Retinal side-effects of sildenafil.
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3',5'-Cyclic-AMP Phosphodiesterases↗
Biomedical subjects
P Walter
Publications and source records attributed to P Walter.
Crystallization of the dimerization-initiation site of genomic HIV-1 RNA: preliminary crystallographic results.
The genomic RNA of all retroviruses is encapsidated in virions as a dimer of single-stranded chains held together near their 5'-end. For HIV-1, the initial site of dimerization has been shown to be a hairpin with a nine-residue loop containing a self-complementary sequence of six residues. This structure is proposed to promote dimerization by loop-loop interaction and formation of a so-called 'kissing complex'. A 23-nucleotide RNA strand containing the loop enclosed by a seven base-pair stem has been synthesized. This oligomer was crystallized by the vapour-diffusion method at 310 K, pH 6.5, with methyl-pentanediol as the precipitant agent in the presence of MgCl2, KCl and spermine. Quasi-complete diffraction data were obtained at 2.7 A resolution with a conventional X-ray source and at 2.3 A resolution on a synchrotron beamline. The space group is P3121 or its enantiomorph P3221, with cell parameters a = b = 60. 1, c = 65.9 A at ambient temperature, or a = b = 59.0, c = 64.3 A in a nitrogen-gas stream. There are two oligomers per asymmetric unit as determined from absorbance measurements of a dissolved crystal whose volume was carefully determined. In some cases, either perfectly or partially twinned crystals were obtained. Perfect twinning is detected by an apparent hexagonal symmetry and yields unusable crystallographic data, whilst partial twinning yields usable data after adequate processing. Structure solution is under way by searching for heavy-atom derivatives and systematically substituting bromo- or iodo-uridines for uridines.
Base Sequence↗
Bioavailability of trospium chloride after intravesical instillation in patients with neurogenic lower urinary tract dysfunction: A pilot study.
Oral drug treatment of detrusor overactivity often causes undesirable side effects in other organs. For some patients, in particular those with neurogenically induced detrusor overactivity (detrusor hyperreflexia), the tolerance level for adverse effects is low and oral treatment may become ineffective. Intravesical administration of the drug can diminish the side effects or increase treatment effectivity in patients who are (partially) refractory to oral treatment because the relative concentration of the drug is increased in the target organ and decreased in the circulation. Six men (19-34 years old) with traumatic spinal cord lesions between C2 and Th11 were randomized to intravesical instillation with 15 or 30 mg trospium chloride in 40 ml saline into the empty bladder. Catheterization was postponed until at least 3 h after instillation, and fluid intake was not allowed during the first 4 h. Blood samples were taken before and 11 times after instillation; the last sample 12 h post instillation. Four positive samples were found in three patients: 0.10 ng/ml after 1 h and 0.13 ng/ml after 2(1/2) h in two patients with 15 mg, and 0.24 ng/ml after 30 min and 0.70 ng/ml after 6 h in one patient with 30 mg instilled trospium chloride. Three adverse effects were reported and were rated as probably not related to the drug. It is concluded that intravesically instilled trospium chloride is not absorbed into the circulation in significant amounts and, thus, it may be expected that this mode of administration will improve the efficacy of trospium chloride therapy by reducing the side effects. Neurourol. Urodynam. 18:447-453, 1999.
Adult↗
Electrophysiological abnormalities in age-related macular degeneration.
BACKGROUND: Results from psychophysical tests indicate that in age related macular degeneration (ARMD) retinal function is globally impaired. Observations in single ARMD cases showing abnormalities of the electrooculogram (EOG) and electroretinogram (ERG) encouraged us to systematically examine ARMD patients by means of electrophysiological tests to confirm a global retinal dysfunction in ARMD. METHODS: Sixty-six patients with ARMD were examined clinically and by means of EOG, ERG, triple scotopic ERG, and fluorescein angiography (FA). RESULTS: EOG data were considerably reduced in ARMD. Scotopic a- and b-waves of the ERG were mildly affected. The bright flash response showed reduced b-waves with normal implicit times. The amplitude of the oscillatory potential OP2 was significantly reduced and photopic responses were also pathologic compared with an age-matched control group. Geographic atrophy and pigment epithelium detachment showed specific abnormalities in the ERG, whereas in soft drusen EOG changes were more conspicuous. CONCLUSIONS: In addition to data from psychophysical tests the results from electrophysiological examinations indicated a global reduction of retinal function in ARMD which seemed to be present not only in the macula but also elsewhere in the retina.
Aged↗
Cardiac myxoma with glandular component: case report and review of the literature.
A 7 cm diameter tumor of the left atrium is reported in a 78 year-old woman with a past history of pT3N1M0 colonic adenocarcinoma. The histological examination of the atrial tumor disclosed areas of highly vascularized myxoid stroma with cells strongly reactive for vimentin. Multiple mucoid spaces lined by a single layer of goblet cells were scattered among those typical areas of myxoma. No nuclear atypia was observed. Cytoplasm of the glandular cells was immunoreactive for epithelial antisera (keratin, EMA), CEA and CA19.9. Two years later, the patient was doing well, with no local recurrence of the cardiac myxoma and no secondary location of the colonic adenocarcinoma. The histological characteristics, the absence of atypia, the absence of tumoral extension or neoplastic lymphatic vascular thrombi in the pedicle or in the interatrial septum, and the finding of typical myxomatous areas supported the diagnosis of cardiac myxoma with glandular component. To our knowledge, 21 cases of myxoma with glandular mucinous component, focal or prominent, have been previously published in the literature. These myxoma were generally sporadic cases with the same clinical features and prognosis as typical myxoma. Immunoreactivity of these glandular structures was constant for epithelial markers. The positive immunostaining by CEA, and by CA19.9 in our case, reflects the histogenetic endodermal origin.
Aged↗
Improvement of visual acuity in patients suffering from diabetic retinopathy after membrane differential filtration: a pilot study.
BACKGROUND: Membrane differential filtration is an extracorporeal treatment procedure which eliminates high molecular weight proteins and lipids from the blood. This pilot study was initiated to investigate the short-term effects on blood rheology and visual function in patients suffering from diabetic retinopathy. METHODS: Six patients with non-proliferative diabetic retinopathy, clinically significant macular edema (five patients, nine eyes) and inactive proliferative diabetic retinopathy (one patient, one eye) underwent a single treatment with a hollow fiber secondary plasma filter. The main parameter measured was visual acuity prior to and after treatment. Biochemical and rheological parameters (whole blood and plasma viscosity, and erythrocyte aggregation) were also measured. The mean follow-up was 25 (range 4-90) days after treatment. RESULTS: The mean improvement of visual acuity was 1.4 lines (SD 0.8 lines, p = 0.002) 24 h after therapy. This remained stable during the follow-up period. The rheological measures were significantly lowered. A significant reduction of total protein, fibrinogen, IgG, IgM, IgA, alpha-2-macroglobulin, total cholesterol, LDL and HDL was found. CONCLUSION: This study demonstrates the rheological impact of membrane differential filtration. It was shown that rheological changes correlated with clinical improvement in patients suffering from diabetic retinopathy with clinically significant macular edema.
Aged↗
Signal sequence recognition and protein targeting.
Intracellular traffic is often controlled not by highways, but by handshakes and partner introductions within a cellular network. Recently determined structures suggest how signal sequences are recognized and how the GTP affinities of the signal recognition particle and its receptor are coupled to the targeting of ribosomes to translocational membrane pores. The structure of signal peptidase suggests how it releases functional proteins.
Base Sequence↗
Structure of the phylogenetically most conserved domain of SRP RNA.
The signal recognition particle (SRP) is a phylogenetically conserved ribonucleoprotein required for cotranslational targeting of proteins to the membrane of the endoplasmic reticulum of the bacterial plasma membrane. Domain IV of SRP RNA consists of a short stem-loop structure with two internal loops that contain the most conserved nucleotides of the molecule. All known essential interactions of SRP occur in that moiety containing domain IV. The solution structure of a 43-nt RNA comprising the complete Escherichia coli domain IV was determined by multidimensional NMR and restrained molecular dynamics refinement. Our data confirm the previously determined rigid structure of a smaller subfragment containing the most conserved, symmetric internal loop A (Schmitz et al., Nat Struct Biol, 1999, 6:634-638), where all conserved nucleotides are involved in nucleotide-specific structural interactions. Asymmetric internal loop B provides a hinge in the RNA molecule; it is partially flexible, yet also uniquely structured. The longer strand of internal loop B extends the major groove by creating a ledge-like arrangement; for loop B however, there is no obvious structural role for the conserved nucleotides. The structure of domain IV suggests that loop A is the initial site for the RNA/protein interaction creating specificity, whereas loop B provides a secondary interaction site.
Base Sequence↗
Primary non familial amyloidosis of the vitreous and subretinal amyloid bodies.
We report a case of primary non familial amyloidosis of the vitreous and subretinal amyloid bodies. Pars plana vitrectomy and subretinal numerable clusters of cystic-like glistering material were extracted. The diagnosis was confirmed only by histological findings.
Amyloidosis↗
Antibiotics and light responses in superfused bovine retina.
1. Our objective was to study effects of clindamycin and ciprofloxacin on the electroretinogram (ERG) of isolated bovine retinas. 2. Electroretinograms of isolated superfused bovine retinas were recorded under normal conditions and during application of clindamycin and ciprofloxacin. The b-wave reduction was plotted against the drug concentration. In several cases retinal oxygen uptake was also measured. Clindamycin was available only in a preparation containing benzyl alcohol. To differentiate between effects caused by the antibiotic and the alcohol, ERGs were also recorded under superfusion with benzyl alcohol. To record drug effects on photoreceptors synaptic transmission was blocked using 1 mM aspartate. 3. At concentrations between 0.3 and 10 mM clindamycin significantly reduced the amplitude of the b-wave of the ERG. A comparable reduction of retinal oxygen uptake was found at concentrations 10-fold higher. Clindamycin, 3 mM, did not affect the a-wave after preincubation with aspartate. Benzyl alcohol at concentrations of 0.3 and 1 mM did not affect the b-wave, whereas at higher concentrations the b-wave was found to be reduced. Considerable b-wave reductions were found with ciprofloxacin at concentrations of between 0.03 and 0.6 mM. All effects proved to be fully reversible and dose-dependent. 4. Ciprofloxacin and clindamycin did both alter neural function in the isolated superfused bovine retina. The nontoxic dosages found here differ considerably from results in rabbits after intravitreal injections. This is probably due to species differences.
Animals↗
[Symptomatic abdominal aortic aneurysm and left-sided infrarenal vena cava].
Coincidence of an abdominal aortic aneurysm and abnormalities of the inferior vena cava is a rare condition but has significance for surgical therapy. By the preoperative use of various imaging techniques and adapted surgical procedure the risk of the operation is decreasing to a minimal level. A case of symptomatic abdominal aneurysm and left-sided infrarenal vena cava is presented and the importance of preoperative examinations and operative strategy is discussed.
Aged↗
Cerebrovascular resistance and blood flow velocity changes after carotid endarterectomy.
BACKGROUND: To study the pattern of cerebral blood flow velocity and cerebral resistance changes after carotid endarterectomy. PATIENTS AND METHODS: In 81 patients (mean age +/- SD, 64 +/- 8 years) with unilateral carotid endarterectomy (CEA) the systolic, diastolic and mean blood velocities, and the pulsatility index (PI) were recorded in both middle cerebral arteries preoperatively and repetitively postoperatively with the use of transcranial Doppler ultrasound (TCD). RESULTS: In the middle cerebral artery ipsilateral to CEA mean blood velocity was increased 6 hours (64 +/- 25 cm/sec; p < 0.005) and 7 days (54 +/- 15 cm/sec; p < 0.05) after CEA and had returned to the preoperative level (49 +/- 11 cm/sec) after 3 months. Compared to preoperatively (0.86 +/- 22), the PI was significantly increased at 6 hours examination (1.03 +/- 23, p < 0.005), and remained increased thereafter. A pathologically increased mean blood velocity (> 83 cm/sec) 6 hours after CEA occurred in 11 patients, two of them developed a slight hyperperfusion syndrome. In the contralateral middle cerebral artery, only the diastolic blood velocity showed significant changes (preoperatively, 35 +/- 12 cm/sec; 3 months after CEA, 33 +/- 8 cm/sec; p < 0.05). CONCLUSIONS: Using TCD, hemodynamic changes occur predominantly in the middle cerebral arteries ipsilateral to CEA. Early postoperative TCD studies may be of help to identify patients at risk to develop a hyperperfusion syndrome.
Aged↗
Structure of the most conserved internal loop in SRP RNA.
The signal recognition particle (SRP) directs translating ribosomes to the protein translocation apparatus of endoplasmic reticulum (ER) membrane or the bacterial plasma membrane. The SRP is universally conserved, and in prokaryotes consists of two essential subunits, SRP RNA and SRP54, the latter of which binds to signal sequences on the nascent protein chains. Here we describe the solution NMR structure of a 28-mer RNA composing the most conserved part of SRP RNA to which SRP54 binds. Central to this function is a six-nucleotide internal loop that assumes a novel Mg2+-dependent structure with unusual cross-strand interactions; besides a cross-strand A/A stack, two guanines form hydrogen bonds with opposite-strand phosphates. The structure completely explains the phylogenetic conservation of the loop bases, underlining its importance for SRP54 binding and SRP function.
Base Sequence↗
Functional changes in the structure of the SRP GTPase on binding GDP and Mg2+GDP.
Ffh is a component of a bacterial ribonucleoprotein complex homologous to the signal recognition particle (SRP) of eukaryotes. It comprises three domains that mediate both binding to the hydrophobic signal sequence of the nascent polypeptide and the GTP-dependent interaction of Ffh with a structurally homologous GTPase of the SRP receptor. The X-ray structures of the two-domain 'NG' GTPase of Ffh in complex with Mg2+GDP and GDP have been determined at 2.0 A resolution. The structures explain the low nucleotide affinity of Ffh and locate two regions of structural mobility at opposite sides of the nucleotide-binding site. One of these regions includes highly conserved sequence motifs that presumably contribute to the structural trigger signaling the GTP-bound state. The other includes the highly conserved interface between the N and G domains, and supports the hypothesis that the N domain regulates or signals the nucleotide occupancy of the G domain.
Amino Acid Sequence↗
Approach of the US food and nutrition board to daily nutrient requirements: 'a useful basis for the European discussion on risk assessment of nutrients?' Report on a workshop organized by the European Academy of Nutritional Sciences (EANS) and TNO Food and Nutrition Research Institute, 11 December 1998, Brussels.
OBJECTIVE: To discuss the approach of the US Food and Nutrition Board (FNB) to daily nutrient requirements and its relevance for Europe. SETTING: A workshop for experts from academia and regulatory bodies, together with members from the FNB Dietary Reference Intakes Subcommittee on Upper Reference Levels of Intake, and from the B-vitamins Expert panel. The workshop was organised by the European Academy of Nutritional Sciences and TNO Nutrition and Food Research Institute (The Netherlands). CONCLUSIONS: Classical approaches to recommended dietary allowances (RDA) are no longer satisfactory, because they do not take into account newly emerging science with regard to intakes beyond the RDA. There is an urgent need for global harmonisation of criteria used for assessing adequacy of intake and for harmonisation of terminology. For sound advice to consumers, the development of tolerable upper intake levels is necessary. The discussion of principal issues relating to criteria for nutrient adequacy should be pursued on an international level. SPONSORSHIP: Roche Vitamins Europe Ltd, Birsfelden, Switzerland
Europe↗
[Current strategies for treatment of CMV retinitis in patients with AIDS].
BACKGROUND: CMV retinitis is the most common manifestation of active CMV infection in patients with AIDS. Before ganciclovir became available, the prognosis of CMV retinitis was very poor. Meanwhile a number of strategies for the management of CMV retinitis have evolved. To date no antiviral agent has proved effective in preventing reactivation of retinitis. Therefore the available antiviral agents delay rather than prevent relapse of CMV retinitis. Each relapse produces a more serious disease and retinitis becomes progressively less manageable. METHOD: A review of current therapeutic strategies for the treatment of CMV retinitis with regard to the challenge of clinical resistance is given. CONCLUSION: Effective treatment of clinically resistant CMV retinitis must consider the individual conditions. Thus, it is probable, that integration of both local and systemic therapies may be required to reduce the frequency of reactivation and thereby to decelerate the progression of the disease. Literature search in medline.
AIDS-Related Opportunistic Infections↗
[Modification of vision by change in rheologic parameters in senile macular degeneration through membrane differential filtration--initial results of a randomized study].
BACKGROUND: Membrane differential filtration (MDF) is known to optimize rheological parameters by eliminating high molecular weight proteins und lipoproteins from the blood and was shown to influence ocular perfusion parameters. Following the hypothesis that these changes may influence the natural course of age-related macular degeneration (AMD) we tested their efficacy in improving visual function in these patients in a randomized trial. PATIENTS AND METHODS: 20 patients (36 eyes) were randomized into two groups. Ten patients (18 eyes) were treated with MDF and ten (18 eyes) served as controls. The first group was treated five times over a period of 21 weeks. In both groups 8/18 of the eyes showed subfoveolar subretinal neovascularisations. Main parameter of the study was visual acuity. Macular visual evoked potentials were also recorded. Plasmaviscosity, whole blood viscosity and erythrocyte aggregation were measured. RESULTS: The ten patients, treated repeatedly over a period of 21 weeks, showed a mean improvement 1.1 (SD 1.9) lines after 21 weeks, while the control group showed a deterioration of visual acuity (0.6 lines, SD 1.7). The macular visual evoked potentials showed an increase of 0.28 microV (SD 1.12) for the therapy group and a deterioration of 0.57 microV (SD 1.31) in the control group. The rheological parameters were lowered in all patients. CONCLUSIONS: We conclude that repetitive treatment with MDF is able to improve visual function in patients with AMD. Further research is necessary to show how to optimize the selection of patients and how to create an individual treatment strategy.
Aged↗
Two endoplasmic reticulum (ER) membrane proteins that facilitate ER-to-Golgi transport of glycosylphosphatidylinositol-anchored proteins.
Many eukaryotic cell surface proteins are anchored in the lipid bilayer through glycosylphosphatidylinositol (GPI). GPI anchors are covalently attached in the endoplasmic reticulum (ER). The modified proteins are then transported through the secretory pathway to the cell surface. We have identified two genes in Saccharomyces cerevisiae, LAG1 and a novel gene termed DGT1 (for "delayed GPI-anchored protein transport"), encoding structurally related proteins with multiple membrane-spanning domains. Both proteins are localized to the ER, as demonstrated by immunofluorescence microscopy. Deletion of either gene caused no detectable phenotype, whereas lag1Delta dgt1Delta cells displayed growth defects and a significant delay in ER-to-Golgi transport of GPI-anchored proteins, suggesting that LAG1 and DGT1 encode functionally redundant or overlapping proteins. The rate of GPI anchor attachment was not affected, nor was the transport rate of several non-GPI-anchored proteins. Consistent with a role of Lag1p and Dgt1p in GPI-anchored protein transport, lag1Delta dgt1Delta cells deposit abnormal, multilayered cell walls. Both proteins have significant sequence similarity to TRAM, a mammalian membrane protein thought to be involved in protein translocation across the ER membrane. In vivo translocation studies, however, did not detect any defects in protein translocation in lag1Delta dgt1Delta cells, suggesting that neither yeast gene plays a role in this process. Instead, we propose that Lag1p and Dgt1p facilitate efficient ER-to-Golgi transport of GPI-anchored proteins.
Adaptor Proteins, Signal Transducing↗