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↗
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↗
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↗
Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signaling pathway in Saccharomyces cerevisiae.
The TOR (target of rapamycin) signal transduction pathway is an important mechanism by which cell growth is controlled in all eucaryotic cells. Specifically, TOR signaling adjusts the protein biosynthetic capacity of cells according to nutrient availability. In mammalian cells, one branch of this pathway controls general translational initiation, whereas a separate branch specifically regulates the translation of ribosomal protein (r-protein) mRNAs. In Saccharomyces cerevisiae, the TOR pathway similarly regulates general translational initiation, but its specific role in the synthesis of ribosomal components is not well understood. Here we demonstrate that in yeast control of ribosome biosynthesis by the TOR pathway is surprisingly complex. In addition to general effects on translational initiation, TOR exerts drastic control over r-protein gene transcription as well as the synthesis and subsequent processing of 35S precursor rRNA. We also find that TOR signaling is a prerequisite for the induction of r-protein gene transcription that occurs in response to improved nutrient conditions. This induction has been shown previously to involve both the Ras-adenylate cyclase as well as the fermentable growth medium-induced pathways, and our results therefore suggest that these three pathways may be intimately linked.
Adenylyl Cyclases↗
Neisseria gonorrhoeae PilA is an FtsY homolog.
The pilA gene of Neisseria gonorrhoeae was initially identified in a screen for transcriptional regulators of pilE, the expression locus for pilin, the major structural component of gonococcal pili. The predicted protein sequence for PilA has significant homology to two GTPases of the mammalian signal recognition particle (SRP), SRP54 and SRalpha. Homologs of SRP54 and SRalpha were subsequently identified in bacteria (Ffh and FtsY, respectively) and appear to form an SRP-like apparatus in prokaryotes. Of the two proteins, PilA is the most similar to FtsY (47% identical and 67% similar at the amino acid level). Like FtsY, PilA is essential for viability and hydrolyzes GTP. The similarities between PilA and the bacterial FtsY led us to ask whether PilA might function as the gonococcal FtsY. In this work, we show that overproduction of PilA in Escherichia coli leads to an accumulation of pre-beta-lactamase, similar to previous observations with other bacterial SRP components. Low-level expression of pilA in an ftsY conditional mutant can complement the ftsY mutation and restore normal growth to this strain under nonpermissive conditions. In addition, purified PilA can replace FtsY in an in vitro translocation assay using purified E. coli SRP components. A PilA mutant that is severely affected in its GTPase activity cannot replace FtsY in vivo or in vitro. However, overexpression of the GTPase mutant leads to the accumulation of pre-beta-lactamase, suggesting that the mutant protein may interact with the SRP apparatus to affect protein maturation. Taken together, these results show that the gonococcal PilA is an FtsY homolog and that the GTPase activity is necessary for its function.
Bacterial Proteins↗
[Therapeutic results of conization with diathermy].
OBJECTIVE: To assess the frequency, histological grade and time interval of residual and recurrent lesions after loop electrosurgical excision procedure and to analyse their associated risk factors. METHODS: 288 patients treated by loop electrosurgical excision procedure between February 1991 and July 1995 were prospectively included in this study. They agreed to a postoperative cytological and colposcopic follow-up with a first visit between 3 and 6 months after excision, a second one between 9 and 15 months and a third one between 24 and 36 months. We used univariate and multivariate analyses to evaluate the association between clinical variables and residual or recurrent lesions. RESULTS: The pathologic diagnosis of the specimens included 21 normal cervices (7.3%), 35 CIN 1 (12.2%), 43 CIN 2 (14.9%), 180 CIN 3 (62.5%), 1 adenocarcinoma in situ (0.3%) and 8 microinvasive cancers (2.8%). The pathologist considered the excision complete in 244 cases (85%). Among the other 44 patients, 27 had involved endocervical margins, 17 involved exocervical margins but none had both margins involved. The mean postoperative follow-up +/- standard deviation was 39 +/- 13 months (range 24-68 months). Treatment failure, defined as the persistence or recurrence of a cervical lesion, was observed in 20 patients (6.9%) having a squamous cancer stage IB (n = 1), a CIN 3 (n = 15), an adenocarcinoma in situ (n = 1) or a CIN 1 (n = 1). In 6 cases the second treatment was performed before the first cytological and colposcopic visit because of an excision considered incomplete by the pathologist. Overall 19 out of the 20 treatment failures were diagnosed within the first two years of the follow-up. The endocervical localisation of the initial lesion (adjusted RR 13.7; 95% CI 1.3, 150.1; P < 0.05) and incomplete excision (adjusted RR 9.1; 95% CI 3.0, 27.3; P < 0.001) were the only independent risk factors for treatment failure. CONCLUSION: Residual or recurrent lesions occurs rarely after loop electrosurgical excision procedure. They are favoured by totally endocervical lesion and an incomplete excision. With the association of cytology and colposcopy, 95% of treatment failures can be detected in the first 2 postoperative years.
Adult↗
A functional GTPase domain, but not its transmembrane domain, is required for function of the SRP receptor beta-subunit.
The signal recognition particle and its receptor (SR) target nascent secretory proteins to the ER. SR is a heterodimeric ER membrane protein whose subunits, SRalpha and SRbeta, are both members of the GTPase superfamily. Here we characterize a 27-kD protein in Saccharomyces cerevisiae (encoded by SRP102) as a homologue of mammalian SRbeta. This notion is supported (a) by Srp102p's sequence similarity to SRbeta; (b) by its disposition as an ER membrane protein; (c) by its interaction with Srp101p, the yeast SRalpha homologue; and (d) by its role in SRP-dependent protein targeting in vivo. The GTP-binding site in Srp102p is surprisingly insensitive to single amino acid substitutions that inactivate other GTPases. Multiple mutations in the GTP-binding site, however, inactivate Srp102p. Loss of activity parallels a loss of affinity between Srp102p and Srp101p, indicating that the interaction between SR subunits is important for function. Deleting the transmembrane domain of Srp102p, the only known membrane anchor in SR, renders SR soluble in the cytosol, which unexpectedly does not significantly impair SR function. This result suggests that SR functions as a regulatory switch that needs to associate with the ER membrane only transiently through interactions with other components.
Amino Acid Sequence↗
Crystal structure of the signal sequence binding subunit of the signal recognition particle.
The crystal structure of the signal sequence binding subunit of the signal recognition particle (SRP) from Thermus aquaticus reveals a deep groove bounded by a flexible loop and lined with side chains of conserved hydrophobic residues. The groove defines a flexible, hydrophobic environment that is likely to contribute to the structural plasticity necessary for SRP to bind signal sequences of different lengths and amino acid sequence. The structure also reveals a helix-turn-helix motif containing an arginine-rich alpha helix that is required for binding to SRP RNA and is implicated in forming the core of an extended RNA binding surface.
Amino Acid Sequence↗
What is your neurologic diagnosis? Anomalous development of C3 and C4 resulting in subluxation and spinal cord compression at C3-4.
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Animals↗
Heterodimer SRP9/14 is an integral part of the neural BC200 RNP in primate brain.
BC200 RNA is a brain-specific, small non-messenger RNA with a somatodendritic localization in primate neurons and a constituent of a ribonucleoprotein (RNP) complex. The primary and secondary structure of the 5' domain of BC200 RNA resembles that of the Alu domain of 7SL RNA, which is an integral part of the signal recognition particle (SRP). This would predict that similar proteins bind to this defined domain of both RNA species in vitro and in vivo. The data presented in this paper reveal that a protein that binds BC200 RNA in vivo is immunoreactive with antibodies against SRP9. This further supports the notion that the 5' domain of the BC200 RNA can fold into structures similar to the SRP Alu domain and, as a result, bind identical or similar proteins in vivo. The SRP9 protein binds only as dimer with SRP14 protein to the Alu domain of 7SL RNA to form a subdomain that, in SRP, is functional in translation arrest. Therefore, our data also indicate that the neuronal BC200 RNP is a candidate for regulating decentralized protein biosynthesis in dendrites, possibly with a mechanism that resembles translation arrest of the SRP.
Animals↗
Autologous platelet treatment for optic disc pit associated with persistent macular detachment.
PURPOSE: To determine the effectiveness of autologous platelets in repair of optic disc pit associated with persistent macular detachment. PATIENT: We report on a 44-year-old woman with optic disc pit associated with persistent macular detachment. The patient underwent an uneventful pars plana vitrectomy with autologous platelets injected over the optic disc pit. Good anatomical and functional results were obtained. CONCLUSION: This surgical approach may be a valuable adjunct to the surgical management of optic disc pit associated with persistent macular detachment.
Adult↗
Temporary vitreous gas tamponade by perfluoromethylcyclopentane.
Using perfluoromethylcyclopentane (FMCP; US patent no. 5,441,989, granted 1995) we have developed a new vitreous gas tamponade in a rabbit model that allows complete filling of the vitreous cavity without vitrectomy and without a significant increase in intraocular pressure. In humans this procedure would allow the blockage of inferior and posterior retinal holes without special positioning of the patient. Perfluoromethylcyclopentane (FMCP), a liquid perfluorocarbon with a boiling point slightly above body temperature, is injected in minute volumes into the vitreous cavity, where it vaporizes, thereby filling a gas volume approximately 500 times its liquid volume. FMCP was injected into the midvitreous in six rabbits (six eyes). After 2-3 days a complete gas tamponade was achieved in three eyes. Two eyes showed 75-90% filling, and one eye was filled only 50% with gas. Intraocular pressure was highest in the completely filled eyes, ranging from 26.6 to 38.8 mmHg. In all eyes the maximum expansion of the gas bubble lasted 2 weeks. One eye developed a retinal detachment. All eyes showed transient subcapsular cataracts. The results of this study showed that intravitreal injection of FMCP, a new perfluorocarbon liquid, results in a complete gas tamponade of the vitreous cavity which lasts 2 weeks without severe intraocular pressure rise and without vitrectomy. This procedure will be especially useful for eyes that have retinal detachment from inferior or posterior retinal holes. Injection of a conventional gas such as SF6 or C3F8 usually does not block retinal holes in inferior or posterior locations without tedious positioning and risk of (transient) glaucoma. Since the mechanism of transition of FMCP from liquid to gas in the vitreous is poorly understood, we are currently studying FMCP vaporization in an in vitro eye model.
Animals↗
Unilateral pigmentary degeneration of the retina associated with heterochromia iridis.
BACKGROUND: For the past 5 years, a 56-year-old patient has been displaying monocular progressive pigmentary changes in the left eye. Heterochromy of the left eye has been known since childhood. The other eye is clinically and functionally normal. The patient was adopted and he has no children. Therefore, we have no family history. METHODS: The patient was examined clinically and by means of electroretinography, electrooculography, perimetry, computer tomography, pulsatile ocular blood flow (POBF) measurement, serology and Doppler sonography. RESULTS: Electrophysiology displayed a considerable reduction of scotopic and photopic ERGs, a reduced dark-through, and a reduced light-rise in the left eye, whereas the fellow eye was normal. The visual field was limited to 5 deg around the fixation point, and a peripheral crescent-shaped arch encircled the temporal-inferior quadrant concomitant to the pigmentary changes. By computer tomography and Doppler sonography a vascular affection was excluded. The left eye displayed lower POBF values. All serological tests were found negative. CONCLUSION: The clinical picture and negative exclusion criteria indicate a unilateral retinitis pigmentosa. However, with regard to the literature an unequivocal diagnosis can only be made upon hereditary evidence.
Blood Flow Velocity↗
Variability of velocity and duration of microembolic signals detected by bigated transcranial Doppler sonography in carotid endarterectomy.
OBJECTIVE: To differentiate between gaseous and particular microemboli in carotid surgery one clinical approach is the interpretation of the effective sample volume length (SVL). We investigated whether such a clinical interpretation is based on reproducible measurements. METHODS: Microembolic signals (MES) recorded during carotid endarterectomy by a bigated transcranial Doppler device were analyzed off-line. In the two sample volumes, the duration and the velocity of the MES were measured by two observers independently from each other twice within 2 weeks. The SVL of the MES were calculated by multiplying duration with velocity. RESULTS: In the anatomical proximal sample volume 215 MES were recorded of which 203 (94.5%) were also present in the distal. The SVL medians of the MES were 2.2-4.1 mm lower in the distal than in the proximal sample volume as a result of lower velocity and shorter duration of the MES in the distal sample volume. The median of the paired differences of the SVL was 0.2 mm (interquartile range: 0.0-1.2) in the proximal sample volume and 0.8 mm (0.2-1.8) in the distal sample volume for observer 1, and 0.6 mm (0.4-2.2) and 0.9 mm (0.5-1.6) for observer 2. The median of the paired differences of the SVL between the observers was 1.4 mm (1.2-2.9) in the proximal sample volume and 1.6 mm (1.3-3.0) in the distal. CONCLUSION: The intra- and interobserver agreement on calculating SVL is good. However, the depth of insonation influences some features of embolic signals.
Aged↗
The unfolded protein response: an intracellular signalling pathway with many surprising features.
The unfolded protein response (UPR) is an intracellular signalling pathway--originating in the endoplasmic reticulum (ER) and leading to the cell nucleus--that controls transcription of genes encoding ER-resident proteins. Recent developments in this field show that this pathway utilizes unique regulatory mechanisms, including translational attenuation and a regulated mRNA splicing step catalysed by a bifunctional transmembrane kinase/endoribonuclease and tRNA ligase. This review describes the characterization of the UPR signalling pathway, focusing on the novel regulatory mechanisms that it has revealed.
Endoplasmic Reticulum↗
[Multi-flash ERG in cone dystrophies and cone-rod dystrophies].
BACKGROUND: Scotopic electroretinograms elicited with a multiple flash procedure were reported to be helpful in diagnosis of macular diseases. To evaluate the contribution of rods and cones to the recovery of light responses as recorded with this technique we performed a triple flash ERG procedure in patients with cone dystrophies and cone-rod dystrophies. MATERIALS AND METHODS: In 8 patients with cone dystrophy and 8 patients with cone-rod dystrophy and also in 18 healthy controls we recorded a standard ERG and the scotopic triple flash ERG with intensities between 0.01 and 0.2 cds/m2. Interflash intervals were adjusted at 140, 280, and 560 ms. Responses of the standard ERG were analysed as well as b-wave amplitudes at the short dark interval (140 ms) and the longer dark interval (280 ms). These responses were compared to responses after a long interflash interval (560 ms). Using a theoretical model parameters of b-wave recovery were determined and compared between the groups. RESULTS: In cone dystrophies responses of the scotopic triple flash ERG and the b-wave recovery parameters were normal whereas in combined dystrophies the triple flash responses were abnormal and the recovery data were pathologic. CONCLUSIONS: Cones did neither contribute to responses obtained with the multiple flash technique nor did they affect b-wave recovery as tested with this technique. Pathologic responses as described earlier with this technique in macular diseases could only be attributed to pathomechanisms globally affecting the rod system, e.g. dysfunction of retinal energy metabolism.
Adolescent↗