ABSTRACT
In skeletal muscle, excitation-contraction (EC) coupling relies on the mechanical coupling between two ion channels: the L-type voltage-gated calcium channel (CaV1.1), located in the sarcolemma and functioning as the voltage sensor of EC coupling, and the ryanodine receptor 1 (RyR1), located on the sarcoplasmic reticulum serving as the calcium release channel. To this day, the molecular mechanism by which these two ion channels are linked remains elusive. However, recently, skeletal muscle EC coupling could be reconstituted in heterologous cells, revealing that only four proteins are essential for this process: CaV1.1, RyR1, and the cytosolic proteins CaVß1a and STAC3. Due to the crucial role of these proteins in skeletal muscle EC coupling, any mutation that affects any one of these proteins can have devastating consequences, resulting in congenital myopathies and other pathologies.Here, we summarize the current knowledge concerning these four essential proteins and discuss the pathophysiology of the CaV1.1, RyR1, and STAC3-related skeletal muscle diseases with an emphasis on the molecular mechanisms. Being part of the same signalosome, mutations in different proteins often result in congenital myopathies with similar symptoms or even in the same disease.
Subject(s)
Channelopathies , Muscular Diseases , Humans , Ryanodine Receptor Calcium Release Channel/genetics , Ryanodine Receptor Calcium Release Channel/metabolism , Muscle Fibers, Skeletal/metabolism , Channelopathies/genetics , Adaptor Proteins, Signal Transducing , Excitation Contraction Coupling/physiology , Muscle, Skeletal/physiology , Muscular Diseases/genetics , Calcium Channels, L-Type/genetics , Calcium Channels, L-Type/metabolism , Calcium/metabolism , Calcium SignalingABSTRACT
PURPOSE: To describe endoscope-assisted Carlevale intraocular lens (IOL) implantation. METHODS: Twelve eyes underwent posterior vitrectomy combined with Carlevale IOL implantation and endoscopy in a single procedure, using a technique developed by the authors. Transscleral incisions were performed under direct visualization of the sulcus using the endoscope, and the final lens position was checked at the end of each intervention. The main outcome was to determine the exact position of all lens fixation points. RESULTS: All plugs were correctly placed in the sulcus, but in seven eyes (58.3%), at least one of the closed-loop haptics was folded over the ciliary body. Repositioning was performed during the same procedure. Given that each IOL has four closed-loop haptics, the incidence of this complication was 23% (11/48). CONCLUSION: Blind implantation of Carlevale IOL may cause a high incidence of haptic malpositioning. Because the sulcus and the ciliary body are not visible under the microscope, endoscopy is the only way to ensure correct lens implantation. This new technique ensures that all lens fixation points are correctly placed by the end of surgery, avoiding complications such as decentration or tilting of the IOL, damage to the iris or the ciliary body, and uveitis.
Subject(s)
Lens, Crystalline , Lenses, Intraocular , Lenses , Humans , Lens Implantation, Intraocular/methods , Endoscopes , Suture TechniquesABSTRACT
Non-cell-autonomous mechanisms contribute to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), in which astrocytes release unidentified factors that are toxic to motoneurons (MNs). We report here that mouse and patient iPSC-derived astrocytes with diverse ALS/FTD-linked mutations (SOD1, TARDBP, and C9ORF72) display elevated levels of intracellular inorganic polyphosphate (polyP), a ubiquitous, negatively charged biopolymer. PolyP levels are also increased in astrocyte-conditioned media (ACM) from ALS/FTD astrocytes. ACM-mediated MN death is prevented by degrading or neutralizing polyP in ALS/FTD astrocytes or ACM. Studies further reveal that postmortem familial and sporadic ALS spinal cord sections display enriched polyP staining signals and that ALS cerebrospinal fluid (CSF) exhibits increased polyP concentrations. Our in vitro results establish excessive astrocyte-derived polyP as a critical factor in non-cell-autonomous MN degeneration and a potential therapeutic target for ALS/FTD. The CSF data indicate that polyP might serve as a new biomarker for ALS/FTD.
Subject(s)
Amyotrophic Lateral Sclerosis , Frontotemporal Dementia , Amyotrophic Lateral Sclerosis/genetics , Animals , Astrocytes , C9orf72 Protein/genetics , Culture Media, Conditioned/pharmacology , Frontotemporal Dementia/genetics , Humans , Mice , Motor Neurons , PolyphosphatesABSTRACT
Storeoperated calcium entry (SOCE) is important for refilling endoplasmic reticulum (ER) Ca2+ stores and Ca2+ signaling. Extracellular Ca2+ is conducted by highly Ca2+selective Orai channels that are activated by stromal interaction molecule proteins (STIMs), which are sensitive ER Ca2+ sensors. We found an approximately fivefold increase in annexin A3a (anxa3a) expression levels in stim2b knockout zebrafish. The present study investigated whether annexin A3 protein is involved in SOCE. We used Ca2+ imaging and electrophysiological recordings to determine the effect of annexin A2, A3, and A6 overexpression on SOCE and Orai-dependent Ca2+ currents (ICRAC) in cultured cells. Annexin A3 increased SOCE amplitude and potentiated Ca2+ ICRAC currents. These results suggest that annexin A3 is a positive modulator of SOCE.
Subject(s)
Annexin A3/metabolism , Calcium Channels , Calcium , Animals , Calcium/metabolism , Calcium Channels/genetics , Calcium Channels/metabolism , Calcium Signaling , ORAI1 Protein , Stromal Interaction Molecule 1/genetics , Zebrafish/metabolismABSTRACT
PURPOSE: To evaluate swept source optical coherence tomography angiography (SS-OCTA) in patients treated with hydroxychloroquine (HCQ) for more than 5 years and to compare results with the tests currently recommended for screening of HCQ retinopathy. METHODS: In this controlled pilot study, consecutive patients treated with HCQ for more than 5 years underwent SS-OCTA, SS-OCT B-scan and en-face C-scan, fundus autofluorescence (FAF), 10-2 automated visual field (AVF) testing and multifocal electroretinography (mfERG). On SS-OCTA, evaluation of the retinal superficial capillary plexus, middle capillary plexus, and deep capillary plexus (DCP) and the choriocapillaris (CC) was obtained. RESULTS: We included 10 patients under HCQ treatment (20 eyes, mean age 38.91±11.73 years) and 18 healthy control patients (36 eyes, mean age 38.87±8.6 years). Mean duration of HCQ treatment was 10.0±3.25 (5-15) years and HCQ cumulative dose/body weight was 15.86±5.56 g/kg. The HCQ group showed a reduction of the vessel density in the 1 mm central, in the nasal and temporal subfields of DCP and in the 1 mm central subfield of CC, an increased foveal avascular zone in the three capillary plexuses, a greater frequency of CC flow voids and a reduced foveal choroidal thickness (p<0.05). Best-corrected visual acuity (BCVA), mfERG, SS-OCT B-scan and C-scan, AVF and FAF were normal in 20/20 eyes (100%). CONCLUSIONS: In patients treated with HCQ for more than 5 years, choroidal thinning and flow abnormalities at SS-OCTA in the retinal capillary plexuses and CC may be observed even if BCVA, FAF, mfERG, AVF and SS-OCT are normal.
Subject(s)
Fluorescein Angiography/methods , Forecasting , Hydroxychloroquine/therapeutic use , Retinal Diseases/drug therapy , Retinal Vessels/pathology , Tomography, Optical Coherence/methods , Visual Acuity , Adult , Antirheumatic Agents , Cross-Sectional Studies , Electroretinography/methods , Female , Follow-Up Studies , Humans , Macula Lutea/blood supply , Macula Lutea/pathology , Male , Middle Aged , Pilot Projects , Prospective Studies , Retinal Diseases/diagnosis , Retinal Diseases/physiopathology , Retinal Vessels/physiopathology , Treatment Outcome , Young AdultABSTRACT
BACKGROUND/AIMS: To identify objective glaucoma-related structural features based on peripapillary (p) and macular (m) spectral domain optical coherence tomography (SD-OCT) parameters and assess their discriminative ability between healthy and glaucoma patients. METHODS: Two hundred and sixty eyes (91 controls and 169 glaucoma) were included in this prospective study. After a complete examination, all participants underwent the posterior pole and the peripapillary retinal nerve fibre layer (pRNFL) protocols of the Spectralis SD-OCT. Principal component analysis (PCA), a data reduction method, was applied to identify and characterise the main information provided by the ganglion cell complex (GCC). The discriminative ability between healthy and glaucomatous eyes of the first principal components (PCs) was compared with that of conventional SD-OCT parameters (pRNFL, macular RNFL (mRNFL), macular ganglion cell layer (mGCL)and macular inner plexiform layer (mIPL)) using 10-fold cross-validated areas under the curve (AUC). RESULTS: The first PC explained 58% of the total information contained in the GCC and the pRNFL parameters and was the result of a general combination of almost all variables studied (diffuse distribution). Other PCs were driven mainly by pRNFL and mRNFL measurements. PCs and pRNFL had similar AUC (0.95 vs 0.96, p=0.88), and outperformed the other structural measurements: mRNFL (0.91, p=0.002), mGCL (0.92, p=0.02) and mIPL (0.92, p=0.0001). CONCLUSIONS: PCA identified a diffuse representation of the papillary and macular SD-OCT parameters as the most important PC to summarise structural data in healthy and glaucomatous eyes. PCs and pRNFL parameters showed the greatest discriminative ability between healthy and glaucoma cases.
Subject(s)
Glaucoma/diagnosis , Optic Disk/pathology , Principal Component Analysis/methods , Retinal Ganglion Cells/pathology , Tomography, Optical Coherence/methods , Cross-Sectional Studies , Female , Follow-Up Studies , Glaucoma/physiopathology , Humans , Intraocular Pressure/physiology , Male , Middle Aged , Nerve Fibers/pathology , Prospective Studies , ROC CurveABSTRACT
PURPOSE: To present long-term results of modified bleb-limiting conjunctivoplasty as a successful treatment for intractable bleb dysesthesia and to review the literature on the surgical management of dysesthetic bleb. METHODS: Consecutive case series and literature review. We present four cases of surgically reduced painful blebs. Our technique consisted of the following steps: (1) conjunctival, radial incision to the bare sclera in the desired limit of the bleb; (2) suturing with buried, interrupted sutures at the nearest edge of the filtering bleb; (3) lower limbal peritomy including unwanted area of the extended bleb; (4) dissection and removal of the underlying fibrous tissue when present; (5) conjunctival and resorbable sutures. In addition, a systematic literature review was performed. Only reports presenting outcomes of surgical treatment of bleb dysesthesia after filtering procedure were included in review. RESULTS: Four eyes were included consecutively in the study in a period of 4 years. On average, they developed circumferential bleb dysesthesia 9.3 ± 4.7 months after uneventful combined phacotrabeculectomy with Mitomycin C as primary procedure. Surgical reduction was decided after failure of lubricants in controlling ocular discomfort. Two cases showed a dense fibrous tissue beneath the conjunctiva that was excised to ensure filtration. In all cases, a rapid disappearance of symptoms with very good aesthetic and functional outcome was observed. After 12-month follow-up, patients remained asymptomatic and maintained intraocular pressure of 10.7 ± 1.2 mmHg without treatment. A systematic review of the literature obtained 15 eligible case series (n = 123) with rates of success within 46-100%, favoring less aggressive approaches to reduce bleb size. CONCLUSION: Bleb dysesthesia is a rare complication of filtering glaucoma surgery. This modified bleb-limiting conjunctivoplasty technique (with removal of subjacent fibrous tissue if present) is able to target the underlying etiology providing ocular discomfort relief while maintaining bleb function and may be considered as first-choice surgical treatment.
ABSTRACT
During myogenesis, a long splice variant of STIM1, called STIM1L is getting expressed, while the level of STIM1 remains constant. Previous work demonstrated that STIM1L is more efficient in eliciting store-operated Ca2+ entry (SOCE), but no current analysis of the channel(s) activated by this new STIM1L isoform was performed until now. In this study, we investigate the ionic channel(s) activated by STIM1L and whether differences exist between the two STIM1 isoforms, using HEK-293 T cells as a model system. Our data show that STIM1 and STIM1L activate Orai1 channel but also the endogenously expressed TRPC1. The channel activation occurs in two steps, with first Orai1 activation followed, in a subset of cells, by TRPC1 opening. Remarkably, STIM1L more frequently activates TRPC1 and preferentially interacts with TRPC1. In low intracellular Ca2+ buffering condition, the frequency of TRPC1 opening increases significantly, strongly suggesting a Ca2+-dependent channel activation. The ability of STIM1L to open Orai1 appears decreased compared to STIM1, which might be explained by its stronger propensity towards TRPC1. Indeed, increasing the amount of STIM1L results in an enhanced Orai1 current. The role of endogenous TRPC1 in STIM1- and STIM1L-induced SOCE was confirmed by Ca2+ imaging experiments. Overall, our findings provide a detailed analysis of the channels activated by both STIM1 isoforms, revealing that STIM1L is more prone to open TRPC1, which might explain the larger SOCE elicited by this isoform.
Subject(s)
Calcium Signaling , Calcium/metabolism , Ion Channel Gating , Neoplasm Proteins/metabolism , Stromal Interaction Molecule 1/metabolism , TRPC Cation Channels/metabolism , Alternative Splicing/genetics , Egtazic Acid/analogs & derivatives , Egtazic Acid/metabolism , HEK293 Cells , Humans , Protein BindingABSTRACT
The authors present the first case of macular hole (MH) after a single inhalation of poppers. A 13-year-old girl presented with vision loss in the left eye (OS). Pediatric and neurology exams were normal. Funduscopy revealed bilateral papilledema and yellow foveal spot OS. Optic neuritis was diagnosed and treated. Due to foveal alteration, optical coherence tomography was performed, and MH was diagnosed. Twenty-three-gauge pars plana vitrectomy, peeling of the internal limiting membrane, and SF6 exchange were performed. Postoperatively, vision restoration and MH closure were observed. Although MH mechanism in the poppers context is unknown, the classic surgery is effective. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:897-900.].
Subject(s)
Fluorescein Angiography/methods , Illicit Drugs/adverse effects , Macula Lutea/pathology , Retinal Perforations/chemically induced , Tomography, Optical Coherence/methods , Visual Acuity , Administration, Inhalation , Adolescent , Female , Fundus Oculi , Humans , Retinal Perforations/diagnosis , Retinal Perforations/surgery , VitrectomyABSTRACT
PURPOSE: To present the outcomes of hybrid multifocal and monofocal intraocular lenses (IOLs) and to compare with refractive and diffractive multifocal IOLs (MFIOLs). METHODS: Three hundred twenty eyes (160 patients) underwent cataract surgery with randomized IOLs bilateral implantation. Changes in uncorrected and distance-corrected logMAR distance, intermediate and near (UNVA and DCNVA) visual acuity (VA), contrast sensitivity (CS), presence of dysphotopsia, spectacle independence, and patient satisfaction were analyzed. RESULTS: Postoperative VA in the hybrid (OptiVis) group was improved in all distances (p < 0.001). OptiVis acted superiorly to monofocal IOLs in UNVA and DCNVA (p < 0.001 for both) and to refractive ones in DCNVA (p < 0.005). Distance, mesopic, without glare CS in OptiVis was lower than in the monofocal group and similar to other MFIOLs. No differences in dysphotopsia pre- and postoperatively and spectacle independence in near for OptiVis and refractive MFIOLs were detected. OptiVis patients were more satisfied than those with monofocal IOLs (p=0.015). CONCLUSIONS: After cataract surgery, patients with OptiVis improved VA in all distances. Near and intermediate VA was better than monofocal, and DCNVA was better than the refractive group. CS was lower in OptiVis than in the monofocal group, but there was no difference between MFIOLs. Patient satisfaction was higher in OptiVis than in the monofocal group. This trial is registered with NCT03512626.
ABSTRACT
PURPOSE: To evaluate the visual outcomes and complications of phacoemulsification in previously vitrectomized eyes. PATIENTS AND METHODS: A retrospective analysis of 87 consecutive vitrectomized eyes (87 patients) which had undergone phacoemulsification with intraocular lens implantation between 2013 and 2016. RESULTS: The mean interval from pars plana vitrectomy (PPV) to cataract surgery (CS) was 18.8 months. Mean age at CS was 61.5 years. Intraoperative complications included anterior rhexis tear (1 eye) and hyphema (1 eye). Postoperative complications included macular edema (17.2%, mean 42 days), posterior capsule opacification (13.8%, mean 14 months), ocular hypertension (11.5%), and anterior uveitis (1.1%). Preoperative mean best-corrected visual acuity improved from 20/50 to 20/25. Ninety-one percent of the eyes gained 2 or more lines, and 95% achieved visual acuity ≥20/40 after CS. Preoperative mean spherical equivalent improved from -4.35 to -0.17. Eyes with clear lens prior to the PPV had later CS (clear lens 27.1 vs no clear lens 9.7 months; p=0.016). Patients >55 years with clear lens at PPV (n=21) had earlier CS than younger ones with clear lens (n=24) (11.8 vs 40.5 months; p=0.033). Mean follow-up was 14.5 months. CONCLUSION: Phacoemulsification is a safe procedure in vitrectomized eyes, with substantial gains in vision in most cases. Patients of advanced age and eyes without clear lens prior to the PPV had earlier CS.
ABSTRACT
PURPOSE: To evaluate the accuracy of the macular retinal layer segmentation software of the Spectralis spectral-domain (SD) optical coherence tomography (OCT) device (Heidelberg Engineering, Inc., Heidelberg, Germany) to discriminate between healthy and early glaucoma (EG) eyes. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Forty EG eyes and 40 healthy controls were included. METHODS: All participants were examined using the standard posterior pole and the peripapillary retinal nerve fiber layer (pRNFL) protocols of the Spectralis OCT device. Using an Early Treatment Diagnostic Retinopathy Study circle at the macular level, the automated retinal segmentation software was applied to determine thicknesses of the following parameters: total retinal thickness, inner retinal layer (IRL), macular retinal nerve fiber layer (mRNFL), macular ganglion cell layer (mGCL), macular inner plexiform layer (mIPL), macular inner nuclear layer (mINL), macular outer plexiform layer (mOPL), macular outer nuclear layer (mONL), photoreceptors (PR), and retinal pigmentary epithelium (RPE). The ganglion cell complex (GCC) was determined by adding the mRNFL, mGCL, and mIPL parameters and the ganglion cell layer-inner plexiform layer (mGCL-IPL) was determined by combining the mGCL and mIPL parameters. Thickness of each layer was compared between the groups, and the layer and sector with the best area under the receiver operating characteristic curve (AUC) were identified. MAIN OUTCOME MEASURES: Comparison of pRNFL, IRL, mRNFL, mGCL, mIPL, mGCC, mGCL-IPL, mINL, mOPL, mONL, PR, and RPE parameters and total retinal thicknesses between groups for the different areas and their corresponding AUCs. RESULTS: Peripapillary RNFL was significantly thinner in the EG group globally and in all 6 sectors assessed (P < 0.0005). For the macular variables, retinal thickness was significantly reduced in the EG group for total retinal thickness, mIRL, mRNFL, mGCL, and mIPL. The 2 best isolated parameters to discriminate between the 2 groups were pRNFL (AUC, 0.956) and mRNFL (AUC, 0.906). When mRNFL, mGCL, and mIPL measurements were combined (mGCC and mGCL plus mIPL), then its diagnostic performance improved (AUC, 0.940 and 0.952, respectively). CONCLUSIONS: Macular RNFL, mGCL-IPL, and mGCC measurements showed a high diagnostic capability to discriminate between healthy and EG participants. However, macular intraretinal measurements still have not overcome standard pRNFL parameters.
Subject(s)
Glaucoma/diagnosis , Nerve Fibers/pathology , Optic Disk/pathology , Retinal Ganglion Cells/pathology , Tomography, Optical Coherence/methods , Adult , Aged , Aged, 80 and over , Area Under Curve , Cross-Sectional Studies , Female , Humans , Intraocular Pressure , Male , Middle Aged , Photography , Prospective Studies , Reproducibility of Results , Visual Field Tests , Visual FieldsABSTRACT
BACKGROUND: We report the enhanced depth imaging optical coherence tomography (EDI-OCT) characteristics and variations in a patient with subretinal fluid secondary to a carotid cavernous fistula. CASE PRESENTATION: A 59-year-old man presented with blurred vision in his right eye. Venous congestion of the epiescleral and retinal vessels were observed. EDI-OCT disclosed macular subretinal fluid with an increase of choroidal thickness up to 341 µm. Brain and orbital computerized tomography showed an enlarged right superior ophthalmic vein. Orbital magnetic resonance imaging and angiography disclosed a decrease in blood flow, an indirect sign of carotid cavernous fistula. After a 3 months follow-up, spontaneous closure of the fistula occurred. Both the dilation of the conjunctiva and retinal veins improved. EDI-OCT showed resolution of the subfoveal fluid and a reduction of the subfoveal choroidal thickness to 271 µm after a 3 months follow-up and 168 µm after a 8 months follow-up. CONCLUSION: Serous retinal detachment has been described as a rare complication of carotid cavernous fistula. In our patient, EDI-OCT examinations revealed a thicker choroidal thickness when subretinal fluid was present as compared to that observed in the contralateral eye or after subretinal fluid resolution.
Subject(s)
Carotid-Cavernous Sinus Fistula/pathology , Choroid/pathology , Retinal Detachment/pathology , Fluorescein Angiography , Humans , Male , Middle Aged , Remission, Spontaneous , Tomography, Optical CoherenceABSTRACT
PURPOSE: To present the visual outcome and postoperative complications of pars plana vitrectomy and intraocular lenses (IOL) removal with or without IOL exchange of late in-the-bag IOL dislocation after uneventful cataract surgery. METHODS: Retrospective analysis of a consecutive series of 83 eyes with late in-the-bag dislocated IOL treated with pars plana vitrectomy and anterior chamber IOL (25 eyes), transscleral suture-fixated posterior chamber IOL (38 eyes), or aphakia (20 eyes). RESULTS: High myopia was the major predisposing factor (40%). The interval between cataract surgery and the dislocation was 10.9 years. The complication rate after the second surgery was 43%; being transient hypotony (19%) and hypertension (15%) the most frequent. Postoperative best-corrected visual acuity improvement was statistically significant (P < 0.001), with a mean of 3 Snellen lines. This improvement was also significant in 2 subgroups, patients with sutured posterior chamber IOL (20/80-20/40; P < 0.001) and in patients with anterior chamber IOL (20/125-20/40; P < 0.001). However, best-corrected visual acuity did not improve in aphakic patients (20/63-20/63; P = 0.13). Postoperative astigmatism increased significantly (P < 0.001), with a mean of -1 D. Mean follow-up was 24 months. CONCLUSION: The major predisposing factor for late in-the-bag IOL dislocation is myopia. Despite a complication rate of 43%, mostly minor and transient, IOL exchange surgery is an effective procedure with a good visual outcome (mean 3 Snellen lines improvement). There were no statistically significant differences in the final best-corrected visual acuity or complication rate between anterior chamber IOL and sutured posterior chamber IOL, thus, both surgical techniques may be considered to treat this condition.
Subject(s)
Artificial Lens Implant Migration/surgery , Lens Implantation, Intraocular , Lenses, Intraocular , Vitrectomy , Adolescent , Adult , Aged , Aged, 80 and over , Artificial Lens Implant Migration/physiopathology , Child , Child, Preschool , Device Removal , Female , Follow-Up Studies , Humans , Male , Middle Aged , Myopia, Degenerative/diagnosis , Postoperative Complications , Reoperation , Retrospective Studies , Suture Techniques , Visual Acuity/physiologyABSTRACT
There is a growing body of evidence that near infrared (NIR) light exerts beneficial effects on cells. Its usefulness in the treatment of cancer, acute brain injuries, strokes and neurodegenerative disorders has been proposed. The mechanism of the NIR action is probably of photochemical nature, however it is not fully understood. Here, using a relatively simple biological model, human red blood cells (RBCs), and a polychromatic non-polarized light source, we investigate the impact of NIR radiation on the oxygen carrier, hemoglobin (Hb), and anion exchanger (AE1, Band 3). The exposure of intact RBCs to NIR light causes quaternary transitions in Hb, dehydration of proteins and decreases the amount of physiologically inactive methemoglobin, as detected by Raman spectroscopy. These effects are accompanied by a lowering of the intracellular pH (pHi) and changes in the cell membrane topography, as documented by atomic force microscopy (AFM). All those changes are in line with our previous studies where alterations of the membrane fluidity and membrane potential were attributed to NIR action on RBCs. The rate of the above listed changes depends strictly on the dose of NIR light that the cells receive, nonetheless it should not be considered as a thermal effect.
Subject(s)
Anion Exchange Protein 1, Erythrocyte/metabolism , Erythrocytes/metabolism , Hemoglobins/metabolism , Infrared Rays , Protein Processing, Post-Translational/radiation effects , Humans , Hydrogen-Ion ConcentrationSubject(s)
Anemia, Iron-Deficiency/diagnosis , Retinal Diseases/diagnosis , Anemia, Iron-Deficiency/blood , Anemia, Iron-Deficiency/therapy , Erythrocyte Transfusion , Ferritins/blood , Humans , Iron/blood , Iron Compounds/therapeutic use , Male , Middle Aged , Retinal Diseases/blood , Retinal Diseases/therapy , Visual Acuity , Visual FieldsABSTRACT
OBJECTIVE: To assess whether autoantibodies against ribosomal P (anti-P), which are possibly pathogenic in neuropsychiatric systemic lupus erythematosus (NPSLE), alter glutamatergic synaptic transmission and to what extent the cross-reacting neuronal surface P antigen (NSPA) is involved. METHODS: We analyzed glutamatergic transmission and long-term potentiation (LTP) mediated by AMPA receptor (AMPAR) and N-methyl-d-aspartate receptor (NMDAR) by field excitatory postsynaptic potential (EPSP) at the CA3-CA1 synapse. AMPAR activation by patch-clamp recordings in primary ventral spinal cord neurons was analyzed. In primary hippocampal neurons, NSPA distribution was assessed by double immunofluorescence, and intracellular calcium changes were evaluated using Fura-2 AM. NSPA-LacZ reporter-knockin mice expressing a truncated NSPA were used to assess NSPA expression pattern and function in the brain using ß-galactosidase staining and comparative electrophysiology, calcium responses, and water maze memory tests. RESULTS: NSPA was expressed in the brain in hippocampal CA1, dentate gyrus and ventral, but not dorsal, CA3 regions, encompassing postsynaptic regions and partial colocalization with NMDAR. Notably, NSPA-LacZ reporter-knockin mice showed impaired memory, and decreased NMDAR activity and LTP, with neurons insensitive to anti-P autoantibodies. Anti-P autoantibodies enhanced CA1 postsynaptic transmission, increasing AMPAR and NMDAR activity and leading to LTP abrogation after prolonged (20-minute) incubation. CONCLUSION: Our findings indicate that the neuronal cell surface target of anti-P, NSPA, is involved in glutamatergic synaptic transmission and plasticity related to memory in the hippocampus, and mediates the deleterious effects of anti-P on these processes. Cognitive impairment, as well as other diffuse NPSLE manifestations, may develop when anti-P autoantibodies have access to brain regions coexpressing NSPA, AMPAR, and NMDAR.