1‐(2‐Hydroxyethyl)‐2‐imidazolidinone,a heparanase and matrix metalloproteinase inhibitor,improves epidermal basement membrane structure and epidermal barrier function

Daily exposure to sunlight is known to affect the structure and function of the epidermal basement membrane (BM), as well as epidermal differentiation and epidermal barrier function. The aim of this study is to clarify whether the inhibition of BM‐degrading enzymes such as heparanase and matrix metalloproteinase 9 (MMP‐9) can improve the epidermal barrier function of facial skin, which is exposed to the sun on a daily basis. 1‐(2‐hydroxyethyl)‐2‐imidazolidinone (HEI) was synthesized as an inhibitor of both heparanase and MMP‐9. HEI inhibited not only the BM damage at the DEJ but also epidermal proliferation, differentiation, water contents and transepidermal water loss abnormalities resulting from ultraviolet B (UVB). This was determined in this study by the use of UVB‐induced human cultured skins as compared with the control without HEI. Moreover, topical application of HEI improved epidermal barrier function by increasing water content and decreasing transepidermal water loss in daily sun‐exposed facial skin as compared with non‐treated skins. These results suggest that the inhibition of both heparanase and MMP‐9 is an effective way to care for regularly sun‐exposed facial skin by protecting the BM from damage.     

The prevalence of TT virus (TTV) infection and its relationship to hepatitis in children

TT virus (TTV) is a newly discovered virus from a patient with post-transfusion hepatitis. We investigated the frequency and pathogenesis of TTV infection in children. A semi-nested PCR assay was used to amplify TTV-DNA in serum samples from 254 ambulatory children without liver disease, 20 with hepatitis of unknown etiology, and 18 transfusion recipients or hemophiliacs. In positive samples, TTV-DNA was quantified by real-time quantitative PCR using a fluorescent probe. We detected TTV-DNA in 20% of children with hepatitis of unknown etiology, which was not statistically different from the 23% prevalence in ambulatory children. In transfusion recipients or hemophiliacs, the frequency was higher (50%) than that in ambulatory children (P = 0.01). Among ambulatory children, TTV-DNA was frequently detected in children with acute gastroenteritis (36%). TTV-DNA was detected in 10% of the infants under 6 months old, and 20% of the children from 7 to 12  months old. The prevalence was constant after the age of 1 year; however, the copy number of TTV-DNA was significantly higher in children under 1 year of age (mean: 10^5.4 versus 10^3.8 copies/ml, P= 0.008). Finally, TTV-DNA was quantified serially in three children with chronic hepatitis who were positive for TTV-DNA. The presence or amount of TTV-DNA was unrelated to the serum alanine aminotransferase level. These results indicate that TTV infection is common in children. The larger quantity of TTV-DNA in infants and the high prevalence of TTV in children of all ages suggest that TTV may be transmitted in early childhood. Its relationship to hepatitis is doubtful in children. Received: 8 April 1999     

Blood compatibility of surfaces modified by plasma polymerization

Tubular blood-contacting polymeric materials were modified by plasma polymerization and evaluated in the baboon with respect to their capacity to induce both acute and chronic arterial thrombosis. Polymer surface composition was determined by electron spectroscopy for chemical analysis. Steady-state arterial thromboembolism was initiated by introducing tubular segments into chronic arteriovenous shunts. Rates of platelet destruction induced by the test materials were calculated from 111In-platelet survival measurements. Nine plasma polymers based on tetrafluoroethylene, hexafluoroethane, hexafluoroethane/H2, and methane, when deposited on silicone rubber, consumed platelets at rates ranging from 1.1-5.6 x 10(8) platelets/cm2-day. Since these values were near the lower detection limit for this test system, the plasma polymers were considered relatively nonthrombogenic. Acute thrombus formation was initiated by inserting expanded Teflon (Gore-Tex PTFE) vascular grafts into the shunt system. 111In-platelet deposition was measured by scintillation camera imaging over a 1-h exposure period. Standard PTFE grafts (10 cm x 4 mm i.d.) accumulated approximately 1 x 10(10) platelets over this interval. While modification of PTFE grafts with a plasma polymer based on hexafluoroethane/H2 did not alter graft surface morphology, platelet deposition was reduced by 87% as compared to the controls (p less than 0.001). We conclude that both the surface chemistry and texture of prosthetic materials influence thrombogenesis. The method of plasma polymerization may be useful for assessing the importance of these variables independently and, perhaps, for minimizing certain adverse blood-material interactions.     

Reduction in length of stay for patients undergoing oesophageal and gastric resections with implementation of enhanced recovery packages

Introduction

The high mortality and morbidity associated with resection for oesophagogastric malignancy has resulted in a conservative approach to the postoperative management of this patient group. In August 2009 we introduced an enhanced recovery after surgery (ERAS) pathway tailored to patients undergoing resection for oesophagogastric malignancy. We aimed to assess the impact of this change in practice on standard clinical outcomes.

Methods

Two cohorts were studied of patients undergoing resection for oesophagogastric malignancy before (August 2008 – July 2009) and after (August 2009 – July 2010) the implementation of the ERAS pathway. Data were collected on demographics, interventions, length of stay, morbidity and in-hospital mortality.

Results

There were 53 and 55 oesophagogastric resections undertaken respectively for malignant disease in each of the study periods. The median length of stay for both gastric and oesophageal resection decreased from 15 to 11 days (Mann– Whitney U, p<0.001) following implementation of the ERAS pathway. There was no significant increase in morbidity (gastric resection 23.1% vs 5.3% and oesophageal resection 25.9% vs 16.7%) or mortality (gastric resection no deaths and oesophageal resection 1.8% vs 3.6%) associated with the changes. There was a significant decrease in the number of oral contrast studies used following oesophageal resection, with a reduction from 21 (77.8%) in 2008–2009 to 6 (16.7%) in 2009–2010 (chi-squared test, p<0.0001).

Conclusions

The introduction of an enhanced recovery programme following oesophagogastric surgery resulted in a significant decrease in length of median patient stay in hospital without a significant increase in associated morbidity and mortality.     

Hypothermia attenuates apoptosis and protects contact between myelin basic protein‐expressing oligodendroglial‐lineage cells and neurons against hypoxia–Ischemia

Periventricular leukomalacia (PVL) is a major form of brain injury among preterm infants, which is characterized by extensive loss and dysfunction of premyelinating oligodendrocytes (pre‐OLs) induced by hypoxia–ischemia (HI). Therapeutic hypothermia, which is a standard treatment for term infants with HI encephalopathy, is not indicated for preterm infants because its safety and effect have not been established. Here we investigate the effectiveness and mechanism of hypothermia for the inhibition of pre‐OLs damage in PVL. For in vivo studies, 6‐day‐old rats underwent left carotid artery ligation, followed by exposure to 6% oxygen for 1 hr under hypothermic or normothermic conditions. The loss of myelin basic protein (MBP) was inhibited by hypothermia. For in vitro studies, primary pre‐OLs cultures were subjected to oxygen–glucose deprivation (OGD) under normothermic or hypothermic conditions, and dorsal root ganglion neurons were subsequently added. Hypothermia inhibited apoptosis of pre‐OLs, and, despite specific downregulation of 21.5‐ and 17‐kDa MBP mRNA expression during hypothermia, recovery of the expression after OGD was superior compared with normothermia. OGD caused disarrangement of MBP distribution, decreased the levels of phosphorylated 21.5‐kDa MBP, and disturbed the capacity to contact with neurons, all of which were restored by hypothermia. Pharmacological inhibition of ERK1/2 phosphorylation with U0126 during and after OGD significantly reduced the protective effects of hypothermia on apoptosis and myelination, respectively. These data suggest that phosphorylated exon 2‐containing (21.5‐ and possibly 17‐kDa) MBP isoforms may play critical roles in myelination and that hypothermia attenuates apoptosis and preserves the contact between OLs and neurons via ERK1/2 phosphorylation. © 2014 Wiley Periodicals, Inc.     

Heparanase activation induces epidermal hyperplasia,angiogenesis, lymphangiogenesis and wrinkles

Please cite this paper as: Heparanase activation induces epidermal hyperplasia, angiogenesis, lymphangiogenesis and wrinkles. Experimental Dermatology 2010; 19 : 965–972. Abstract: To clarify the difference between cutaneous responses to single and repeated barrier disruption, changes of epidermal gene expression were examined by using RT‐PCR. In repeatedly barrier‐disrupted skin, heparanase was specifically up‐regulated in epidermis. In addition, there was a marked decrease in heparan sulfate (HS) chains of perlecan in basement membrane at the dermal–epidermal junction (DEJ) compared with singly disrupted skin. HS chains form a reservoir for heparan sulfate‐binding growth factors. In repeatedly barrier‐disrupted skin, expression of vascular endothelial growth factor‐A (VEGF‐A), an angiogenic factor, was induced in epidermis, whereas thrombospondin‐1 (TSP‐1), an angiogenesis inhibitor, was down‐regulated, and concomitantly blood vessels were elongated and enlarged in dermis. Expression of VEGF‐C, a lymphangiogenesis factor, was augmented in epidermis of repeatedly barrier‐disrupted skin, concomitantly with an increase in the number and size of lymphatic vessels. Topical application of a synthetic heparanase inhibitor, 1‐[4‐(1H‐benzoimidazol‐2‐yl)phenyl]‐3‐[4‐(1H‐benzoimidazol‐2‐yl)phenyl]urea, to skin after barrier disruption significantly suppressed wrinkle formation, degradation of HS chains in the basement membrane, epidermal hyperplasia and the changes of blood and lymphatic vessels. These results suggest that chronic barrier disruption activates heparanase and induces gene expression changes, leading to increased growth factor interaction between epidermis and dermis, and facilitating various cutaneous changes, including wrinkle formation.     

Evaluation of the safety of xenon/bandpass light in vitrectomy using the A2E-laden RPE model

Background The purpose of the study was to investigate the brightness of the xenon/bandpass light in vitrectomy and assess its phototoxic effects using A2E-laden retinal pigment epithelial (RPE) cells. Methods The total luminous flux and spectral irradiance of 20- and 25-gauge endoilluminators connected to xenon lamps were measured and compared to those of 20- and 25-gauge endoilluminators connected to a halogen lamp. In vitro, A2E-laden cells were evenly exposed to xenon/bandpass light for 5 to 30 min positioned at 1 cm and 2 cm for a standard light probe and an implantable “chandelier” light probe, respectively, above the cells, and the cell viability was assessed using WST-1 assay. The cell viability was compared with cells exposed to 30 min of halogen light projected through a 20-gauge endoilluminator. Results The maximal total luminous flux of xenon/bandpass light emitted through the 20-gauge endoilluminator was 2.8 times higher than that of the halogen light. The total luminous flux of the 25-gauge endoilluminators was 0.6-1.1 times greater than the 20-gauge endoilluminators connected to the halogen light. The viability of the A2E-laden cells after exposure to the xenon/bandpass light was no different than that of the cells exposed to the halogen light when the total luminous flux of these lights was at the same level. Xenon/bandpass light from an implantable “chandelier” light probe induced A2E-mediated RPE damage to a similar extent as that of the halogen light through a 20-gauge endoilluminator. Conclusions A2E-mediated phototoxicity of xenon/bandpass light is comparable to that of halogen light.