Transcutaneous bone-anchoring prosthesis with hip replacement: A novel treatment for amputees

Background Over the last two decades, Transcutaneous Bone-Anchored Prosthesis (TCBAP) has proven to be an effective alternative for prosthetic attachment for above knee amputees, particularly for individuals suffering from socket interface related complications. [1-17] Amputees with a very short femoral residuum (<15 cm) are at a considerable higher risk for these complications as well as high risk of implant failure, if they underwent a typical TCBAP due to the relatively small bony-implant contact leading to a need of a novel technique. Aim A. To describe the surgical procedure combining THR with TCBAP for the first time; and B. To present preliminary data on potential risks and benefits with assessment of clinical and functional outcomes at follow up Method We used a TCBAP connected to the stem of a Total Hip Replacement (THR) prosthesis enabling the femoral residuum and the hip joint to act as weight sharing structures by transferring the load directly to the pelvis. We performed a tri-polar THR connected to a custom made TCBAP at the first stage followed by creating a skin implant interface as a second stage. We retrospectively reviewed three cases of transfemoral amputations presenting with extremely short femoral residuum. Patients were assessed clinically and functionally including standard measures of health-related quality of life, amputee mobility predictor tool, ambulation tests and actual activity level. Progress was monitored for 6-24 months. Results Clinical outcomes including adverse events show no major complications. Functional outcomes improved for all participants as early as 6 months follow up. All cases were wheelchair bound preoperatively (K0 – AMPRO) improved to walking with One stick (K3 – AMPRO) at 3 months follow up. Discussion & Conclusion THR and TCBAP were combined for the first time in this proof-of-concept case series. The preliminary outcomes indicated that this procedure is potentially a safe and effective alternative despite the theoretical increase in risk of ascending infection through the skin-implant interface to the external environment for this patient group. We suggest larger comparative series to further validate these results.

hSSB1 (NABP2/ OBFC2B) is required for the repair of 8-oxo-guanine by the hOGG1-mediated base excision repair pathway

The maintenance of genome stability is essential to prevent loss of genetic information and the development of diseases such as cancer. One of the most common forms of damage to the genetic code is the oxidation of DNA by reactive oxygen species (ROS), of which 8-oxo-7,8-dihydro-guanine (8-oxoG) is the most frequent modification. Previous studies have established that human single-stranded DNA-binding protein 1 (hSSB1) is essential for the repair of double-stranded DNA breaks by the process of homologous recombination. Here we show that hSSB1 is also required following oxidative damage. Cells lacking hSSB1 are sensitive to oxidizing agents, have deficient ATM and p53 activation and cannot effectively repair 8-oxoGs. Furthermore, we demonstrate that hSSB1 forms a complex with the human oxo-guanine glycosylase 1 (hOGG1) and is important for hOGG1 localization to the damaged chromatin. In vitro, hSSB1 binds directly to DNA containing 8-oxoguanines and enhances hOGG1 activity. These results underpin the crucial role hSSB1 plays as a guardian of the genome.

Tumor-associated mutations inO6-methylguanine DNA-methyltransferase (MGMT) reduce DNA repair functionality

MGMT is the primary vehicle for cellular removal of alkyl lesions from the O-6 position of guanine and the O-4 position of thymine. While key to the maintenance of genomic integrity, MGMT also removes damage induced by alkylating chemotherapies, inhibiting the efficacy of cancer treatment. Germline variants of human MGMT are well-characterized, but somatic variants found in tumors were, prior to this work, uncharacterized. We found that MGMT G132R, from a human esophageal tumor, and MGMT G156C, from a human colorectal cancer cell line, are unable to rescue methyltransferase-deficient Escherichia coli as well as wild type (WT) human MGMT after treatment with a methylating agent. Using pre-steady state kinetics, we biochemically characterized these variants as having a reduced rate constant. G132R binds DNA containing an O6-methylguanine lesion half as tightly as WT MGMT, while G156C has a 40-fold decrease in binding affinity for the same damaged DNA versus WT. Mammalian cells expressing either G132R or G156C are more sensitive to methylating agents than mammalian cells expressing WT MGMT. G132R is slightly resistant to O6-benzylguanine, an inhibitor of MGMT in clinical trials, while G156C is almost completely resistant to this inhibitor. The impared functionality of expressed variants G132R and G156C suggests that the presence of somatic variants of MGMT in a tumor could impact chemotherapeutic outcomes.

Development of a cultured tissue substitute to repair the ageing retina

This project provides a foundation for the use of silk membranes in a tissue engineered therapy for the treatment of devastating retinal diseases such as age-related macular degeneration. The three-dimensional tissue model described in this thesis has great potential for use in basic research of retinal pathologies, and the potential to be implemented into clinical approaches after appropriate refinement.

The use of a synthetic prostaglandin e1 analogue (misoprostol) as an adjunct to pancreatic enzyme replacement in cystic fibrosis

Eleven cystic fibrosis children (mean age, 9.6 years) were chosen at random to participate in a study to observe the effects of concurrently stimulating gastric/duodenal bicarbonate secretion and inhibiting gastric acid secretion, using a methylated prostaglandin E1 analogue in patients with pancreatic insufficiency and taking pancreatic enzymes. Percentage fat absorption in 3-day stool collections were calculated before and after commencing therapy with misoprostol, 400 μg/day in divided doses. We found a significant reduction in fat output (14.7 ± 11.7 versus 7.5 ± 3.5 g/day, p < 0.05) in the study group as a whole and a significant reduction in steatorrhoeic level as a percentage of fat intake in all of the patients with abnormal base-line collections (23.1% versus 9.2% p < 0.002). We conclude that misoprostol should be considered in cystic fibrosis patients with steatorrhoea as a means of improving nutrient absorption. © 1988 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

The use of a synthetic prostaglandin-E1 analog (misoprostol) as an adjunct to pancreatic-enzyme replacement in cystic-fibrosis

Eleven cystic fibrosis children (mean age, 9.6 years) were chosen at random to participate in a study to observe the effects of concurrently stimulating gastric/duodenal bicarbonate secretion and inhibiting gastric acid secretion, using a methylated prostaglandin E1 analogue in patients with pancreatic insufficiency and taking pancreatic enzymes. Percentage fat absorption in 3-day stool collections were calculated before and after commencing therapy with misoprostol, 400 μg/day in divided doses. We found a significant reduction in fat output (14.7 ± 11.7 versus 7.5 ± 3.5 g/day, p < 0.05) in the study group as a whole and a significant reduction in steatorrhoeic level as a percentage of fat intake in all of the patients with abnormal base-line collections (23.1% versus 9.2%, p < 0.002). We conclude that misoprostol should be considered in cystic fibrosis patients with steatorrhoea as a means of improving nutrient absorption.

Home monitoring for infants at risk of the sudden infant death syndrome

This study evaluates the effectiveness and social implications of home monitoring of 31 infants at risk of sudden infant death syndrome (SIDS). Thirteen siblings of children dying of SIDS, nine near miss SIDS infants and nine preterm infants with apnoea persisting beyond 40 weeks post conceptual age were monitored from a mean age of 15 days to a mean of 10 months. Chest movement detection monitors were used in 27 and thoracic impedance monitors in four. Genuine apnoeic episodes were reported by 21 families, and 13 infants required resuscitation. Apnoeic episodes occurred in all nine preterm infants but in only five (38%) of the siblings of SIDS (P<0.05). Troublesome false alarms were a major problem occurring with 61% of the infants and were more common with the preterm infants than the siblings of SIDS. All but two couples stated that the monitor decreased anxiety and improved their quality of life. Most parents accepted that the social restrictions imposed by the monitor were part of the caring process but four couples were highly resentful of the changes imposed on their lifestyle. The monitors used were far from ideal with malfunction occurring in 17, necessitating replacement in six, repair in six and cessation of monitoring in three. The parents became ingenious in modifying the monitors to their own individual requirements Although none of these 31 ‘at risk’ infants died the study sample was far too small to conclude whether home monitoring prevented any cases of SIDS.

Optimized group replacement scheduling for water pipeline network

Replacement of deteriorated water pipes is a capital-intensive activity for utility companies. Replacement planning aims to minimize total costs while maintaining a satisfactory level of service and is usually conducted for individual pipes. Scheduling replacement in groups is seen to be a better method and has the potential to provide benefits such as the reduction of maintenance costs and service interruptions. However, developing group replacement schedules is a complex task and often beyond the ability of a human expert, especially when multiple or conflicting objectives need to be catered for, such as minimization of total costs and service interruptions. This paper describes the development of a novel replacement decision optimization model for group scheduling (RDOM-GS), which enables multiple group-scheduling criteria by integrating new cost functions, a service interruption model, and optimization algorithms into a unified procedure. An industry case study demonstrates that RDOM-GS can improve replacement planning significantly and reduce costs and service interruptions.

Osseointegrated total knee replacement connected to a lower limb prosthesis: 4 cases

Background and purpose — Osseointegrated implants are an alternative for prosthetic attachment in individuals with amputation who are unable to wear a socket. However, the load transmitted through the osseointegrated fixation to the residual tibia and knee joint can be unbearable for those with transtibial amputation and knee arthritis. We report on the feasibility of combining total knee replacement (TKR) with an osseointegrated implant for prosthetic attachment. Patients and methods — We retrospectively reviewed all 4 cases (aged 38–77 years) of transtibial amputations managed with osseointegration and TKR in 2012–2014. The below-the-knee prosthesis was connected to the tibial base plate of a TKR, enabling the tibial residuum and knee joint to act as weight-sharing structures. A 2-stage procedure involved connecting a standard hinged TKR to custom-made implants and creation of a skin-implant interface. Clinical outcomes were assessed at baseline and after 1–3 years of follow-up using standard measures of health-related quality of life, ambulation, and activity level including the questionnaire for transfemoral amputees (Q-TFA) and the 6-minute walk test. Results — There were no major complications, and there was 1 case of superficial infection. All patients showed improved clinical outcomes, with a Q-TFA improvement range of 29–52 and a 6-minute walk test improvement range of 37–84 meters. Interpretation — It is possible to combine TKR with osseointegrated implants.

Nutritional intake of opioid replacement therapy patients in community pharmacies: A pilot study

Aim: Opioid replacement therapy (ORT) is an established therapy for a patient group that has been associated with nutrition-related comorbidities. This paper aims to assess the nutritional intake and supplementation in ORT patients, determine the extent of nutritional/dietary advice supplied to ORT patients and to briefly examine patients' perception of pharmacists' provision of nutritional advice. Methods: The nutritional intake of ORT patients receiving treatment in community pharmacies within the Australian Capital Territory was assessed via a 24-hour recall survey. Food intake data were analysed via nutrient analysis software and compared with Australian Nutrition Reference Values and the nutrient intakes of the Australian population. Patients were surveyed to determine supplement use and perceptions of nutritional advice gained by pharmacists. Results: Potential insufficient intake of various macronutrients and micronutrients was observed in both sexes. Less than 25 of patients recorded supplement use. Fifteen percent of males and 21 of females stated that they had approached a pharmacist with a nutrition-related query. All patients who received nutritional advice followed the advice. Conclusions: ORT patients dosing at community pharmacies appear to have poor nutritional intake. ORT patients appear to be receptive to pharmacist's advice. Community pharmacists can potentially increase the beneficial health outcomes in this population through the proactive supply of accurate nutritional advice.

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 x 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-kappaB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

Dislocation after total hip replacement: there is no such thing as a safe zone for socket placement with the posterior approach

Introduction Malorientation of the socket contributes to instability after hip arthroplasty but the optimal orientation of the cup in relation to the pelvis has not been unequivocally described. Large radiological studies are few and problems occur with film standardisation, measurement methodology used and alternative definitions of describing acetabular orientation. Methods A cohort of 1,578 patients from a single institution is studied where all patient data was collected prospectively. Risk factors for patients undergoing surgery are analysed. Radiological data was compared between a series of non-dislocating hips and dislocating cases matched 2:1 by operation type, age and diagnosis. Results The overall dislocation rate for all 1,578 cases was 3.23% but the rate varied according to the type of surgery performed. The rate in uncomplicated primary cases was 2.4% which increased to 9.3% for second stage implantation for a two stage procedure for infection. There was no significant difference in the variability of the dislocating and non-dislocating groups for either inclination (p = 0.393) or anteversion (p = 0.661). Conclusions A “safe zone” for socket orientation to avoid dislocation could not be defined. The cause of dislocation is multifactorial, re-establishing the anatomic centre of rotation, balancing soft tissues and avoidance of impingement around the hip are important considerations.

Epigenetics Underpinning DNA Damage Repair

Epigenetics is the study of heritable changes in gene expression that are not the result of genetic alterations. These changes include DNA methylation, histone modifications, or indeed microRNA expression. Chromatin is a tightly compacted DNA–protein complex that allows approximately two meters of DNA to be packaged inside a cell, only a few micrometers across. Although the resulting DNA structure is very stable, it is not very amiable to DNA-dependent processes, so mechanisms have to exist to allow processes such as transcription, replication, and DNA repair to occur. This chapter will look at how a cell responds to and deals with genomic instability at the epigenetic level and highlight how critical chromatin remodeling is for correct DNA repair and cell survival following DNA damage. This chapter will initially look at the DNA repair pathways that function in human cells and then at how the repair of DNA damage is controlled by epigenetics.

Safety of Repair, Maintenance, Minor Alteration, and Addition (RMAA) Works: A New Focus of Construction Safety

"Safety of RMAA works is an almost uncharted topic of rising importance internationally. Small construction contractors are particularly dependant on RMAA work, especially during times of recession, and they undertake more risks on these jobs than large companies do. This book is based on unique international research and consultancy projects which detail, investigate, and suggest solutions to the specific challenges of safety in RMAA works, based on case studies. Starting with an overview of safety in the wider construction industries of developed countries, the first half of this book also provides a comprehensive summary of relevant rules, regulations, and the resulting safety performances. The systems in the UK, US and Hong Kong are described and contrasted, giving the reader an understanding of how different regulatory approaches have yielded a variety of results. From this solid introduction, specific problems observed in RMAA work are examined through case studies, with reference to the underlying cultural and demographic factors, and a variety of practical engineering and management solutions are explored. This important and practical international work is essential reading for postgraduate students of health and safety in construction, construction project management, or construction in developing countries, as well as policy-makers and construction project managers."--Publisher website