structures, including four-stranded Guanine quadruplexes (G4 DNA), have been observed readily in vitro, but their regulatory importance within cells has been particularly challenging to demonstrate conclusively. We have discovered a G4 DNA binding protein, Lia3, that specifically regulates programmed DNA elimination events in Tetrahymena thermophila. This ciliate deletes nearly one-third of its germline genome from each developing somatic nucleus. These genomic deletion events must be accurate as the thousands of DNA regions excised are located near genes and/or their promoters, thus aberrant excision may alter gene expression. When we knocked out the gene encoding Lia3, we found that the boundaries of the excised regions were heterogeneous for a subset of loci that are flanked by G-rich (5’-AAAAAGGGGG-3’) boundary controlling sequences. When we tested whether Lia3 bound this sequence, we discovered that the sequence itself formed G4 DNA and that Lia3 bound only when the sequence adopted this conformation. Our findings that Lia3 binds G4 DNA and that deletion of the gene encoding Lia3 perturbs the boundaries of the excised loci which are flanked by this quadruplex-forming DNA provides compelling evidence that this non-canonical DNA structure has a critical role during development of these cells

Exchange reactions of organic halides and organo-silicon compounds with boron tribromide and boron triiodide

Reactions of the boron halides with organic halides and organo-silicon compounds have been investigated. The results show exchange of halogens between the BX3 (X = Br# 1) and the organic halidef exchange of the halogen of the C-X bond being proved. The rates of halogen exchange vary. Reaction of the heavier halides with organo-silicon compounds indicated that the silicon-carbon bonds ruptured in the absence of electronegative atom attached to the silicon. The presence of an electronegative atom (halogen or oxygen) attached to the silicon causes the bond between the silicon and the electronegative atom to be preferentially broken. Products of exchange reactions of the boron halides and the organic halides or the organo-silicon compounds were studied by use of 1H NMR and GC/MS. From these results some possible mechanisms for the exchange reactions are postulated, but further work is indicated to prove the real courses of the reaction