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Biomedical subjects

L L Hansen

Publications and source records attributed to L L Hansen.

At least 19 recordsLinked to original sources
PubMed2007

Treatment of central retinal vein occlusion by radial optic neurotomy in 107 cases.

BACKGROUND: To evaluate the potential role of radial optic neurotomy (RON), a new surgical technique has been recently proposed for treating central retinal vein occlusion (CRVO). It is hypothesized that CRVO constitutes a neurovascular compartment syndrome at the site of the lamina cribrosa, which can be alleviated by performing a radial incision at the nasal part of the optic nerve head, relaxing the cribriform plate and the adjacent sclera. METHODS: One hundred and seven patients were treated with RON for CRVO at five collaborating ophthalmologic centers. All patients were evaluated by a standardized protocol. For analysis of the angiographic and fundus findings, reference images were used. Intraoperative and postoperative complications were reviewed. RESULTS: On 55 right and 52 left eyes of 107 patients (55.6% male, 44.4% female) with a median age of 68 years (range 21-91 years), RON was performed. The median follow-up time was 6 months (range 1-24 months). The median preoperative visual acuity (VA) was 0.05 (logMAR 1.3), increasing to a median postoperative VA of 0.08 (logMAR 1.1). Patients with an interval of more than 90 days between RON and onset of CRVO showed no significant change in VA at the 6-month follow-up. Severe peripapillary swelling of the optic nerve head prior to RON resulted in an average increase of 4.2 lines in VA at the 6-month follow-up. Angiographic findings of shunt vessels were seen in 18/30 cases after 12 months and were accompanied by an average improvement of VA of six lines. Visual field tests showed various defects in 86.8% of all cases. In one patient an iatrogenic injury of the central retinal artery occurred (0.9%). CONCLUSION: Despite the potential risk of visual field defects, RON seems to be a quite safe procedure. The majority of patients showed rapid normalization of the morphologic fundus findings, with an improvement in VA uncommon for the natural history of CRVO. No significant change in VA was seen in patients with an interval of more than 90 days between the onset of CRVO and RON. A prospective study is warranted for further investigation.

Adult↗
PubMed2006

Carboxymethylcellulose as a new carrier substance for intravitreal injection of reproducible amounts of triamcinolone.

BACKGROUND: Intravitreal application of triamcinolone acetonide has become increasingly popular for the treatment of various retinal disorders. However, dosage, mode of preparation and application differ worldwide. The aim of this study was to find a safe vehicle that would allow intravitreal injection of an exact amount of triamcinolone acetonide without potentially retinotoxic preservatives. METHODS: Solutions of triamcinolone acetonide with a theoretical concentration of 4 mg/0.2 ml were prepared following one sedimentation (A) and two filtration (B, C) methods. In addition, a filtration method using carboxymethylcellulose 2% as a carrier (D) was established. During processing and after injection into an eye model, the crystals were quantified by weight and high-performance liquid chromatography (HPLC), and, hence, the rate of crystal loss during this process was determined. RESULTS: The initial preparation contained 93-106% of the calculated quantity. Method A, containing the entire vehicle, delivered 45%+/-7.3% of the target quantity to the eye model, whereas the vehicle-free methods B and C delivered 15%+/-6.9% and 11%+/-3.2%, respectively. Using carboxymethylcellulose 2% as a preservative-free vehicle, we found 93%+/-3.7% of the calculated amount in the eye model. The missing crystals were mainly sticking to the walls of the syringes and needles used for transfer. CONCLUSION: Common methods for preparing triamcinolone acetonide vary in the amount of drug actually injected intravitreally. Carboxymethylcellulose is an ideal carrier substance for intravitreal application of an exact dose of triamcinolone acetonide without preservatives.

Carboxymethylcellulose Sodium↗
PubMed2003

[Angioproliferative retinal disease caused by ischemia].

Ischemia is a major stimulus for angiogenesis, a biological response mechanism that describes the formation of new blood vessels from existing vessels. An ischemic cell communicates with endothelial cells by soluble factors such as VEGF (vascular endothelial growth factor) and its receptors. A major transcriptional factor for VEGF is HIF-1 (hypoxia inducible factor). Proliferation of endothelial cells alone does not result in stable vascular tubes, this is only achieved by recruiting additional cells such as pericytes. The stabilisation and destabilisation of vessels, which are important prerequisites for vascular growth, are in a dynamic equilibrium which can be modified by additional growth factors such as angiopoietins. In this review we discuss some of the molecular mechanisms leading from ischemia to proliferative retinopathy with a special focus on retinopathy of prematurity and the closely related mouse model of hyperoxia-induced retinopathy. This model is very useful when developing new antiangiogenic therapies based on the increasing understanding of the molecular pathogenesis of ischemic proliferative retinopathy.

Animals↗
PubMed2003

[Retinal vein occlusions].

There are still gaps in understanding the etiology and pathogenesis of circulatory disorders of the central retinal vein. Although various new therapeutic approaches have been developed in the past few years, existing therapy forms are subject to controversy and available data are to some extent inconsistent. This discussion in the German-language literature is associated with varied and nonuniform terminology, which should do justice in particular to concepts of pathomechanism and degree of specificity. The general designation, "occlusion" seems to be the most suitable of all available terms since this implies no conclusions on possible etiological factors. Retinal vein occlusions develop at different sites and to varying extents. Depending on t he location of the occlusion, they can be classified into occlusions of the central vein, hemicentral vein, major branch vein, and macular branch vein. This overview provides information on the current knowledge of the pathogenesis and both established approaches and those in ongoing clinical trials for the treatment of central venous and branch vein occlusions.

Diagnosis, Differential↗
PubMed2003

Early growth restriction leads to down regulation of protein kinase C zeta and insulin resistance in skeletal muscle.

Epidemiological studies have revealed a relationship between early growth restriction and the subsequent development of type 2 diabetes. A rat model of maternal protein restriction has been used to investigate the mechanistic basis of this relationship. This model causes insulin resistance and diabetes in adult male offspring. The aim of the present study was to determine the effect of early growth restriction on muscle insulin action in late adult life. Rats were fed either a 20% or an isocaloric 8% protein diet during pregnancy and lactation. Offspring were weaned onto a 20% protein diet and studied at 15 Months of age. Soleus muscle from growth restricted offspring (LP) (of dams fed 8% protein diet) had similar basal glucose uptakes compared with the control group (mothers fed 20% protein diet). Insulin stimulated glucose uptake into control muscle but had no effect on LP muscle. This impaired insulin action was not related to changes in expression of either the insulin receptor or glucose transporter 4 (GLUT 4). However, LP muscle expressed significantly less (P<0.001) of the zeta isoform of protein kinase C (PKC zeta) compared with controls. This PKC isoform has been shown to be positively involved in GLUT 4-mediated glucose transport. Expression levels of other isoforms (betaI, betaII, epsilon, theta) of PKC were similar in both groups. These results suggest that maternal protein restriction leads to muscle insulin resistance. Reduced expression of PKC zeta may contribute to the mechanistic basis of this resistance.

Animals↗
PubMed2001

Fluvoxamine inhibits the CYP2C9 catalyzed biotransformation of tolbutamide.

OBJECTIVE: Our objective was to examine the interaction between fluvoxamine and tolbutamide to confirm that fluvoxamine inhibits CYP2C9. METHODS: The study was carried out as an open, randomized, crossover design with 14 healthy participants. In period A, all volunteers took 500 mg of tolbutamide orally. In period B, the volunteers were randomly assigned to one of two groups. Each group took either 150 mg or 75 mg of fluvoxamine a day for 5 days (day -3 to day 2). The groups then took 500 mg of tolbutamide as a single dose (day 0). In both periods, blood and urine were sampled at regular intervals. Plasma was analyzed for tolbutamide, and urine was analyzed for tolbutamide and its two metabolites, 4-hydroxytolbutamide and carboxytolbutamide by means of HPLC. RESULTS: During treatment with fluvoxamine, there was a statistically significant decrease in the median of the total clearance of tolbutamide, from 845 mL/h to 688 mL/h, among the volunteers who received 75 mg/d. There was a reduction that reached borderline statistical significance in the group that received 150 mg/d of tolbutamide. The clearance by means of 4-hydroxytolbutamide and carboxytolbutamide was significantly reduced in both groups (ie, from 901 mL/h to 318 mL/h in the group that received 150 mg of tolbutamide per day and from 723 mL/h to 457 mL/h in the group that received 75 mg of tolbutamide per day). Thus there was a tendency toward a more pronounced inhibition of the 4-hydroxylation during treatment with 150 mg/d of fluvoxamine compared with 75 mg/d, but the difference was not statistically significant. CONCLUSION: Fluvoxamine is a moderate inhibitor of CYP2C9 in vivo.

Adult↗
PubMed2001

Cellular mechanism of nutritionally induced insulin resistance in Psammomys obesus: overexpression of protein kinase Cepsilon in skeletal muscle precedes the onset of hyperinsulinemia and hyperglycemia.

The sand rat (Psammomys obesus) is an animal model of nutritionally induced diabetes. We report here that several protein kinase C (PKC) isoforms (alpha, epsilon, and zeta, representing all three subclasses of PKC) are overexpressed in the skeletal muscle of diabetic animals of this species. This is most prominent for the epsilon isotype of PKC. Interestingly, increased expression of PKCepsilon could already be detected in normoinsulinemic, normoglycemic (prediabetic) animals of the diabetes-prone (DP) line when compared with a diabetes-resistant (DR) line. In addition, plasma membrane (PM)-associated fractions of PKCalpha and PKCepsilon were significantly increased in skeletal muscle of diabetic animals, suggesting chronic activation of these PKC isotypes in the diabetic state. The increased PM association of these PKC isotypes revealed a significant correlation with the diacylglycerol content in the muscle samples. Altered expression/activity of PKCepsilon, in particular, may thus contribute to the development of diabetes in these animals; along with other PKC isotypes, it may be involved in the progression of the disease. This may possibly occur through inhibition of insulin receptor (IR) tyrosine kinase activity mediated by serine/threonine phosphorylation of the IR or insulin receptor substrate 1 (IRS-1). However, overexpression of PKCepsilon also mediated down-regulation of IR numbers in a cell culture model (HEK293), resulting in attenuation of insulin downstream signaling (reduced protein kinase B [PKB]/Akt activity). In accordance with this, we detected decreased 125I-labeled insulin binding, probably reflecting a downregulation of IR numbers, in skeletal muscle of Psammomys animals from the DP line. The number of IRs was inversely correlated to both the expression and PM-associated levels of PKCepsilon. These data suggest that overexpression of PKCepsilon may be causally related to the development of insulin resistance in these animals, possibly by increasing the degradation of IRs.

Animal Nutritional Physiological Phenomena↗
PubMed2000

Influence of temperature and storage time after light exposure on the quinine monohydrochloride chemical actinometric system.

The ICH guideline on photostability has proposed quinine monohydrochloride chemical actinometric system as a standard method for measuring light exposure during photostability testing. A change in the absorption at 400 nm of quinine monohydrochloride after light exposure corresponds to a defined dose of light. The present work investigated the effect of temperature, light exposure level and the dark reactions following light exposure on the change of absorbance obtained. The change in the absorbance was linear with respect to time, the rate increased threefold in the temperature range of 25-52 degrees C, and the calculated activation energy was 30 kJ/mol as calculated by the Arrhenius equation. For the dark reactions the change in absorbance was non-linear with respect to time. The rate of the dark reactions was smaller than during light exposure and dependent on the light exposure level prior to the dark reactions. The calculated activation energy of the dark reactions was 18 kJ/mol when calculated by the Arrhenius equation on the initial reaction rates. The different activation energy of the light reaction and the dark reactions indicated different degradation patterns of the two reactions. The present study shows that the absorbance change of quinine monohydrochloride chemical actinometric system is dependent on temperature during light exposure and on storage time and storage temperature after light exposure. The method proposed in the ICH guideline should therefore be optimized in terms of definition of temperature and limitations in storage time after light exposure.

Calorimetry↗
PubMed2000

[Amiodarone-associated optic neuropathy: an independent syndrome? Three patients with bilateral optic neuropathy].

BACKGROUND: Optic neuropathy has been reported to occur during antiarrhythmic therapy with amiodarone. Whether or not there is a causal relationship has been discussed controversely. PATIENTS: Three patients presented with a visual impairment three to seven months after starting amiodarone therapy. In all three patients both optic discs were swollen and showed hemorrhages on the margin. After discontinuing amiodarone, the vision improved and the swelling of the optic discs resolved. CONCLUSION: The bilateral occurrence at the same time, the close time correlation with the amiodarone application and the improvement after discontinuing amiodarone suggest that our three patients suffered from a toxic effect of amiodarone rather than an incidental other disease, as for instance ischemic optic neuropathy.

Aged↗
PubMed2000

TP53 mutation is an independent prognostic marker for poor outcome in both node-negative and node-positive breast cancer.

TP53 gene-mutation and protein expression of p53 are described as being of prognostic importance for the outcome of breast cancer. The present study was therefore carried out to evaluate whether TP53 mutation would be a feasible prognostic marker in the routine diagnostic evaluation of breast cancer, and, in particular, to analyse the relationship between TP53 mutation and nodal status. Tumour material was obtained from women with sporadic early breast cancer. Gene mutations in exon 2-11 were identified using denaturing gradient gel electrophoresis (DGGE) as the initial scanning procedure and characterized by sequencing. All patients were treated according to the guidelines of the Danish Breast Cancer Cooperative Group for the DBCG 89 protocols. The results were correlated with clinico-pathological parameters and the prognosis evaluated by uni- and multivariate analysis using local control, freedom from distant metastasis, disease-free survival, and overall survival as endpoints. The study included 294 patients. TP53 mutations were found in 23% of cases. Mutations were significantly more frequent in tumours from patients who were node-positive and with tumours characterized as being ductal, large of size, with a high degree of anaplasia, and oestrogen receptor negative. Using univariate analysis, it was found that distant metastasis, disease-free, and overall survival were correlated to tumour size, nodal status, degree of anaplasia, oestrogen receptor status, and TP53 mutation. In addition, overall survival was also correlated to age and menopausal status. When analysed according to nodal status, TP53 mutation was found to have a significantly poor survival probability in each of the subgroups. A Cox proportional hazard analysis, including all 294 patients, demonstrated that positive nodal status and TP53 mutation were the only parameters that had an independent poor influence on the risk of developing distant metastasis and reduced recurrence-free survival. The same factors together with postmenopausal status were found to be significantly associated with increased risk of death. TP53 mutation is a strong marker for the prediction of overall and disease-free survival in breast cancer, irrespective of nodal status. A better understanding of the role of the p53 pathway, including analysis of different types of TP53 mutations, is required in order further to investigate the prognostic potential of this marker.

Adult↗
PubMed2000

Heterogeneity in the clinical phenotype of TP53 mutations in breast cancer patients.

TP53 mutation is a strong independent marker for survival in breast cancer with some heterogeneity in the clinical phenotype of various types of mutations. Based on 315 patients with breast carcinoma, we suggest a new model for the differentiation of TP53 mutations. Although TP53 mutation in general was associated with aggressive tumor/patient characteristics, missense mutations outside any conserved or structural domain did not affect the clinical outcome (risk of disseminated disease and death). In contrast, patients with missense mutations affecting amino acids directly involved in DNA or zinc binding displayed a very aggressive clinical phenotype. Null mutations (including missense mutations disrupting the tetramerization domain) and the remaining missense mutations displayed an intermediate aggressive clinical phenotype. When patients with primary early breast cancer were divided into three groups (wild-type together with missense mutations outside structural/conserved domains, null mutations and missense mutations with intermediate clinical phenotype, and very aggressive missense mutations), disease-specific survival rates were 89%, 58%, and 35% (5-year actuarial values, P < 0.0001), respectively. In a Cox proportional hazards analysis, separation of TP53 mutations according to these criteria eliminated the prognostic importance of all investigated classical factors except nodal status.

Alleles↗