Granular anchors under vertical loading - axial pull

Granular anchors are a relatively new concept in ground engineering with relatively little known regarding their load–displacement behaviour, failure modes, ultimate pullout capacity and also potential applications. A granular anchor consists of three main components: a base plate; tendon and compacted granular backfill. The tendon is used to transmit the applied load to the base plate which compresses the granular material to form the anchor. A study of the load–displacement response and ultimate pullout capacity of granular anchors constructed in intact lodgement till and made ground deposits is reported in this paper. Parallel tests were also performed on cast insitu concrete anchors which are traditionally used for anchoring purposes. A new method of analysis for the determination of the ultimate pullout capacity of granular anchors is presented and verified experimentally, with the dominant mode of failure controlled by the column length to diameter ratio. Granular anchors with L/D > 7 principally failed on bulging whereas short granular anchors failed on shaft resistance, with the latter mobilising similar pullout capacities as conventional concrete anchors.

The NAD(P)H : quinone oxidoreductase IC609T polymorphism modifies the risk of Barrett esophagus and esophageal adenocarcinoma

Purpose: The role of genetic susceptibility to esophageal adenocarcinorna and its precursor lesion Barrett esophagus has not been fully elucidated. This study investigated the effect of polymorphisms in the manganese superoxide dismutase (MnSOD) and NAD(P)H:quinone oxicloreductase 1 (NQO1) genes in modulating the risk of developing Barrett esophagus or esophageal adenocarcinoma. Methods: A total of 584 patients (146 esophagitis, 200 Barrett esophagus, 144 esophageal adenocarcinoma, and 94 controls) were genotyped for the MnSOD C14T and NQO1 C609T polymorphisms using polymerase chain reaction and restriction fragment length polymorphism analysis. Results: The NQO1 TT genotype was less common in Barrett esophagus (2.0%) and esophageal adenocarcinoma (1.4%) patients, compared with both esophagitis patients (7.6%) and controls (5.4%). After adjustment for sex, age, body mass index, reflux symptoms, and smoking status, patients with the homozygous TT genotype had a 4.5-fold decreased risk of developing Barrett esophagus (odds ratio = 0.22, 95% confidence interval = 0.07-0.76, P = 0.01) and a 6.2-fold decreased risk of esophageal adenocarcinorna (odds ratio = 0.16, 95% confidence intervals = 0.03-0.94, P = 0.04) compared with individuals with the TC and CC genotypes. No significant differences between groups were observed for the MnSOD polymorphism (P = 0.289). Conclusions: Overall, the results of this study suggest that the NQO1 TT genotype may offer protection from reflux complications such as Barrett esophagus and esophageal adenocarcinoma.

Effect of tea polyphenols and tea pigments on the inhibition of precancerous liver lesions in rats

The objective of this study was to investigate the inhibitory effect of tea components, tea polyphenols and tea pigments, on precancerous liver lesions in rats. A rat liver precancerous lesion model was established by multiple low-dosage N-nitrosodiethylamine (NDEA) injections, followed by intraperitoneal CCl4 injection and partial hepatectomy (PH). Tea pigments (0.1%) or tea polyphenols (0.1%) were given to Wistar rats in drinking water during the eight weeks of the experiment. The number and area of glutathione S-transferase Pi-positive foci in the rat liver were used as biomarkers of precancerous liver lesions. Western and Northern blot techniques were used to detect rat liver GST-Pi expression at the protein and mRNA levels. At the end of the experiment tea polyphenols and tea pigments significantly decreased the number and area of GST-Pi-positive foci that were overexpressed in the NDEA-CCl4-PH-treated rats compared with the positive control group. The results also showed that GST-Pi mRNA and protein expression increased significantly in the NDEA-CCl4-PH-treated group, which is consistent with the changing of GST-Pi-positive foci. Tea pigments and tea polyphenols had an inhibitory effect on the overexpression of GST-Pi mRNA and protein in NDEA-CCl4-PH-treated rats. These results suggest that tea pigments and tea polyphenols are effective in preventing the occurrence and progression of precancerous liver lesions in rats.

Development of a bovine collagen-apatitic calcium phosphate cement for potential fracture treatment through vertebroplasty

The aim of this study was to examine the potential of incorporating bovine fibres as a means of reinforcing a typically brittle apatite calcium phosphate cement for vertebroplasty. Type I collagen derived from bovine Achilles tendon was ground cryogenically to produce an average fibre length of 0.96 ± 0.55 mm and manually mixed into the powder phase of an apatite-based cement at 1, 3 or 5 wt.%. Fibre addition of up to 5 wt.% had a significant effect (P = 0.001) on the fracture toughness, which was increased by 172%. Adding =1 wt.% bovine collagen fibres did not compromise the compressive properties significantly, however, a decrease of 39-53% was demonstrated at =3 wt.% fibre loading. Adding bovine collagen to the calcium phosphate cement reduced the initial and final setting times to satisfy the clinical requirements stated for vertebroplasty. The cement viscosity increased in a linear manner (R = 0.975) with increased loading of collagen fibres, such that the injectability was found to be reduced by 83% at 5 wt.% collagen loading. This study suggests for the first time the potential application of a collagen-reinforced calcium phosphate cement as a viable option in the treatment of vertebral fractures, however, issues surrounding efficacious cement delivery need to be addressed. © 2012 Acta Materialia Inc.

Protein kinase C{delta} deficiency accelerates neointimal lesions of mouse injured artery involving delayed reendothelialization and vasohibin-1 accumulation

To use protein kinase C (PKC) d-knockout mice to investigate the role of PKCd in lesion development and to understand the underlying mechanism of the vascular disease.

Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow

X-box binding protein 1 (XBP1) is a key signal transducer in endoplasmic reticulum stress response, and its potential role in the atherosclerosis development is unknown. This study aims to explore the impact of XBP1 on maintaining endothelial integrity related to atherosclerosis and to delineate the underlying mechanism. We found that XBP1 was highly expressed at branch points and areas of atherosclerotic lesions in the arteries of ApoE(-/-) mice, which was related to the severity of lesion development. In vitro study using human umbilical vein endothelial cells (HUVECs) indicated that disturbed flow increased the activation of XBP1 expression and splicing. Overexpression of spliced XBP1 induced apoptosis of HUVECs and endothelial loss from blood vessels during ex vivo cultures because of caspase activation and down-regulation of VE-cadherin resulting from transcriptional suppression and matrix metalloproteinase-mediated degradation. Reconstitution of VE-cadherin by Ad-VEcad significantly increased Ad-XBP1s-infected HUVEC survival. Importantly, Ad-XBP1s gene transfer to the vessel wall of ApoE(-/-) mice resulted in development of atherosclerotic lesions after aorta isografting. These results indicate that XBP1 plays an important role in maintaining endothelial integrity and atherosclerosis development, which provides a potential therapeutic target to intervene in atherosclerosis.

Fundus autofluorescence in exudative age-related macular degeneration

Aim: To evaluate the distribution of fundus autofluorescence in patients with age-related macular degeneration and choroidal neovascularisation (CNV). Methods: Colour fundus photographs, fundus fluorescein angiograms (FFA) and fundus autofluorescence images were obtained from a group of 40 patients (43 eyes) with age-related macular degeneration and purely classic or occult CNV. Only patients with newly diagnosed CNV and in whom autofluorescence images were obtained within 2 weeks from FFA were included. The distribution of autofluorescence was qualitatively evaluated, and the findings compared with those from colour fundus photographs and FFA. Results: 29 (67%) eyes had classic CNV and 14 (33%) had occult CNV. In 26 (90%) eyes with classic CNV, a low autofluorescence signal was detected at the site of the CNV; in 7 (50%) eyes with occult CNV, multiple foci of low autofluorescence signal were detected. Outside the area affected by the lesion, homogeneous autofluorescence was observed in most of the cases (n = 33, 77%). Similarly, homogeneous autofluorescence was commonly observed in fellow eyes (62%). A pattern of focal increased autofluorescence was rarely seen in eyes with CNV (n = 4, 9%) or in fellow eyes (n = 4, 15%). In 11 of 43 (25%) eyes, areas of increased autofluorescence, other than a pattern of focal increased autofluorescence, were detected. In four patients, autofluorescence images had been obtained before the development of CNV; in none was any increased autofluorescence detected before the formation of CNV. Conclusions: Distinct patterns of autofluorescence were observed in eyes with pure classic and occult CNV. Increased autofluorescence was rarely seen in eyes with CNV and in fellow eyes, suggesting that increased autofluorescence, and thus, retinal pigment epithelium lipofuscin, may not play an essential part in the formation of CNV.

Iris cysts in children:Classification, incidence, and management. The 1998 Torrence A Makley Jr Lecture

Background - Iris cysts in children are uncommon and there is relatively little information on their classification, incidence, and management. Methods - The records of all children under age 20 years who were diagnosed with iris cyst were reviewed and the types and incidence of iris cysts of childhood determined. Based on these observations recommendations were made regarding management of iris cysts in children. Results - Of 57 iris cysts in children, 53 were primary and four were secondary. There were 44 primary cysts of the iris pigment epithelium, 34 of which were of the peripheral or iridociliary type, accounting for 59% of all childhood iris cysts. It was most commonly diagnosed in the teenage years, more common in girls (68%), was not recognised in infancy, remained stationary or regressed, and required no treatment. The five mid-zonal pigment epithelial cysts were diagnosed at a mean age of 14 years, were more common in boys (83%), remained stationary, and required no treatment. The pupillary type of pigment epithelial cyst was generally recognised in infancy and, despite involvement of the pupillary aperture, also required no treatment. There were nine cases of primary iris stromal cysts, accounting for 16% of all childhood iris cysts. This cyst was usually diagnosed in infancy, was generally progressive, and required treatment in eight of the nine cases, usually by aspiration and cryotherapy or surgical resection. Among the secondary iris cysts, two were post-traumatic epithelial ingrowth cysts and two were tumour induced cysts, one arising from an intraocular lacrimal gland choristoma and one adjacent to a peripheral iris naevus. Conclusions - Most iris cysts of childhood are primary pigment epithelial cysts and require no treatment. However, the iris stromal cyst, usually recognised in infancy, is generally an aggressive lesion that requires treatment by aspiration or surgical excision.

Primary cysts of the iris pigment epithelium. Clinical features and natural course in 234 patients

Objective: To describe the clinical characteristics, natural course, and complications of a large group of patients with primary iris pigment epithelium (IPE) cysts. Design: Observational case series. Participants: Two hundred thirty-four patients with primary IPE cysts participated. Results: Primary IPE cysts were classified as central in 6 patients (3%), midzonal in 50 patients (21%), peripheral in 170 patients (73%), and dislodged in 8 patients (3%). Central (pupillary) IPE cysts were found only in males, peripheral IPE cysts were found most often in females (69%), and no gender predilection was detected for midzonal and dislodged IPE cysts. Central and peripheral IPE cysts occurred in young patients (mean age, 20 and 33 years, respectively), whereas midzonal and dislodged IPE cysts were seen in slightly older patients (mean age, 52 and 45 years, respectively). Central IPE cysts were visible when the pupil was not dilated and appeared most often as a round or collapsed brown lesion arising from the pupillary margin, most commonly superonasally. Midzonal IPE cysts were brown and fusiform, best visualized after pupillary dilation. Peripheral IPE cysts produced a characteristic bulging in the iris stroma near the iris root, but they were directly visible in only 78% of cases. After wide dilation and patient and slit-lamp positioning, they appeared as a round clear lesion behind the iris, most often in the inferotemporal quadrant. Finally, dislodged IPE cysts appeared as a brown oval lesion, free floating in the anterior chamber (12%) or in the vitreous (12%), or fixed in the anterior chamber angle (75%). One hundred twenty-four patients (53%) were followed for a mean of 35 months (range, 3 months-19 years). In these patients, complications associated with IPE cysts included lens subluxation in one case (1%), iritis in one case (1%), focal cataract in two cases (2%), glaucoma in two cases (2%), and corneal touch in five cases (4%). Conclusion: Primary IPE cysts have characteristic clinical features that serve to differentiate them from intraocular malignancies. Most cysts have a benign clinical course, and treatment is rarely necessary.

External beam radiotherapy in exudative age-related macular degeneration: a pooled analysis of phase I data

In recent years external beam radiotherapy (EBRT) has been proposed as a treatment for the wet form of age-related macular degeneration (AMD) where choroidal neovascularization (CNV) is the hallmark. While the majority of pilot (Phase I) studies have reported encouraging results, a few have found no benefit, i.e. EBRT was not found to result in either improvement or stabilization of visual acuity of the treated eye. The natural history of visual loss in untreated CNV of AMD is highly variable. Loss of vision is influenced mainly by the presenting acuity, and size and composition of the lesion, and to a lesser extent by a variety of other factors. Thus the variable outcome reported by the small Phase I studies of EBRT published to date may simply reflect the variation in baseline factors. We therefore obtained information on 409 patients treated with EBRT from eight independent centres, which included details of visual acuity at baseline and at subsequent follow-up visits. Analysis of the data showed that 22.5% and 14.9% of EBRT-treated eyes developed moderate and severe loss of vision, respectively, during an average follow-up of 13 months. Initial visual acuity, which explained 20.5% of the variation in visual loss, was the most important baseline factor studied. Statistically significant differences in loss of vision were observed between centres, after considering the effects of case mix factors. Comparisons with historical data suggested that while moderate visual loss was similar to that of the natural history of the disease, the likelihood of suffering severe visual loss was halved. However, the benefit in terms of maintained/improved vision in the treated eye was modest.

Genetic screening protocol for familial hypercholesterolemia which includes splicing defects gives an improved mutation detection rate

Familial hypercholesterolemia (FH) is a common single gene disorder, which predisposes to coronary artery disease. In a previous study, we have shown that in patients with definite FH around 20% had no identifiable gene defect after screening the entire exon coding area of the low density lipoprotein receptor (LDLR) and testing for the common Apolipoprotein B (ApoB) R3500Q mutation. In this study, we have extended the screen to additional families and have included the non-coding intron splice regions of the gene. In families with definite FH (tendon xanthoma present, n = 68) the improved genetic screening protocol increased the detection rate of mutations to 87%. This high detection rate greatly enhances the potential value of this test as part of a clinical screening program for FH. In contrast, the use of a limited screen in patients with possible FH (n = 130) resulted in a detection rate of 26%, but this is still of significant benefit in diagnosis of this genetic condition. We have also shown that 14% of LDLR defects are due to splice site mutations and that the most frequent splice mutation in our series (c.1845 + 11 c > g) is expressed at the RNA level. In addition, DNA samples from the patients in whom no LDLR or ApoB gene mutations were found, were sequenced for the NARC-1 gene. No mutations were identified which suggests that the role of NARC-1 in causing FH is minor. In a small proportion of families (

Mutation screening and genotype:phenotype correlation in familial hypercholesterolaemia

The aim of this study was to develop a mutation screening protocol for familial hypercholesterolaemia (FH) patients and to assess genotype/phenotype effects in terms of pre-treatment lipid profiles and presentation of tendon xanthomata (TX). A total of 158 families with clinical definitions of possible (120) or definite (38) FH were studied using a tiered screening protocol. Mutations were identified in 52 families, 44 families showing 23 different LDLR gene defects and eight families showing the common Apo B100 gene defect R3500Q. LDLR defects were detected in various regions of the gene with 56% in the LDL binding domain (exons 2-6) and 37% in the EGF precursor homology domain (exons 7-14). The most common mutations were D461N(7), C210X(5), 932delA(5), and C163Y(4). Frameshift mutations accounted for 20% with nonsense 13%, mis-sense 35%, splice 3%, Apo B 13% and 2% large deletion, 13% of clinically definite FH remained undefined. In conclusion, DNA based diagnosis is possible in 79% (30/38) of clinically definite FH families and of the 120 possible FH families at the start of the screening program, 18% (22/120) now have defined mutations. Overall 60 families from the original 158 meet the clinical and/or genetic criteria for definite FH. Tendon xanthomata were present in only 58% (30/52) of genetically defined FH families, thus limiting its use as a strict diagnostic criteria. Families with low density lipoprotein receptor (LDLR) defects present with higher total and LDL cholesterol levels and a higher incidence of TX than do those with the common Apo B variant, and frameshift mutations appear to have the most severe presentation. Copyright (C) 1999 Elsevier Science Ireland Ltd.

Molecular mapping the presence of druggable targets in preinvasive and precursor breast lesions:a comprehensive review of biomarkers related to therapeutic interventions

The analysis of clinical breast samples using biomarkers is integral to current breast cancer management. Currently, a limited number of targeted therapies are standard of care in breast cancer treatment. However, these targeted therapies are only suitable for a subset of patients and resistance may occur. Strategies to prevent the occurrence of invasive lesions are required to reduce the morbidity and mortality associated with the development of cancer. In theory, application of targeted therapies to pre-invasive lesions will prevent their progression to invasive lesions with full malignant potential. The diagnostic challenge for pathologists is to make interpretative decisions on early detected pre-invasive lesions. Overall, only a small proportion of these pre-invasive lesions will progress to invasive carcinoma and morphological assessment is an imprecise and subjective means to differentiate histologically identical lesions with varying malignant potential. Therefore differential biomarker analysis in pre-invasive lesions may prevent overtreatment with surgery and provide a predictive indicator of response to therapy. There follows a review of established and emerging potential druggable targets in pre-invasive lesions and correlation with lesion morphology.

Temporary tattoos:a novel OSCE assessment tool

Background: There are many issues regarding the use of real patients in objective structured clinical examinations (OSCEs). In dermatology OSCE stations, standardised patients (SPs) with clinical photographs are often used. Temporary transfer tattoos can potentially simulate skin lesions when applied to an SP. This study aims to appraise the use of temporary malignant melanoma tattoos within an OSCE framework. Method: Within an 11-station OSCE, a temporary malignant melanoma tattoo was developed and applied to SPs in a 'skin lesion' OSCE station. A questionnaire captured the opinions of the candidate, SP and examiners, and the degree of perceived realism of each station was determined. Standard post hoc OSCE analysis determined the psychometric reliability of the stations. Results: The response rates were 95.9 per cent of candidates and 100 per cent of the examiners and SPs. The 'skin lesion' station achieved the highest realism score compared with other stations: 89.0 per cent of candidates felt that the skin lesion appeared realistic; only 28 per cent of candidates had ever seen a melanoma before in training. The psychometric performance of the melanoma station was comparable with, and in many instances better than, other OSCE stations. Discussion: Transfer tattoo technology facilitates a realistic dermatology OSCE station encounter. Temporary tattoos, alongside trained SPs, provide an authentic, standardised and reliable experience, allowing the assessment of integrated dermatology clinical skills.

Glycation, glycoxidation, and cross-linking of collagen by glucose. Kinetics, mechanisms, and inhibition of late stages of the Maillard reaction

The Maillard or browning reaction between sugar and protein contributes to the increased chemical modification and cross-linking of long-lived tissue proteins in diabetes. To evaluate the role of glycation and oxidation in these reactions, we have studied the effects of oxidative and antioxidative conditions and various types of inhibitors on the reaction of glucose with rat tail tendon collagen in phosphate buffer at physiological pH and temperature. The chemical modifications of collagen that were measured included fructoselysine, the glycoxidation products N epsilon-(carboxymethyl)lysine and pentosidine and fluorescence. Collagen cross-linking was evaluated by analysis of cyanogen bromide peptides using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by changes in collagen solubilization on treatment with pepsin or sodium dodecylsulfate. Although glycation was unaffected, formation of glycoxidation products and cross-linking of collagen were inhibited by antioxidative conditions. The kinetics of formation of glycoxidation products proceeded with a short lag phase and were independent of the amount of Amadori adduct on the protein, suggesting that autoxidative degradation of glucose was a major contributor to glycoxidation and cross-linking reactions. Chelators, sulfhydryl compounds, antioxidants, and aminoguanidine also inhibited formation of glycoxidation products, generation of fluorescence, and cross-linking of collagen without significant effect on the extent of glycation of the protein. We conclude that autoxidation of glucose or Amadori compounds on protein plays a major role in the formation of glycoxidation products and cross-liking of collagen by glucose in vitro and that chelators, sulfhydryl compounds, antioxidants, and aminoguanidine act as uncouplers of glycation from subsequent glycoxidation and cross-linking reactions.