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L Hesse

Publications and source records attributed to L Hesse.

At least 37 records · Page 2Linked to original sources
PubMed1998

Copper-binding amyloid precursor protein undergoes a site-specific fragmentation in the reduction of hydrogen peroxide.

The extracellular domain of transmembrane Abeta amyloid precursor protein (APP) has a Cu(II) reducing activity upon Cu(II) binding associated with the formation of a new disulfide bridge. The complete assignment of the disulfide bond revealed the involvement of cysteines 144 and 158 around copper-binding histidine residues. The vulnerability of APP-Cu(I) complexes to reactive oxygen species was elaborated as a site-specific and random fragmentation of APP in a time-dependent manner and at low concentrations of H2O2. Analysis of the specific reaction revealed the generation of C-terminal polypeptides, containing the Abeta domain. APP catalyzed the reduction of H2O2 and oxidation of Cu(I) to Cu(II) in a "peroxidative" reaction in vitro. The resulting bound copper-hydroxyl radical intermediate [APP-Cu(II)(.OH)] then likely participated in a Fenton type of reaction with radical formation as a prerequisite for protein degradation. Evidence from two observations suggests that the reaction takes place in two phases. Bathocuproine, a trapping agent for Cu(I), abolished the initial fragmentation, and chelation of Cu(II) by DTPA (diethylenetriaminepentaacetic acid) interrupted the reaction cascade induced by H2O2 at later stages. Consequently, the results suggest that a cytotoxic gain-of-function of APP-Cu(I) complexes might result in a perturbation of free radical homeostasis. What significance such a perturbation may have for the pathogenesis of Alzheimer's disease remains to be determined.

Amino Acid Sequence↗
PubMed1998

Inhibition of platelet activation by the Alzheimer's disease amyloid precursor protein.

The amyloid precursor protein (APP) of Alzheimer's disease is abundantly expressed in the platelet alpha-granule where its role remains unclear. This study describes a novel function for APP in regulating human platelet activation. Preincubation of platelet-rich plasma with recombinant secreted APP (sAPP) isoforms dose-dependently inhibited platelet aggregation and secretion induced by ADP or adrenaline. Similarly, sAPP potently inhibited low-dose thrombin-induced activation in washed platelet suspensions, indicating that the activity does not require plasma cofactors. There were no functional differences between sAPP forms with or without the Kunitz protease inhibitor domain or derived from either alpha- or beta-secretase cleavage. In fact, the N-terminal cysteine-rich region of APP (residues 18-194) was as effective as the entire sAPP region in the inhibition of platelet activation. The inhibitory activity of sAPP correlated with a significant reduction in the agonist-induced production of the arachidonic acid (AA) metabolites thromboxane B2 and prostaglandin E2. However, sAPP did not affect AA-induced platelet aggregation or secretion, indicating the enzymatic conversion of AA was not inhibited. The addition of a threshold dose of AA reversed the sAPP-inhibition of agonist-induced platelet activation. This suggests that sAPP decreases the availability of free AA, although the mechanism is not yet known. These data provide evidence that the release of sAPP upon platelet degranulation may result in negative feedback regulation during platelet activation.

Adenosine Diphosphate↗
PubMed1997

Human amyloid precursor-like protein 1--cDNA cloning, ectopic expression in COS-7 cells and identification of soluble forms in the cerebrospinal fluid.

Amyloid precursor-like protein 1 (APLP1) represents an integral membrane type 1 protein of unknown function which was originally cloned from a mouse cDNA library on the basis of sequence similarity with the Alzheimer's amyloid precursor protein (APP). Here we report on the molecular cloning and expression of the human APLP1 (hAPLP1). hAPLP1 consists of 650 amino acids, displays 89% identity on the amino acid level to its mouse homologue and has a calculated molecular mass of 72 kDa. hAPLP1 synthesized in a cell-free system displays an apparent molecular mass of approximately 80 kDa in SDS-containing gels and becomes N-glycosylated when the in vitro translation is performed in the presence of microsomes. The hAPLP1 cDNA was also expressed ectopically in COS-7 cells and the protein expression was analyzed by immunoprecipitation and western blotting. We have demonstrated that hAPLP1 represents a novel glycoprotein which carries both N- and O-linked glycans. Moreover, hAPLP1 undergoes limited proteolysis which results in the secretion of the carboxy-terminal truncated molecule into the cells conditioned medium. Examination of cells transfected with hAPLP1 cDNA by confocal laser microscopy reveals an intense perinuclear and Golgi staining, a pattern resembling the subcellular distribution of APP. Using a novel hAPLP1-specific antiserum, we identified soluble hAPLP1 in the human cerebrospinal fluid, which suggests that secretion of hAPLP1 from brain cells also takes place in vivo.

Amino Acid Sequence↗
PubMed1997

Reactive oxygen species and Alzheimer's disease.

Although a consensus that Alzheimer's disease (AD) is a single disease has not been reached yet, the involvement of the amyloid precursor protein (APP) and betaA4 (A beta) in the pathologic changes advances our understanding of the underlying molecular alterations. Increasing evidence implicates oxidative stress in the neurodegenerative process of AD. This hypothesis is based on the toxicity of betaA4 in cell cultures, and the findings that aggregation of betaA4 can be induced by metal-catalyzed oxidation and that free oxygen radicals may be involved in APP metabolism. Another neurological disorder, familial amyotrophic lateral sclerosis (FALS), supports our view that AD and FALS may be linked through a common mechanism. In FALS, SOD-Cu(I) complexes are affected by hydrogen peroxide and free radicals are produced. In AD, the reduction of Cu(II) to Cu(I) by APP involves an electron-transfer reaction and could also lead to a production of hydroxyl radicals. Thus, copper-mediated toxicity of APP-Cu(II)/(I) complexes may contribute to neurodegeneration in AD.

Aging↗
PubMed1997

[Retinal detachment in Ehlers-Danlos syndrome. Treatment by pars plana vitrectomy].

UNLABELLED: Ehlers-Danlos syndrome (EDS) is an hereditary connective tissue disorder caused by defective collagen synthesis, the main features being hyperelasticity and vulnerability of the skin, recurrent bleeding from fragile blood vessels, and secondary deformities of the joints. Ocular involvement is a rare occurrence, e.g., corneal and scleral rupture from minor blunt injury, lens displacement, rhegmatogenous retinal detachment. To date, few reports exist concerning the treatment of retinal detachment in Ehlers-Danlos syndrome, all of them dealing exclusively with conventional scleral buckling surgery. PATIENT AND METHODS: We report on a 47-year-old male patient suffering from EDS type VI (so-called ocular type, lysine-hydroxylase deficiency). He presented with rhegmatogenous retinal detachment in his only eye. A scleral buckling procedure was not feasible because of marked scleral atrophy. A three-port vitrectomy was therefore carried out. RESULTS: During the operation, pronounced choroidal detachment and bleeding developed, subsiding within weeks postoperatively. Closure of the sclerotomies was difficult due to scleral thinning. Two revitrectomies were necessary because anterior PVR with traction retinal detachment occurred. The last revitrectomy was performed 18 months ago, and the retina has been completely reattached under 5000 cs silicone oil since then. Visual acuity is 0.1. CONCLUSION: Primary vitrectomy permits successful treatment of retinal detachment in EDS patients if a buckling procedure cannot be performed because of scleral atrophy. However, serious complications may occur. Surgical procedures other than primary vitrectomy should therefore always be carefully considered, e.g., pneumatic retinopexy, temporary balloon, dura patch with episcleral pocket.

Ehlers-Danlos Syndrome↗
PubMed1997

[Reduction of cataract by plasma etching of intraocular lenses. An animal experiment study].

BACKGROUND: We studied if a modification of the silicon intraocular lens (IOL) by plasma etching is able to promote a bonding of the IOL surface and the capsular bag which might inhibit proliferation and migration of lens epithelial cells. METHODS: Silicon-disc lenses (90D, Adatomed), as disposable for regular cataract surgery, were used. Their haptic surface was etched via the use of a SO2 plasma, leaving the optic unmodified. The experiments were done on dwarf rabbits to allow for tight apposition of IOL and bag. Nine rabbits underwent extracapsular lensectomy using propofol anaesthesia and phaco/clear cornea surgical technique. Six eyes each received either no, a regular or a modified IOL. After 11 weeks the eyes were enucleated. Capsular bag and IOL were digitized using a flatbed scanner with transparency adapter. The data obtained were calibrated against a densitometric standard. The densities of the various specimen were analyzed quantitatively using self designed software. RESULTS: In aphacic eyes no significant posterior capsule opacification (PCO) was detectable. In the same time-span the regular IOL had developed a dense, heterogenous PCO. The plasma-treated IOL showed, especially in the central areas, a significant reduction of PCO as compared to untreated IOL. CONCLUSION: The reduction of PCO could not be explained by adhesion of the IOL surface and the capsular bag, which would impair migration of lens epithelial cells and thereby PCO. Likewise, lower PCO may be related to improved hydrophilic properties of the surface-modified IOL.

Animals↗
PubMed1997

Blood transfusion. Iron load and retinopathy of prematurity.

UNLABELLED: To study the relationship between blood transfusion, iron load and retinopathy of prematurity (ROP), we performed a prospective observational cohort study in a level III neonatal intensive care unit. During a 24-month period, data on the volume of blood transfused during the first 6 weeks of life and on the incidence of ROP were collected in all surviving very low birth weight infants (n = 114; median birth weight 1130 g. range 520-1500 g). Associations between these data and values for serum iron, transferrin and ferritin measured at weekly intervals were analysed in a nested case-control design by logistic regression. There was a significant association between the volume of blood transfused and the incidence of ROP. After adjustment for gestational age at birth, duration of oxygen therapy (FiO2 > 0.3) and duration of mechanical ventilation, the relative risk of developing ROP was 6.4 (95% CI 1.2-33.4) for infants who had received 16-45 ml/kg, and 12.3 (1.6-92.5) for those who had received more than 45 ml/kg of blood (reference, 0-15 ml/kg). In contrast, there was no independent relationship between ROP and any of the parameters on iron metabolism analysed. CONCLUSION: This study confirms the role of blood transfusions as an independent risk factor for ROP. This relationship, however, does not appear to be mediated via an increased iron load.

Case-Control Studies↗
PubMed1997

[Acute glaucoma caused by massive subretinal hemorrhage in age-related macular degeneration and disordered thrombocyte function].

BACKGROUND: Hemorrhages from subretinal neovascularizations in age-related macular degeneration are not uncommon, but usually limited to the posterior pole. A therapy-resistant angle closure glaucoma following displacement of the lens-iris diaphragm due to massive choroidal and subretinal hemorrhages has rarely been reported. CASE REPORT: A 72-year-old female patient was first seen in September 1993 because of decreased vision in the right eye. An age related macular degeneration with an extended untreatable neovascularisation membrane was diagnosed. One year later sudden pain attacks were initiated by secondary angle closure glaucoma, caused by a massive choroidal and subretinal bleeding. At first the IOP could be regulated by drug therapy, however, recurring hemorrhages led to continuously elevated IOP. The reason for the recurrent massive hemorrhages was found to be a disorder of the platelet function. Since the IOP (50-80 mm Hg) could not be controlled any further, we decided to perform a sclerotomy in an attempt to drain the blood. Within one day another bleeding occurred and again led to an increase in IOP. Finally, the patient agreed to have the eye enucleated. CONCLUSION: In case of massive hemorrhages in age related macular degeneration a haematological systemic disorder must be included in the diagnostic considerations. If the intraocular pressure can not be lowered neither medically nor surgically, enucleation can not be avoided.

Acetaminophen↗
PubMed1997

Silicone oil for recurrent vitreous hemorrhage in previously vitrectomized diabetic eyes.

AIMS: To investigate the clinical course of vitrectomized patients with recurrent diabetic vitreous hemorrhage who were treated by revitrectomy with silicone oil (SO) as a hemostyptic tamponade. PATIENTS AND METHODS: Fifteen patients with recurrent vitreous hemorrhage due to proliferative diabetic vitreoretinopathy were included in this retrospective study. All eyes had had at least one vitrectomy prior to use of SO and the retina was completely attached at any time before revitrectomy with SO instillation. Thirteen patients had a blind fellow eye. There were 6 males and 9 females (mean age 62.7 years, range 45-76 years). The mean duration of SO tamponade was 25.8 months (range 9-35 months). The average follow-up period was 30.4 months (range 20-48 months). RESULTS: Ten out of 15 eyes (66.6%) improved postoperatively, 9 eyes had a visual acuity of > or = 0.02 at the latest follow-up visit. Secondary glaucoma occurred in 4 eyes, leading to phthisis in 1 eye. All 5 phakic eyes developed a cataract. CONCLUSION: A revitrectomy combined with a long-term hemostyptic SO tamponade offers a chance for restoration of useful visual acuity in diabetic eyes with persistent vitreous-hemorrhage that fails to subside after cryocoagulation and vitrectomy without tamponade. Because of possible visual loss from secondary glaucoma related to intraocular SO this treatment should mainly be considered in patients with a blind fellow eye.

Aged↗
PubMed1997

Histopathological and immunohistochemical findings associated with a null mutation in the Norrie disease gene.

PURPOSE: To determine the clinical, histopathological, and immunohistochemical ocular changes associated with a null mutation in the Norrie disease protein (NDP) gene. METHODS: Tissue from a six-month-old boy with bilateral retrolental membranes and retinal detachment was obtained during vitreoretinal surgery. Histological sections were stained immunohistochemically with specific antibodies. No eye diseases with severe visual impairment or blindness were reported in the parents and their families. The NDP gene was analyzed by standard molecular genetic methods. RESULTS: A severe reduction in the number of retinal ganglion cells and a largely disarranged and hypoplastic inner nuclear layer were visible in the tissue specimen. Areas of the tissue with advanced pathology displayed massive fibrovascular proliferation in the vitreous cavity. Shrinkage and traction resulted in folding and detachment of the outer retina. Immunohistochemical reactivity for MIB(1) antigen demonstrated many proliferating cells in the vitreous, but no proliferative activity in the neuroretina. Retinal neurons showed a high grade of differentiation and expressed uniformly neuron-specific enolase and synaptophysin. A 1-base pair insertion (544/545insA) in the NDP gene was found in the affected boy. This mutation predicts a 'functional null-allele' due to a shift in the reading frame and, thus, a premature termination of mRNA translation after 55 instead of 133 amino acids. CONCLUSIONS: Loss of function of the NDP gene causes marked hypoplasia of the inner retinal cell layers and fibrovascular proliferation in the vitreous cavity, leading to retinal folding and detachment. The NDP therefore seems to play a critical role in terminal differentiation of the inner retinal cell layers and establishment and maintaining of anti-proliferative cellular interactions in the vitreous.

Antigens, CD↗
PubMed1996

The amyloid precursor protein of Alzheimer's disease in the reduction of copper(II) to copper(I)

The transition metal ion copper(II) has a critical role in chronic neurologic diseases. The amyloid precursor protein (APP) of Alzheimer's disease or a synthetic peptide representing its copper-binding site reduced bound copper(II) to copper(I). This copper ion-mediated redox reaction led to disulfide bond formation in APP, which indicated that free sulfhydryl groups of APP were involved. Neither superoxide nor hydrogen peroxide had an effect on the kinetics of copper(II) reduction. The reduction of copper(II) to copper(I) by APP involves an electron-transfer reaction and could enhance the production of hydroxyl radicals, which could then attack nearby sites. Thus, copper-mediated toxicity may contribute to neurodegeneration in Alzheimer's disease.

Alzheimer Disease↗
PubMed1996

Regulation of amyloid protein precursor (APP) binding to collagen and mapping of the binding sites on APP and collagen type I.

The specific binding of the amyloid precursor protein (APP) to extracellular matrix molecules suggests that APP regulates cell interactions and has a function as a cell adhesion molecule and/or substrate adhesion molecule. On the molecular level APP has binding sites for collagen, laminin, and glycosaminoglycans which is a characteristic feature of cell adhesion molecules. We have examined the interactions between the APP and collagen types I and IV and identified the corresponding binding sites on APP and collagen type I. We show that APP bound most efficiently to collagen type I in a concentration-dependent and specific manner in the native and heat-denatured states, suggesting an involvement of a contiguous binding site on collagen. This binding site was identified on the cyanogen bromide fragment alpha 1(I)CB6 of collagen type I, which also binds heparin. APP did not bind to collagen type I-heparin complexes, which suggests that there are overlapping binding sites for heparin and APP on collagen. We localized the site of APP that mediates collagen binding within residues 448-465 of APP695, which are encoded by the ubiquitously expressed APP exon 12, whereas the high affinity heparin binding site of APP is located in exon 9. Since a peptide encompassing this region binds to collagen type I and inhibits APP-collagen type I binding in nanomolar concentrations, this region may comprise the major part of the collagen type I binding site of APP. Moreover, our data also indicate that the collagen binding site is involved in APP-APP interaction that can be modulated by Zn(II) and heparin. Taken together, the data suggest that the regulation of APP binding to collagen type I by heparin occurs through the competitive binding of heparin and APP to collagen.

Amino Acid Sequence↗
PubMed1996

Reduced iron-associated antioxidants in premature newborns suffering intracerebral hemorrhage.

Oxygen radical injury may be a common pathogenic mechanism in several neonatal diseases. The term "oxygen radical disease of prematurity" has been proposed in the face of the greater incidence of intracerebral hemorrhage, bronchopulmonary dysplasia, and retinopathy in premature neonates. To test the hypothesis that overload with ionic iron due to decreased concentrations of iron-oxidizing and iron-binding proteins induces free radical damage in premature asphyxiated newborns suffering periventricular-intraventricular hemorrhage (PIVH), blood plasma of newborns with PIVH (n = 7) was compared with that of controls (n = 10) within the first 12 h of life. We found reduced transferrin (2.05 vs. 2.24 g/l; p < 0.05) and ceruloplasmin (89.9 vs. 126.3 mg/l; p < 0.01) levels and an increased transferrin saturation (54.2 vs. 38.4%; p < 0.05) in those newborns who later developed PIVH. These findings support the theory that iron-catalyzed lipid peroxidation of the brain during reoxygenation after perinatal asphyxia may be involved in the pathogenesis of PIVH.

Apgar Score↗
PubMed1996

[Retinal tear in retinochoroiditis toxoplasmotica].

PATIENT: A 29-year-old white female presented with an episode of recurrent focal toxoplasmic retinochoroiditis in her right eye. Apart from a white active lesion between the temporal vascular arcades, marked vitreous opacification was present. Treatment with oral pyrimethamine and sulfadiazine led to resolution of retinochoroiditis activity including vitreous clearing within 10 weeks. Another 3 weeks later, a fresh peripheral retinal tear was noted on routine fundus examination of the right eye. While the left eye showed no signs of vitreoretinal pathology, biomicroscopy revealed a posterior vitreous detachment and marked vitreous degeneration in the right eye of this emmetropic patient. Prophylactic laser treatment was performed. No further abnormalities were observed during a 5 months follow-up period. CONCLUSION: Retinal tears (and rhegmatogenous retinal detachment) are rare complications of toxoplasmic retinochoroiditis. However, a tear may occur due to vitreoretinal traction following postinflammatory structural alteration of the vitreous. Thus, in toxoplasmic retinochoroiditis the diagnostic attention should not be limited to the evaluation of optical transparency of the vitreous. Vitreous structure should be assessed as well and if structural changes are noted, repeated ophthalmoscopy is mandatory in order to detect retinal tears and rhegmatogenous retinal detachment timely.

Adult↗
PubMed1996

Vitrectomy in diabetic patients with a blind fellow eye.

Results of pars plana vitrectomy for complications of proliferative diabetic retinopathy were analysed in 32 consecutive patients with a blind fellow eye due to diabetic eye disease. The mean follow-up period was 22.3 months. Only 16% of all eyes examined had received full scatter photocoagulation prior to referral for vitrectomy. Out of 9 eyes with vitreous haemorrhage, 8 improved to a visual acuity of > or = 0.2 postoperatively. Amid 23 eyes which were vitrectomized for advanced traction retinal detachment, only 4 eyes improved to a postoperative visual acuity of > or = 0.02. In this group 12 eyes deteriorated after vitrectomy, 3 eyes progressing to no light perception. The postoperative visual outcome after vitrectomy for traction retinal detachment in this group of diabetics with a blind fellow eye (mean postoperative visual acuity 0.03 +/- 0.05) was significantly worse (p < 0.000) compared to a group of 196 patients with a seeing fellow eye who were vitrectomized for traction retinal detachment at our clinic (mean postoperative visual acuity 0.09 +/- 0.11). Therefore we conclude that traction retinal detachment in this subgroup of patients is a particularly severe presentation of diabetic retinopathy with a guarded functional prognosis after vitrectomy. Our results demonstrate the importance of timely full scatter photocoagulation and early vitrectomy in eyes with progressive fibrovascular proliferation not responding to panretinal photocoagulation. We conclude that especially diabetic patients with a blind fellow eye must be followed closely and assigned to vitrectomy at an earlier stage of their disease in order to improve functional prognosis.

Adult↗