Therapeutic follow-up using automatic perimetry in chronic cerebroretinal ischemia in elderly patients. Prospective double-blind study with graduated dose ginkgo biloba treatment (EGb 761)]

The chronic cerebral retinal insufficiency syndrome in elderly patients is an organ specific expression of a generalized vascular cerebral deficiency. The progress of the disease is characterized by complex symptoms, variation in course, spontaneous remissions and, until recently inadequate diagnostic measurement methods. The new method of automated perimetry with the octopus 2000 P offers a patient-friendly procedure for indirect non-invasive diagnosis of circulatory state in limited cerebral retinal perfusion. In the present study measurements were made with this method on 24 patients (4 men and 20 women with an age of 74.9 +/- 6.9 years). The effect of the extract of Ginkgo biloba (EGb 761) on the reversibility of visual field disturbances was tested using a randomized and double blind study-design in two phases and with two dose levels. The main parameter investigated in this study was the change in the luminous density difference threshold after therapy with EGb 761. In group B (EGb 761 dose 160 mg/day) a significant increase in retinal sensitivity was seen within 4 weeks (p less than 0.05). In the lower dose (80 mg EGb 761/day) group (A), this change in retinal sensitivity was first seen after increasing the dose to 160 mg/day (p less than 0.01). The relative sensitivity of damaged retinal areas was more strongly influenced than "healthy" areas. The assessment by both doctors and patients of the general condition of the patients showed a significant improvement after the course of therapy. The results presented here show that damage to the visual field by chronic lack of bloodflow are significantly reversible.(ABSTRACT TRUNCATED AT 250 WORDS)     

RIFLE classification in geriatric patients with acute kidney injury in the intensive care unit

Background

The RIFLE classification is widely used to assess the severity of acute kidney injury (AKI), but its application to geriatric AKI patients complicated by medical problems has not been reported.

Methods

We investigated 256 geriatric patients (≥65 years old; mean age, 74.4 ± 6.3 years) who developed AKI in the intensive care unit (ICU) according to the RIFLE classification. Etiologic, clinical, and prognostic variables were analyzed.

Results

They were categorized into RIFLE-R (n = 53), RIFLE-I (n = 102), and RIFLE-F (n = 101) groups. The overall in-hospital mortality was 39.8 %. There were no significant differences in RIFLE category between survivors and non-survivors. Survivors had significantly less needs for a ventilator and vasopressor, and lower number of failing organs. Survivors had higher systolic blood pressure, hemoglobin level, and serum albumin levels. We performed a logistic regression analysis to identify the independent predictors of in-hospital mortality. In a univariate analysis, hypertension, chronic kidney disease, RIFLE classification, number of failing organs, need for a ventilator and vasopressor, systolic blood pressure, hemoglobin level, and serum albumin levels were identified as prognostic factors of in-hospital mortality. However, in a multivariate analysis, hypertension, chronic kidney disease, number of failing organs, and serum albumin levels were independent risk factors, with no significant difference for in-hospital mortality with the RIFLE classification.

Conclusion

The RIFLE classification might not be associated with mortality in geriatric AKI patients in the ICU. In geriatric patients with AKI, various factors besides severity of AKI should be considered to predict mortality.

     

Effect of short-term culture on functional and stress-related parameters in isolated human islets

The Edmonton protocol for islet transplantation utilizes fresh islet grafts but other protocols increasingly transplant short-term cultured grafts mainly for practical reasons. To improve our understanding of the impact of culture pretreatment of human islets, we assessed post-transplant function by nude mouse bioassay, islet ATP, activity of stress-activated MAP kinases, and expression of stress-related genes by focused cDNA array in freshly isolated and cultured islets. Mean blood glucose levels over 4 weeks after transplantation (2000 IE) of (i) freshly isolated, (ii) cultured and preculture counted (recovery rate; 78 ± 6%), and (iii) cultured and postculture counted islets in diabetic mice were 330 ± 40, 277 ± 65, and 256 ± 52 mg/dl (i versus ii, P  = 0.004; i versus iii, P  = 0.002). During culture, islet ATP/DNA and ATP/ADP increased; JNK and p38 MAPK activities decreased. Among 96 genes studied, mRNA expression of heat shock protein 70 genes decreased >twofold during culture in all four pairs; expression of cyclooxygenase-2, superoxide dismutase-2, interleukin-6 and cytochromes P450 1A1 genes increased. Our results show that culturing human islets before transplantation is not disadvantageous in regard of functional recovery from changes induced by nonphysiologic stimuli during islet isolation. The increase in expression of several stress-related genes during culture also shows that improving culture conditions may further enhance post-transplant islet function.     

Influence of strain and age differences on the yields of porcine islet isolation: extremely high islet yields from SPF CMS miniature pigs

BACKGROUND: Porcine pancreas is a potential source of material for islet xenotransplantation. However, the difficulty in isolating islets, because of their fragility and the variability of isolation outcome in donor age and breed, represents a major obstacle to porcine islet xenotransplantation. In this study, we compared the islet isolation yield of specific pathogen-free (SPF) Chicago Medical School (CMS) miniature pigs with that of another miniature pig breed and market pigs from a local slaughterhouse. METHODS: Nine adult CMS miniature (ACM) pigs (>12 months), six young CMS miniature (YCM) pigs (6-7 months), four adult Prestige World Genetics (PWG) miniature (APM) pigs (>12 months), and 13 adult market (AM) pigs from a local slaughterhouse were used for islet isolation. RESULTS: The islet yield per gram of pancreas from ACM pigs (9589 +/- 2823 IEQ/g) was significantly higher than that from APM pigs (1752 +/- 874 IEQ/g, P < 0.05), AM pigs (1931 +/- 947 IEQ/g, P < 0.05), or YCM pigs (3460 +/- 1985 IEQ/g, P < 0.05). Isolated islets from ACM pigs were significantly larger than those from AM pigs or YCM pigs. The in vitro and in vivo function of isolated islets showed no difference among experimental groups. The pancreases of ACM pigs contained higher mean islet volume density percentages and larger size of islets than those of AM or APM pigs. CONCLUSIONS: We isolated extremely high yields of well-functioning islets from ACM pigs bred under SPF conditions. SPF CMS miniature pigs should be one of the best porcine islet donors for clinical porcine islet xenotransplantation.     

Topological quantum phase transitions driven by external electric fields in Sb₂Te₃ thin films

Using first-principles calculations, we show that topological quantum phase transitions are driven by external electric fields in thin films of Sb(2)Te(3). The film, as the applied electric field normal to its surface increases, is transformed from a normal insulator to a topological insulator or vice versa depending on the film thickness. We identify the band topology by directly calculating the Z(2) invariant from electronic wave functions. The dispersion of edge states is also found to be consistent with the bulk band topology in view of the bulk-boundary correspondence. We present possible applications of the topological phase transition as an on/off switch of the topologically protected edge states in nano-scale devices.     

Association of MCP-1 and CCR2 polymorphisms with the risk of late acute rejection after renal transplantation in Korean patients

Among the factors modulating transplant rejection, chemokines and their respective receptors deserve special attention. Increased expression of monocyte chemoattractant protein-1 (MCP-1) and its corresponding receptor (chemokine receptor-2, CCR2) has been implicated in renal transplant rejection. To determine the impact of the MCP-1-2518G and CCR2-64I genotypes on renal allograft function, 167 Korean patients who underwent transplantation over a 25-year period were evaluated. Genomic DNA was genotyped using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Fifty-five (32.9%) patients were homozygous for the MCP-1-2518G polymorphism. Nine (5.4%) patients were homozygous for the CCR2-64I polymorphism. None of the investigated polymorphism showed a significant shift in long-term allograft survival. However, a significant increase was noted for the risk of late acute rejection in recipients who were homozygous for the MCP-1-2518G polymorphism (OR, 2.600; 95% CI, 1.125-6.012; P = 0.022). There was also an association between the MCP-1-2518G/G genotype and the number of late acute rejection episodes (P = 0.024). Although there was no difference in the incidence of rejection among recipients stratified by the CCR2-V64I genotype, recipients with the CCR2-V64I GG genotype in combination with the MCP-1-2518G/G genotype had a significantly higher risk of acute or late acute rejection among the receptor-ligand combinations (P = 0.006, P = 0.008, respectively). The MCP-1 variant may be a marker for risk of late acute rejection in Korean patients.     

VEGFR-3 Neutralization Inhibits Ovarian Lymphangiogenesis,Follicle Maturation,and Murine Pregnancy

Lymphatic vessels surround follicles within the ovary, but their roles in folliculogenesis and pregnancy, as well as the necessity of lymphangiogenesis in follicle maturation and health, are undefined. We used systemic delivery of mF4-31C1, a specific antagonist vascular endothelial growth factor receptor 3 (VEGFR-3) antibody to block lymphangiogenesis in mice. VEGFR-3 neutralization for 2 weeks before mating blocked ovarian lymphangiogenesis at all stages of follicle maturation, most notably around corpora lutea, without significantly affecting follicular blood angiogenesis. The numbers of oocytes ovulated, fertilized, and implanted in the uterus were normal in these mice; however, pregnancies were unsuccessful because of retarded fetal growth and miscarriage. Fewer patent secondary follicles were isolated from treated ovaries, and isolated blastocysts exhibited reduced cell densities. Embryos from VEGFR-3–neutralized dams developed normally when transferred to untreated surrogates. Conversely, normal embryos transferred into mF4-31C1–treated dams led to the same fetal deficiencies observed with in situ gestation. Although no significant changes were measured in uterine blood or lymphatic vascular densities, VEGFR-3 neutralization reduced serum and ovarian estradiol concentrations during gestation. VEGFR-3–mediated lymphangiogenesis thus appears to modulate the folliculogenic microenvironment and may be necessary for maintenance of hormone levels during pregnancy; both of these are novel roles for the lymphatic vasculature.Ovarian neovascularization provides a unique environment in which to study physiological adult vasculogenesis apart from the traditional settings of wound healing and cancer pathologies. Lymphatic circulation plays a central role in fluid, lipid, and cellular transport,¹ and lymphatic vessels are present within the ovary and surround follicles during development and maturation,^2–5 but the importance of the lymphatic vasculature and lymphangiogenesis in the ovary is unclear. Consequently, the potential roles of lymphatic vessels in follicle maturation and pregnancy, and the extent of involvement or even necessity of maternal lymphangiogenesis in reproduction, are undefined. This contrasts with ovarian blood angiogenesis, whose critical roles in follicular nourishment and maturation and in the formation and maintenance of the corpus luteum are well appreciated; indeed, oocyte fertilization, embryonic implantation, uterine expansion, and successful gestation all require blood angiogenesis.^6–8 Lymphangiogenesis, which is often concurrent with blood angiogenesis,⁹ may also play an important role in these processes.Adult blood angiogenesis requires signaling via vascular endothelial growth factor receptor 2 (VEGFR-2), most potently by VEGF ligation.^10,11 In murine ovaries, VEGF expression increases during angiogenic growth phases,¹² and blockade of VEGFR-2 signaling in mice effectively prevents angiogenesis, resulting in a marked decrease in ovarian weight, blood vessel density, and number of corpora lutea, and in infertility.^13–15 Because gonadotropin treatment apparently does not correct these deficiencies,¹⁶ it is likely that follicle maturation and successful pregnancy are highly dependent on VEGFR-2–mediated neovascularization in the ovary.^6,17 Vascularization also occurs in the uterine wall and decidua during pregnancy, and significant disruption of angiogenesis by VEGFR-2 blockade in these tissues after fertilization has been shown to greatly reduce pregnancy success.¹⁸VEGFR-3 is expressed primarily on lymphatic endothelial cells in adult tissue,^19,20 and its signaling, via ligation by VEGF-C or VEGF-D, is necessary for lymphangiogenesis by inducing lymphatic endothelial cell proliferation and migration.^19–23 Blockade of VEGFR-3 signaling using a function-blocking antibody such as mF4-31C1 (ImClone Systems; Eli Lilly, Indianapolis, IN) completely blocks the initiation of new lymphatic vessels in adult mice without affecting pre-existing lymphatic morphology or function and without apparently affecting blood angiogenesis.^18,21,22 The ovary contains a dense lymphatic network that has been morphologically assessed in large rodents.^24–26 Recent studies in which murine ovarian lymphatic vessel expansion was impaired during development found the dams to be infertile as adults.³We investigated VEGFR-3–mediated lymphangiogenesis and the roles of new lymphatic vessels and lymphangiogenesis in female reproduction and found that lymphangiogenesis occurs within the murine ovary during reproductive cycles and folliculogenesis and that VEGFR-3 neutralization prevents viable, full-term pregnancies. Using combined in vivo, ex vivo, and in vitro methods, we examined which aspects of female fertility are influenced by inhibited maternal lymphangiogenesis including oocyte and follicular development and maturation, uterine implantation, and embryonic development. After we had eliminated direct effects on fetal and uterine VEGFR-3–mediated neovascularization, our results suggested that the new ovarian lymphatic vessels specifically modulate follicle development and hormone production, demonstrating a critical and novel role for ovarian lymphangiogenesis in reproduction.     

Microsatellite alterations in hepatocellular carcinoma and intrahepatic cholangiocarcinoma

A series of 20 hepatocellular carcinomas and 8 intrahepatic cholangiocarcinomas was screened from the Korean population for microsatellite alterations, including a loss of heterozygosity and replication errors using nine microsatellite markers containing several genes. The microsatellite results and our previous comparative genomic hybridization results of two tumors were compared at each locus, and the correlations between these and clinicopathologic variables were examined. The most characteristic findings were found at 13q. Replication errors were prevalent at D13S160 (13q21.2 approximately q31) and D13S292(13q12). The incidence of loss of heterozygosity, however, was higher at D13S153 (13q14.1 approximately q14.3) and D13S265(13q31 approximately q32). In contrast, there were higher deletion frequencies observed in hepatocellular carcinoma (HCC) and higher amplification frequencies observed in intrahepatic cholangiocarcinoma at 13q in our previous comparative genomic hybridization (CGH) study. Higher frequencies of replication errors were observed at D16S408 (13q12 approximately q21) and D16S504(13q23 approximately q24) in the HCC. This study found that significant differences in the patterns of genetic instability of microsatellites were dependent on the chromosomal loci. It is believed that certain genes at altered CGH regions, which are relevant to the development and/or progression of these cancers, are activated by different mutation mechanisms.