Spinal stenosis

This thesis describes in detail the clinical spectrum of spinal stenosis in a series of two hundred and twenty-one patients at the Nuffield Orthopaedic Centre. It depicts those conditions with which spinal stenosis may be confused, and other conditions with which it is associated. Characteristic symptoms and physical signs are reported and the role and value of different methods of investigation are discussed. The aetiology and pathogenesis of spinal stenosis is discussed and the emphasis turned away from absolute measurements of the dimensions of the bony spinal canal, towards the role of the soft tissues and the dynamic response of the canal and its neural contents to postural change and loading, as evidenced by erect flexion and extension radiculography. The spinal reserve capacity measurement on CT approaches more closely the ideal of measurement of volumetric disproportion of canal and contents, but it takes no account of the dynamics of the canal. Magnetic Resonance Imaging may, in the future, provide the most objective criteria for diagnosis if section thickness can be reduced. Experimental spinal stenosis was produced in a group of immature New Zealand white rabbits. This was induced by sublaminar wiring at three levels at the age of eight weeks and allowing the animals to grow for twenty-four months before sacrifice and analysis of the spines. The effect of sublaminar wiring on the growth and development of the lamina and spinal canal was analysed using a Kontron Ibas Image Analysis Computer, and the results described and statistically analysed. The results of surgery were analysed in detail in a group of seventytwo patients with spinal stenosis at the Nuffield Orthopaedic Centre. The long-term results were compared with the initial post-operative result and two groups were identified: the stable result and the unstable result. The indications for and results of re-operation were also analysed in a group of twelve patients. Improved understanding of the aetiology of spinal stenosis has enhanced surgical management and results. The extent of surgical decompression must be precisely planned pre-operatively from radiographic and CT studies, and the surgeon must be able to execute this plan at operation. There is now no place for exploratory operations. The objective of surgery is adequate nerve root decompression without spinal de-stabilisation and when this is achieved, re-operation is redundant

50 Years of Spaceflight with Fourier Transform Spectrometers (FTS) Built at NASA GSFC

Over the past 50 years, NASA Goddard Space Flight Center (GSFC) has been developing, building, testing and flying a series of Fourier Transform Spectrometers (FTS). This began with the IRIS instruments on the Earth-orbiting Nimbus satellites and progressed to more sophisticated designs optimized for interplanetary spacecraft sent to Mars and later to the outer solar system. Adaptions have been made over time, including progressively higher spectral resolution, sensitivity, numbers of detectors and complexity. Instrument operating temperatures have decreased to enable remote sensing of the cold giant planet systems. In this paper we describe the historical evolution of this instrument line, comparing and contrasting different aspects such as optical design and materials, detector types and data handling. We conclude by looking towards the future. At present the CIRS-Lite prototype is being tested at NASA GSFC for potential use on a future mission to the ice giants, Uranus and Neptune. Surpassing the previous performance of the Voyager IRIS instruments remains challenging, and new technologies that could enable these measurements are discussed

Socioeconomic impacts of the second stage of the Southern Nevada Water Project and its alternatives

This study evaluates the socioeconomic impacts of the Second Stage of the Southern Nevada Water Project of the United States Bureau of Reclamation, comparing that project with the alternatives of importing water from Nevada areas somewhat removed from the Las Vegas Valley and of leaving the water supply of the Valley basically as it is, the no project alternative. The study follows, with adaptations and extensions, the general methodology for socioeconomic impact studies as developed and still being evolved in successive socioeconomic analyses of Bureau of Reclamation water projects. The methodology recognizes that the complexity of modern society and water impacts requires that water project analyses extend beyond the dollar cost benefit approach, which usually is the most reliable guide to decision, to considerations of qualitative effects, which often are of dominant importance despite their difficulty of measurement. Such analysis requires the tools of economics, sociology, engineering, law, political science and other related fields. It also dictates a step-by-step process which insures comprehensive consideration of the direct and indirect impacts of water projects on all of the social sectors which command public interest and concern. Such a step-by-step process constitutes the six chapters of this report

Randomised, controlled trial of alternating pressure mattresses compared with alternating pressure overlays for the prevention of pressure ulcers : PRESSURE (pressure relieving support surfaces) trial

Objective To compare whether differences exist between alternating pressure overlays and alternating pressure mattresses in the development of new pressure ulcers, healing of existing pressure ulcers, and patient acceptability. Design Pragmatic, open, multicentre, randomised controlled trial. Setting 11 hospitals in six NHS trusts. Participants 1972 people admitted to hospital as acute or elective patients. Interventions Participants were randomised to an alternating pressure mattress (n = 982) of- an alternating pressure overlay (n = 990). Main outcome measures The proportion of participants developing a new pressure ulcer of grade 2 or worse; time to development of new pressure ulcers; proportions of participants developing a new ulcer within 30 days; healing of existing pressure ulcers; and patient acceptability Results Intention to treat analysis found no difference in the proportions of participants developing a new pressure ulcer of grade 2 or worse (10.7% overlay patients, 10.3% mattress patients; difference 0.4%, 95% confidence interval - 23% to 3.1%, P = 0.75). More overlay patients requested change owing to dissatisfaction (23.3%) than mattress patients (18.9%, P = 0.02). Conclusion No difference was found between alternating pressure mattresses and alternating pressure overlays in the proportion of people who develop a pressure ulcer

Epigenome-wide profiling identifies significant differences in DNA methylation between matched-pairs of T- and B-lymphocytes from healthy individuals

Multiple reports now describe changes to the DNA methylome in rheumatoid arthritis and in many cases have analyzed methylation in mixed cell populations from whole blood. However, these approaches may preclude the identification of cell type-specific methylation, which may subsequently bias identification of disease-specific changes. To address this possibility, we conducted genome-wide DNA methylation profiling using HumanMethylation450 BeadChips to identify differences within matched pairs of T-lymphocytes and B-lymphocytes isolated from the peripheral blood of 10 healthy females. Array data were processed and differential methylation identified using NIMBL software. Validation of array data was performed by bisulfite Pyrosequencing. Genome-wide DNA methylation was initially determined by analysis of LINE-1 sequences and was higher in B-lymphocytes than matched T-lymphocytes (69.8 vs. 65.2%, p ≤ 0.01). Pairwise analysis identified 679 CpGs, representing 250 genes, which were differentially methylated between T-lymphocytes and B-lymphocytes. The majority of sites (76.6%) were hypermethylated in B-lymphocytes. Pyrosequencing of selected candidates confirmed the array data in all cases. Hierarchical clustering revealed perfect segregation of samples into two distinct clusters based on cell type. Differentially methylated genes showed enrichment for biological functions/pathways associated with leukocytes and T-lymphocytes. Our work for the first time shows that T-lymphocytes and B-lymphocytes possess intrinsic differences in DNA methylation within a restricted set of functionally-related genes. These data provide a foundation for investigating DNA methylation in diseases in which these cell types play important and distinct roles

Potent selective inhibitors of protein kinase C

AbstractA series of potent, selective inhibitors of protein kinase C has been derived from the structural lead provided by the microbial broth products, staurosporine and K252a. Our inhibitors block PCK in intact cells (platelets and T cells), and prevent the proliferation of mononuclear cells in response to interleukin 2 (IL2)

Evidence for lateral transfer of genes encoding ferredoxins, nitroreductases, NADH oxidase, and alcohol dehydrogenase 3 from anaerobic prokaryotes to Giardia lamblia and Entamoeba histolytica

Author Posting. © American Society for Microbiology, 2002. This article is posted here by permission of American Society for Microbiology for personal use, not for redistribution. The definitive version was published in Eukaryotic Cell 1 (2002): 181-190, doi:10.1128/EC.1.2.181-190.2002.Giardia lamblia and Entamoeba histolytica are amitochondriate, microaerophilic protists which use fermentation enzymes like those of bacteria to survive anaerobic conditions within the intestinal lumen. Genes encoding fermentation enzymes and related electron transport peptides (e.g., ferredoxins) in giardia organisms and amebae are hypothesized to be derived from either an ancient anaerobic eukaryote (amitochondriate fossil hypothesis), a mitochondrial endosymbiont (hydrogen hypothesis), or anaerobic bacteria (lateral transfer hypothesis). The goals here were to complete the molecular characterization of giardial and amebic fermentation enzymes and to determine the origins of the genes encoding them, when possible. A putative giardia [2Fe-2S]ferredoxin which had a hypothetical organelle-targeting sequence at its N terminus showed similarity to mitochondrial ferredoxins and the hydrogenosomal ferredoxin of Trichomonas vaginalis (another luminal protist). However, phylogenetic trees were star shaped, with weak bootstrap support, so we were unable to confirm or rule out the endosymbiotic origin of the giardia [2Fe-2S]ferredoxin gene. Putative giardial and amebic 6-kDa ferredoxins, ferredoxin-nitroreductase fusion proteins, and oxygen-insensitive nitroreductases each tentatively supported the lateral transfer hypothesis. Although there were not enough sequences to perform meaningful phylogenetic analyses, the unique common occurrence of these peptides and enzymes in giardia organisms, amebae, and the few anaerobic prokaryotes suggests the possibility of lateral transfer. In contrast, there was more robust phylogenetic evidence for the lateral transfer of G. lamblia genes encoding an NADH oxidase from a gram-positive coccus and a microbial group 3 alcohol dehydrogenase from thermoanaerobic prokaryotes. In further support of lateral transfer, the G. lamblia NADH oxidase and adh3 genes appeared to have an evolutionary history distinct from those of E. histolytica.This work was supported by NIH grants (AI33492 to J.S., AI43273 to M.L.S., and AI46516 to B.J.L.). Additional support was provided by the G. Unger Vetlesen Foundation and LI-COR Biotechnology

Precision health in behaviour change interventions: A scoping review

Precision health seeks to optimise behavioural interventions by delivering personalised support to those in need, when and where they need it. Conceptualised a decade ago, progress toward this vision of personally relevant and effective population-wide interventions continues to evolve. This scoping review aimed to map the state of precision health behaviour change intervention research. This review included studies from a broader precision health review. Six databases were searched for studies published between January 2010 and June 2020, using the terms ‘precision health’ or its synonyms, and including an intervention targeting modifiable health behaviour(s) that was evaluated experimentally. Thirty-one studies were included, 12 being RCTs (39 %), and 17 with weak study design (55 %). Most interventions targeted physical activity (27/31, 87 %) and/or diet (24/31, 77 %), with 74% (23/31) targeting two to four health behaviours. Interventions were personalised via human interaction in 55 % (17/31) and digitally in 35 % (11/31). Data used for personalising interventions was largely self-reported, by survey or diary (14/31, 45 %), or digitally (14/31, 45 %). Data was mostly behavioural or lifestyle (20/31, 65 %), and physiologic, biochemical or clinical (15/31, 48 %), with no studies utilising genetic/genomic data. This review demonstrated that precision health behaviour change interventions remain dependent on human-led, low-tech personalisation, and have not fully considered the interaction between behaviour and the social and environmental contexts of individuals. Further research is needed to understand the relationship between personalisation and intervention effectiveness, working toward the development of sophisticated and scalable behaviour change interventions that have tangible public health impact

Genome-wide profiling in treatment-naive early rheumatoid arthritis reveals DNA methylome changes in T and B lymphocytes

AIM: Although aberrant DNA methylation has been described in rheumatoid arthritis (RA), no studies have interrogated this epigenetic modification in early disease. Following recent investigations of T- and B-lymphocytes in established disease, we now characterize in these cell populations genome-wide DNA methylation in treatment-naive patients with early RA. PATIENTS & METHODS: HumanMethylation450 BeadChips were used to examine genome-wide DNA methylation in lymphocyte populations from 23 early RA patients and 11 healthy individuals. RESULTS: Approximately 2000 CpGs in each cell type were differentially methylated in early RA. Clustering analysis identified a novel methylation signature in each cell type (150 sites in T-lymphocytes, 113 sites in B-lymphocytes) that clustered all patients separately from controls. A subset of sites differentially methylated in early RA displayed similar changes in established disease. CONCLUSION: Treatment-naive early RA patients display novel disease-specific DNA methylation aberrations, supporting a potential role for these changes in the development of RA

Ultrastructural identification of uncoated caveolin-independent early endocytic vehicles

Using quantitative light microscopy and a modified immunoelectron microscopic technique, we have characterized the entry pathway of the cholera toxin binding subunit (CTB) in primary embryonic fibroblasts. CTB trafficking to the Golgi complex was identical in caveolin-1null (Cav1−/−) mouse embryonic fibroblasts (MEFs) and wild-type (WT) MEFs. CTB entry in the Cav1−/− MEFs was predominantly clathrin and dynamin independent but relatively cholesterol dependent. Immunoelectron microscopy was used to quantify budded and surface-connected caveolae and to identify noncaveolar endocytic vehicles. In WT MEFs, a small fraction of the total Cav1-positive structures were shown to bud from the plasma membrane (2% per minute), and budding increased upon okadaic acid or lactosyl ceramide treatment. However, the major carriers involved in initial entry of CTB were identified as uncoated tubular or ring-shaped structures. These carriers contained GPI-anchored proteins and fluid phase markers and represented the major vehicles mediating CTB uptake in both WT and caveolae-null cells