Distributed abstraction and verification of an installed optical fibre network.

The management of wavelength routed optical mesh networks is complex with many potential light path routes and numerous physical layer impairments to transmission performance. This complexity can be reduced by applying the ideas of abstraction from computer science where different equipment is described in the same basic terms. The noise-to-signal ratio can be used as a metric to describe the quality of transmission performance of a signal propagated through a network element and accumulates additively through a sequence of such elements allowing the estimation of end-to-end performance. This study aims to explore the robustness of the noise-to-signal ratio metric in an installed fibre infrastructure. We show that the abstracted noise-to-signal ratio is independent of the observers and their location. We confirm that the abstracted noise-to-signal ratio can reasonably predict the performance of light-paths subsequently set in our network. Having a robust network element abstraction that can be incorporated into routeing engines allows the network management controller to make decisions on the most effective way to use the network resources in terms of the routeing and data coding format.

Bidirectional wavelength-division multiplexing transmission over installed fibre using a simplified optical coherent access transceiver.

High-speed broadband services require optical fibres in access networks, in which multiple subscribers are connected to service providers, to satisfy the continuously growing bandwidth demand. The primitive signaling scheme used in access networks enables the use of low-cost equipment but diminishes the bandwidth available to end-users. Thus, current technology will be unable to support future broadband demands. Coherent communication systems offer significantly improved power- and bandwidth-efficiency, but require fundamental simplifications to become economically viable for access networks. Here, we demonstrate a promising simplified coherent receiver exhibiting a robust performance against polarisation fluctuations over an installed fibre network. It enables the realisation of high-order modulation formats and offers high sensitivities, achieving a four-fold increase in the supported number of subscribers and approximately doubling the transmission distance compared to the recently standardized access technology. The proposed solution indicates that digital coherent technology can be feasible and transform the access networks, enabling ubiquitous new services and applications with uncontended, multi-gigabits/user broadband connections.

Adalimumab for psoriasis: practical experience in a U.K. tertiary referral centre.

BACKGROUND: There are few reports of the practical use of adalimumab outside of a clinical trial setting and, to our knowledge, none from the U.K. OBJECTIVES: We assessed the efficacy and safety of adalimumab in a cohort of patients with severe psoriasis attending a tertiary dermatology referral centre in the U.K. METHODS: A retrospective case-note review was used to identify all patients initiated on adalimumab for psoriasis. RESI;TS: Baseline Psoriasis Area and Severity Index (PASI) was 24+/-11 (range 9-54; n=46). After 4 months' treatment with adalimumab 64% (29/45), of patients had achieved PASI 75 (75% decrease from baseline) whilst 80% (36/45) of patients met NICE criteria for continuation of treatment. Therapy was well-tolerated. Importantly, 68% (21/31) of patients who had previously received another tumour necrosis factor alpha inhibitor met NICE criteria for continuation of treatment at 16 weeks. CONCLUSIONS: In a cohort of U.K. patients with severe psoriasis, adalimumab has proved to be a significant addition to the expanding armamentarium of biologics for psoriasis. Pharmacovigilance, in the form of registries, is essential to assess the long-term safety of such drugs.

HEY1 Leu94Met gene polymorphism dramatically modifies its biological functions.

The hairy/enhancer-of-split related with YRPW motif 1 (HEY1) is a member of the basic-helix-loop-helix-Orange (bHLH-O) family of transcriptional repressors that mediate Notch signaling. Several cancer-related pathways also regulate HEY1 expression, and HEY1 itself acts as an indirect positive regulator of the p53 tumor suppressor protein and a negative regulator of androgen receptor activity. In this study we show how a naturally occurring non-synonymous polymorphism at codon 94 of HEY1, which results in a substitution of leucine by methionine (Leu94Met), converts HEY1 from an androgen receptor corepressor to an androgen receptor co-activator without affecting its intrinsic transcriptional repressive domains. The polymorphism Leu94Met also abolishes HEY1-mediated activation of p53 and suppresses the ability of HEY1 to induce p53-dependent cell-cycle arrest and aberrant cell differentiation in human osteosarcoma U2OS cells. Moreover, expression of HEY1, but not of the variant Leu94Met, confers sensitivity to p53-activating chemotherapeutic drugs on U2OS cells. In addition, we have identified motifs in HEY1 that are critical for the regulation of its subcellular localization and analysed how mutations in those motifs affect both HEY1 and HEY1-Leu94Met functions. These findings suggest that the polymorphism Leu94Met in HEY1 radically alters its biological activities and may affect oncogenic processes.

Biologic therapies for psoriasis: practical experience in a U.K. tertiary referral centre.

BACKGROUND: Large-scale clinical trials provide clear evidence of the efficacy and short-term toxicity of biologic therapies for psoriasis. However, to date, there are few reports of the practical use of these therapies outside of the trial setting and, to our knowledge, none from a U.K. cohort of patients with psoriasis. OBJECTIVES: (i) To assess efficacy and safety of efalizumab, etanercept and infliximab in a U.K. cohort of patients with psoriasis, with mean Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index 21.8 and 21.7, respectively, outside of the clinical trial setting. (ii) To examine our approach to the processes involved in the initiation of biologic therapies in the era of National Institute for Health and Clinical Excellence guidance. METHODS: A retrospective case-note review to identify all patients initiated on biologic therapies for psoriasis in a U.K. tertiary referral centre. RESULTS: At 3 months of treatment the efficacy of efalizumab (n = 28), etanercept (n = 70) and infliximab (n = 20), as assessed by PASI 75 (75% decrease from baseline score), was 24%, 35% and 85%, respectively. All three biologics used were well tolerated. Combination therapy with traditional systemic agents was required either at transition to, or to counter relapse while established on, a biologic therapy in 30% of cases. Streamlined approaches to screening and funding significantly (P

The human androgen receptor AF1 transactivation domain: interactions with transcription factor IIF and molten-globule-like structural characteristics.

The AR (androgen receptor) is a ligand-activated transcription factor and member of the steroid receptor superfamily. The AR responds to the ligands testosterone and dihydrotestosterone and activates multiple downstream genes required in development and reproduction. During the events of transactivation, the AR makes specific protein-protein interactions with several basal transcription factors such as TBP (TATA-box-binding protein) and TFIIF (transcription factor IIF). These interactions occur predominantly within a defined region termed AF1 (activation function-1) located within the highly disordered N-terminal domain of the receptor. Our focus is on the structural aspects of AF1 and how this flexible and disordered domain generates functional interactions with regulators of transcription. Our working hypothesis is that AR-AF1 domain exhibits induced folding when contacted by transcription regulators (such as TFIIF) into a more compact and 'active' conformation, enabling further co-regulator recruitment and ultimately transcription. Structural flexibility and intrinsic disorder of AR-AF1 were studied using predictive algorithms and fluorescence spectroscopy under different experimental conditions and the results revealed this domain retains characteristics indicative of molten-globule or pre-molten-globule-like structures. We hypothesize that this partially folded intermediate state is important for, and enables the AF1 domain to make, multiple protein-protein interactions. The structural aspects of AR-AF1 and interactions with TFIIF are discussed.

The Isolation of differentially expressed mRNA sequences by selective amplification via biotin and restriction-mediated enrichment.

Molecular analysis of development frequently implies the isolation and characterization of genes with specific spatial and temporal expression patterns. Several methods have been developed to identify such DNA sequences. The most comprehensive technique involves the genomewide probing of DNA sequence microarrays with mRNA sequences. However, at present this technology is limited to the few organisms for which the entire genome has been sequenced. Here, we describe a subtractive hybridization technique, called selective amplification via biotin and restriction-mediated enrichment (SABRE), which allows the selective amplification of cDNA fragments representing differentially expressed mRNA species. The method involves the competitive hybridization of an excess of driver cDNA fragments (D) to a trace of tester cDNA fragments (T), and the subsequent purification of tester homohybrids (in which both strands are contributed by the tester cDNA). After competitive hybridization, cDNA fragments that are more abundant in the tester than in the driver are enriched in the tester homohybrids. However, as the fraction of tester homohybrids is very small [T(2)/(D + T)(2)], their purification requires highly efficient procedures. In SABRE, the isolation of tester homohybrids is afforded by a combination of three successive steps: removal of biotinylated terminal sequences from most of the heterohybrids by S1 nuclease digestion, capture of biotinylated hybrids with streptavidin-coated paramagnetic beads, and specific release of homohybrids from the beads by restriction nuclease digestion. If several rounds of SABRE selection are performed in series, even relatively rare differentially expressed mRNA sequences may result in the production of predominant cDNA fragments in the final tester homohybrid population.

Circadian expression of the steroid 15 alpha-hydroxylase (Cyp2a4) and coumarin 7-hydroxylase (Cyp2a5) genes in mouse liver is regulated by the PAR leucine zipper transcription factor DBP.

To study the molecular mechanisms of circadian gene expression, we have sought to identify genes whose expression in mouse liver is regulated by the transcription factor DBP (albumin D-site-binding protein). This PAR basic leucine zipper protein accumulates according to a robust circadian rhythm in nuclei of hepatocytes and other cell types. Here, we report that the Cyp2a4 gene, encoding the cytochrome P450 steroid 15alpha-hydroxylase, is a novel circadian expression gene. This enzyme catalyzes one of the hydroxylation reactions leading to further metabolism of the sex hormones testosterone and estradiol in the liver. Accumulation of CYP2A4 mRNA in mouse liver displays circadian kinetics indistinguishable from those of the highly related CYP2A5 gene. Proteins encoded by both the Cyp2a4 and Cyp2a5 genes also display daily variation in accumulation, though this is more dramatic for CYP2A4 than for CYP2A5. Biochemical evidence, including in vitro DNase I footprinting on the Cyp2a4 and Cyp2a5 promoters and cotransfection experiments with the human hepatoma cell line HepG2, suggests that the Cyp2a4 and Cyp2a5 genes are indeed regulated by DBP. These conclusions are corroborated by genetic studies, in which the circadian amplitude of CYP2A4 and CYP2A5 mRNAs and protein expression in the liver was significantly impaired in a mutant mouse strain homozygous for a dbp null allele. These experiments strongly suggest that DBP is a major factor controlling circadian expression of the Cyp2a4 and Cyp2a5 genes in the mouse liver.

Cost of diabetes-related amputations in minorities.

The objective of this study was to identify the direct cost and length of hospitalization of diabetes-related lower extremity amputations among Hispanics, African Americans, non-Hispanic whites, and Asians. The authors used a database from the office of Statewide Planning and Development in California that identified all hospitalizations for lower extremity amputations in the state in 1991. Amputation level was defined by the ICD-9-CM codes 84.11-84.18. The total hospital charges for diabetes-related lower extremity amputations for the state of California in 1991 was $141 million. The mean hospital charge (HC) per patient with all ethnic groups combined was $27,930; and the mean length of stay (LOS) was 15.9 days. African Americans had significantly higher mean charges ($32,383) and longer stays (17.3 days) compared to all other ethnic groups (p < .05). Toe-level amputations had lower HC (p < .05) and LOS (p < .01) than other amputation levels for all race groups. One-quarter of the population received multiple amputations during their hospital stay. These patients incurred significantly higher hospital charges ($44,731) and stayed in the hospital longer (23.4 days) than those receiving only a single amputation. There was a considerable variation in the HC and LOS among ethnic groups by level of amputation. The direct charges reported in this study suggest considerably higher overall direct costs than have been previously reported in the medical literature. The greater burden of disease experienced by African Americans is probably related to their higher amputation cost and longer hospitalization.

Is postural instability exacerbated by off-loading devices in high risk diabetics with foot ulcers?

Pressure reduction is of pivotal importance in any treatment plan designed to heal diabetic foot ulcers. However, to our knowledge, no work has evaluated the effect of ambulatory pressure reducing devices on postural stability (PS) in high risk diabetics. Therefore, the purpose of this study was to compare PS associated with 5 off-loading strategies: total contact casts with cast boot, total contact casts with heel, removable cast walker, half-shoes, and canvas shoes using a repeat measure design. Twenty-six diabetic patients with foot ulcers were enrolled in the study. Using a digital pressure platform, the degree of sway was measured as total deviation of center of force. Three 30 second trials were evaluated using Turkey's studentized range test for multiple comparisons (alpha = 0.05). Sway was significantly greater with total contact casts with heel compared to other devices. While total contact casting remains the gold standard with which to treat neuropathic ulcers, care should be taken when placing patients in any devices that may exacerbate postural instability. The results suggest that total contact casts with an incorporated rubber heel may indeed accentuate sway. It is therefore recommended that the rubber heel be eliminated in lieu of a protective cast boot when using this modality.

Reducing plantar pressure in the neuropathic foot. A comparison of footwear.

OBJECTIVE: To compare the effectiveness of therapeutic, comfort, and athletic shoes with and without viscoelastic insoles. RESEARCH DESIGN AND METHODS: We compared pressure reduction at ulcer sites under the hallux (n = 10), first metatarsal (n = 10), and lesser metatarsals (n = 12), using extra-depth, athletic, and comfort shoes with and without viscoelastic insoles. A rubber-soled canvas oxford was used to establish baseline pressure values. RESULTS: When used in conjunction with a viscoelastic insole, all shoe types reduced mean peak plantar pressure better than their non-insoled counterparts (P < 0.05). Consistently, comfort shoes reduced pressure significantly better than both the cross trainers and extra-depth shoes for ulcers under the first and lesser metatarsals (P < 0.05). For each shoe type, the addition of the viscoelastic insole provided a significant reduction in mean peak pressure (P < 0.05). Compared with stock insoles, viscoelastic insoles reduced pressures an additional 5.4-20.1% at ulcer sites. The same trend was also observed at regions of the foot not associated with an ulceration. CONCLUSIONS: When used in conjunction with a viscoelastic insole, both the comfort and athletic cross-trainer shoes studied were as, if not more, effective than commonly prescribed therapeutic shoes in reducing mean peak first and lesser metatarsal pressures. Furthermore, comfort shoes were as effective as therapeutic shoes in reducing pressure under the great toe. Both of these shoe types may be viable options to prevent the development or recurrence of foot ulcers.

Total contact casts: pressure reduction at ulcer sites and the effect on the contralateral foot.

OBJECTIVE: To compare the effectiveness of total contact casts with a cast boot (TCCB), total contact casts with a cast heel (TCCH), and therapeutic XtraDepth shoes (XDS) to reduce ulcer site pressures and to determine if total contact casts increase contralateral pressures. DESIGN: Repeat measure design with 40 replications nested within each treatment for each patient. METHODS: Peak contralateral foot pressures and ulcer site pressures under the 1st metatarsal (1MET; n = 10), 2nd to 5th metatarsals (2-5MET; n = 10), and great toe (GT; n = 5) were compared using the Novel-Pedar system and three treatments: TCCB, TCCH, and XDS. Baseline pressures were established using canvas oxfords. RESULTS: There was no difference in pressure reduction with TCCH vs. TCCB for 1MET or GT ulcers, but TCCH reduced pressure better for 2-5MET ulcers (p < .001). Contralateral pressures were not elevated in either TCC group. CONCLUSIONS: TCCH were superior to TCCB in reducing 2-5MET ulcer pressures and equivalent to TCCB for 1MET and GT ulcers. Contralateral pressures are not increased by TCC use.

1997 William J. Stickel Bronze Award. Comparison of strategies for reducing pressure at the site of neuropathic ulcers.

Few scientific data are available on the effectiveness of commonly used modalities for reducing pressure at the site of neuropathic ulcers in persons with diabetes mellitus. The authors' aim was to compare the effectiveness of total contact casts, half-shoes, rigid-soled postoperative shoes, accommodative dressings made of felt and polyethylene foam, and removable walking casts in reducing peak plantar foot pressures at the site of neuropathic ulcerations in diabetics. Using an in-shoe pressure-measurement system, data from 32 midgait steps were collected for each treatment. There was a consistent pattern in the devices' effectiveness in reducing foot pressures at ulcer sites under the great toe and ball of the foot. Removable walking casts were as effective as or more effective than total contact casts. Half-shoes were consistently the third most effective modality, followed by accommodative dressings and rigid-soled postoperative shoes.

Effectiveness of diabetic insoles to reduce foot pressures.

The F-Scan system was used to measure peak plantar pressures in 11 diabetics each with a unilateral great toe amputation and an intact contralateral extremity (nonamputated), to evaluate the effectiveness of five footwear-insole strategies: 1) extra-depth shoes without an insole, 2) extra-depth shoes with a Plastizote insole, 3) extra-depth shoes with a Plastizote insole and a metatarsal pad, 4) extra-depth shoes with a Plastizote insole and a medial longitudinal arch pad, and 5) extra-depth shoes with a Plastizote insole and a combination of metatarsal pad and arch pad. When we compared extra-depth shoes with and without insoles, peak pressures were significantly reduced with insoles under the first metatarsal, the lesser metatarsals, and the heel (p < 0.001) in feet with and without an amputation, as well as under the great toe on the contralateral foot (nonamputated, p < 0.001), but not under the lesser toes (giant toe, p = 0.088; nonamputated, p = 0.763). There was no significant difference between the different insole modifications.

Selective amplification via biotin- and restriction-mediated enrichment (SABRE), a novel selective amplification procedure for detection of differentially expressed mRNAs.

We present a novel subtractive enrichment protocol for the identification of differentially expressed mRNA species. This procedure, called SABRE (selective amplification via biotin- and restriction-mediated enrichment), uses selective streptavidin-biotin affinity and restriction enzyme site reconstitution to enrich for cDNA species more abundant in one population than in another. Analysis of liver cDNA from a mouse strain expressing the neomycin resistance gene demonstrated that this procedure is capable of identifying species present in one population but absent from another. Furthermore, experiments to identify genes with circadian expression patterns in mouse liver demonstrated that SABRE is capable of detecting even modest 2- to 10-fold differences in accumulation of moderately rare mRNA species, representing as little as 0.03% of total mRNA. These experiments identified the gene encoding coumarin 7-hydroxylase as displaying circadian expression in mouse liver.

A quantitative assessment of healing sandals and postoperative shoes in offloading the neuropathic diabetic foot.

The purpose of this report is to compare plantar pressures between custom healing sandals and postoperative shoes using unmodified prescription shoe gear as a control. Using a repeat measures design, we recorded the plantar forefoot pressures of eight patients classified as diabetic foot category 1 (neuropathy, no significant deformity, no history of ulceration) with each ambulating in three devices: 1) unmodified prescription shoe gear, 2) postoperative shoe gear, and 3) a custom-fabricated healing sandal. Each subject served as his or her own control. The healing sandal significantly reduced plantar forefoot pressure in all areas of the forefoot except the fifth metatarsal head. The postoperative shoe did not significantly reduce pressure at any site in the forefoot when compared with unmodified prescription shoe gear.

Robots in space into the 21st century.

Describes the technological developments which are establishing the foundation for an exciting era of in situ exploration missions to planets, comets and asteroids with advanced robotic systems. Also outlines important concurrent terrestrial applications and spinoffs of the space robotics technology. These include high-precision robotic manipulators for microsurgical operations and dexterous arm control systems.