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.
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↗
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↗
Failure of sorivudine therapy in progressive outer retinal necrosis caused by varicella zoster virus.
BACKGROUND: We report on the case of a 23-year-old female who presented with ocular signs of progressive outer retinal necrosis (PORN) syndrome and who failed to respond to acyclovir, ganciclovir, foscarnet and oral sorivudine. METHODS: The patient was treated with the antiviral drugs acyclovir, ganciclovir, foscarnet and oral sorivudine. RESULTS: The patient failed to respond to a combination of antiviral drugs. Unfortunately, progression of the retintis occurred, which led to blindness. CONCLUSION: Despite new drugs, the prognosis of PORN is poor and recurrence is common.
AIDS-Related Opportunistic Infections↗
Microembolic signals and intraoperative stroke in carotid endarterectomy.
OBJECTIVES: Microembolic signals (high-intensity transient signals, HITS) detected by means of transcranial Doppler sonography (TCD) may be relevant for intraoperative strokes in carotid endarterectomy (CEA). MATERIAL AND METHODS: An intraoperative HITS detection study was performed on 77 patients (63 men, 14 women, mean age+/-SD, 64+/-8 years) with a total of 81 CEAs. Using the Scandinavian Stroke Scale the patients were clinically examined by a neurologist preoperatively and postoperatively within 6 h. A deterioration of the Scandinavian Stroke Scale was considered an intraoperative stroke if persisting longer than 24 h. Cranial computed tomography (CT scan) was performed preoperatively and 3 to 5 days postoperatively. By means of TCD total HITS count and mean blood velocity changes, for shunting, were recorded sufficiently in the middle cerebral artery in 79 CEAs. RESULTS: HITS were significantly more frequent in symptomatic [n = 53; HITS: median, 15 (range 1-159)] than in asymptomatic stenoses [n = 26; HITS: 6.5 (0-41); P < 0.001]. An intraoperative stroke in the hemisphere ipsilateral to the operation occurred in eight of the 81 CEAs. On postoperative CT scans, five of the eight strokes showed new corresponding territorial infarctions. In the three strokes without new CT lesions, the mean blood velocity changes after clamping indicated normal cerebral perfusion. Total HITS count was significantly higher in procedures with intraoperative strokes [n = 8; HITS: 33 (11-159)] than in the uncomplicated [n = 71; HITS: 10 (0-62); P = 0.002]. No stroke occurred in 37 CEAs with 10 or less HITS, but eight in 42 CEAs with 11 or more HITS [P = 0.006; relative risk 1.23 (95% confidence interval: 1.06 to 1.43)]. CONCLUSION: Microembolism seems clinically relevant in carotid endarterectomy. Asymptomatic patients may run a lower risk of intraoperative embolization.
Aged↗
Intracellular signaling from the endoplasmic reticulum to the nucleus.
Cells respond to an accumulation of unfolded proteins in the endoplasmic reticulum (ER) by increasing transcription of genes encoding ER resident proteins. The information is transmitted from the ER lumen to the nucleus by an intracellular signaling pathway called the unfolded protein response (UPR). Recent work has shown that this signaling pathway utilizes several novel mechanisms, including translational attenuation and a regulated mRNA splicing step. In this review we aim to integrate these recent advances with current knowledge about maintenance of ER composition and abundance.
Animals↗
Intravitreal daunomycin induces multidrug resistance in proliferative vitreoretinopathy.
PURPOSE: Adjuvant intravitreal daunomycin is frequently used for the management of proliferative vitreoretinopathy (PVR). In this study the authors examined whether daunomycin could induce multidrug resistance (MDR), mediated by the mdr-1 gene product P-glycoprotein, in the cells responsible for reproliferation in vivo and in human retinal pigment epithelial (RPE) cells in vitro. METHODS: Expression of P-glycoprotein was examined by immunohistochemistry in surgically removed epiretinal membranes. The cellular source of P-glycoprotein was examined by colabeling for cytokeratin, glial fibrillary acidic protein, and the macrophage marker EBM-11. P-glycoprotein expression by cultured RPE cells was assessed by reverse transcription-polymerase chain reaction and immunoblot analysis. Daunomycin toxicity was quantified by crystal violet assay. RESULTS: P-glycoprotein expression was detected in 10 of 10 patients pre-exposed to intravitreal daunomycin. In contrast, epiretinal membranes from only 2 of 13 patients never exposed to daunomycin showed faint P-glycoprotein expression. P-glycoprotein expression was strong within 8 months after daunomycin treatment and faded thereafter. Colocalization studies demonstrated predominant expression of P-glycoprotein by RPE cells. Pre-exposure of cultured human RPE cells to subtoxic concentrations of daunomycin induced resistance to daunomycin that was sensitive to the MDR inhibitor, verapamil. Induction of the MDR phenotype in RPE cells by daunomycin was associated with a minor increase in the mdr-1 mRNA level but a prominent increase in P-glycoprotein expression, thus suggesting a primarily translational mechanism of MDR development in human RPE cells. CONCLUSIONS: Intravitreal daunomycin induced P-glycoprotein expression in PVR. Reproliferation in daunomycin-pretreated patients probably necessitates cotreatment with daunomycin and inhibitors of multidrug resistance such as verapamil or administration of antiproliferative drugs such as 5-fluorouracil, which act in a MDR-independent fashion.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
A ribosome at the end of the tunnel.
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Biological Transport↗
Translational attenuation mediated by an mRNA intron.
BACKGROUND: The unfolded protein response (UPR) is an intracellular signaling pathway that is activated by the accumulation of unfolded proteins in the endoplasmic reticulum (ER). The UPR results in an increase in transcription of ER-resident proteins that facilitate protein folding in the ER. A key regulatory step in UPR activation is the regulated splicing of HAC1 mRNA, which encodes Hac1p, a transcription factor dedicated to this pathway. Hac1p can be detected only when the spliced form of HAC1 mRNA (termed HAC1i mRNA, for induced) is produced; this was surprising because the unspliced HAC1u mRNA (HAC1u for uninduced) is equally stable in cells. RESULTS: We show that in contrast to most other unspliced pre-mRNAs, the HAC1u mRNA is transported from the nucleus into the cytosol. Although HAC1u mRNA is associated with polyribosomes, no detectable Hac1pu is produced unless the intron is removed, indicating that the presence of the intron prevents mRNA translation. When it is produced, Hac1pu has a stability similar to that of Hac1pi, the form of the Hac1p that is produced from the spliced mRNA and that differs from Hac1pu by a short carboxy-terminal tail sequence. Hac1pu, however, is differently modified and less active in activating transcription. Interestingly, when transplanted into the 3' untranslated region of a completely unrelated mRNA, the HAC1 intron is sufficient to attenuate translation of the preceding open reading frame. CONCLUSIONS: We have shown that the HAC1 mRNA intron is both necessary and sufficient to prevent complete translation of polyribosome-associated mRNAs. To our knowledge, this identifies a new way by which translation of a mRNA can be attenuated.
Basic-Leucine Zipper Transcription Factors↗