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Seminars in Ophthalmology Aug 2023To determine whether the temporal-superior or the nasal-superior iris area becomes thinner (more optimal) for laser peripheral iridotomy (LPI) after pilocarpine...
Effect of Topical Pilocarpine Instilled Before Laser Peripheral Iridotomy on Regional Iris Thickness in Primary Angle Closure Disease: A Swept-Source Anterior Segment Optical Coherence Tomography Pilot Study.
PURPOSE
To determine whether the temporal-superior or the nasal-superior iris area becomes thinner (more optimal) for laser peripheral iridotomy (LPI) after pilocarpine instillation in primary angle closure disease (PACD); and to identify an angle for optimal penetration of the laser beam.
PATIENTS AND METHODS
Iris thickness at 2 mm from the iris root in the preset scanning axes was measured using swept-source anterior segment optical coherence tomography before and 60 minutes after the instillation of pilocarpine 2% in one eye of 30 consecutive Japanese PACD patients with thick, dark brown iris. Iris thickness at 1:30 and 10:30 clock hour positions were evaluated in sagittal and oblique directions, resulting sagittal iris thickness (SIT) and minimum iris thickness (MIT) parameters, respectively.
RESULTS
Compared to the baseline values, iris thickness decreased significantly (P < .001) in both locations after pilocarpine instillation. Both before and after pilocarpine instillation the temporal-superior iris thickness was significantly smaller than the nasal-superior thickness (P ≤ .001). After pilocarpine instillation, the temporal-superior iris was significantly thinner in an approximately 13° angle direction temporal to the sagittal direction than in the sagittal direction (MIT: 0.322 mm; SIT: 0.346 mm, P < .001).
CONCLUSIONS
After pilocarpine instillation, the temporal-superior iris and an approximately 13° angle temporal to the sagittal direction may provide an optimal location and laser beam angle for LPI in PACD eyes.
Topics: Humans; Pilocarpine; Pilot Projects; Anterior Eye Segment; Iridectomy; Tomography, Optical Coherence; Glaucoma, Angle-Closure; Intraocular Pressure; Gonioscopy; Prospective Studies; Iris; Laser Therapy
PubMed: 36715463
DOI: 10.1080/08820538.2023.2169580 -
Acta Stomatologica Croatica Sep 2023Guanylin peptides are considered to be the only intrinsic regulators of salivary glands secretion. Therefore, the aim of this study was to determine the effects of...
OBJECTIVES
Guanylin peptides are considered to be the only intrinsic regulators of salivary glands secretion. Therefore, the aim of this study was to determine the effects of systemic uroguanylin (UGN) of the salivary flow and ion composition. Besides, the objective was to investigate whether those effects include activation of guanylate cyclase C (GC-C).
MATERIAL AND METHODS
This study was conducted on 7 months old C57Bl6NCrl (wild type, WT) and GC-C knockout (KO) mice. Salivary flow rate and ion composition were determined after pilocarpine stimulation with UGN (30 µg/animal) or saline i.p. application. The expression of mRNA for AQPs, NHEs, NBCn1, Slc26a3/a6 and CFTR were determined by qPCR in submandibular salivary glands.
RESULTS
When applied i.p., UGN decreased the pilocarpine stimulated saliva flow rate and increased the concentration of Na, H and Cl. In GC-C KO mice, UGN showed no effect on saliva flow rate, while the concentrations of Na, H and Cl are the same in GC-C KO littermates when compared to WT mice. UGN increased expression of Slc26a6 while in GC-C KO mice Slc26a6 had a higher expression when compared to WT mice, suggesting involvement of GC-C independent signalling pathway for UGN. The difference in Slc26a6 in GC-C KO mice is not unique for salivary glands because it was also found in duodenum and kidney cortex.
CONCLUSIONS
The effects of UGN via basolateral membrane of salivary glands cells have not been considered up to date. In our study, UGN, when applied i.p., decreased salivary flow rate, pH, and changed the composition of other ions. Therefore, plasma UGN, an hour after a meal, could have physiological and pathological importance (development of cavities, inflammations or demineralizations), and the inhibition of systemic UGN effects could be considered a new approach in treatment of those conditions.
PubMed: 37808412
DOI: 10.15644/asc57/3/8 -
Brain : a Journal of Neurology May 2024Alterations in the extracellular matrix are common in patients with epilepsy and animal models of epilepsy, yet whether they are the cause or consequence of seizures and...
Alterations in the extracellular matrix are common in patients with epilepsy and animal models of epilepsy, yet whether they are the cause or consequence of seizures and epilepsy development is unknown. Using Theiler's murine encephalomyelitis virus (TMEV) infection-induced model of acquired epilepsy, we found de novo expression of chondroitin sulfate proteoglycans (CSPGs), a major extracellular matrix component, in dentate gyrus (DG) and amygdala exclusively in mice with acute seizures. Preventing the synthesis of CSPGs specifically in DG and amygdala by deletion of the major CSPG aggrecan reduced seizure burden. Patch-clamp recordings from dentate granule cells revealed enhanced intrinsic and synaptic excitability in seizing mice that was significantly ameliorated by aggrecan deletion. In situ experiments suggested that dentate granule cell hyperexcitability results from negatively charged CSPGs increasing stationary cations on the membrane, thereby depolarizing neurons, increasing their intrinsic and synaptic excitability. These results show increased expression of CSPGs in the DG and amygdala as one of the causal factors for TMEV-induced acute seizures. We also show identical changes in CSPGs in pilocarpine-induced epilepsy, suggesting that enhanced CSPGs in the DG and amygdala may be a common ictogenic factor and potential therapeutic target.
Topics: Animals; Dentate Gyrus; Amygdala; Chondroitin Sulfate Proteoglycans; Mice; Seizures; Male; Theilovirus; Mice, Inbred C57BL; Disease Models, Animal; Mice, Knockout; Aggrecans; Neurons
PubMed: 38146224
DOI: 10.1093/brain/awad430 -
Biomedicines Oct 2023The trabecular meshwork is an important structure in the outflow pathway of aqueous humor, and its movement ability directly affects the resistance of aqueous humor...
The trabecular meshwork is an important structure in the outflow pathway of aqueous humor, and its movement ability directly affects the resistance of aqueous humor outflow, thereby affecting the steady state of intraocular pressure (IOP). (1) Objective: The purpose of this study was to preliminarily estimate the effects of pilocarpine eye drops and trabeculotomy tunneling trabeculoplasty (3T) on trabecular meshwork (TM) pulsatile motion via phase-sensitive optical coherence tomography (Phs-OCT). (2) Method: In a prospective single-arm study, we mainly recruited patients with primary open-angle glaucoma who did not have a history of glaucoma surgery, and mainly excluded angle closure glaucoma and other diseases that may cause visual field damage. The maximum velocity (MV) and cumulative displacement (CDisp) of the TM were quantified via Phs-OCT. All subjects underwent Phs-OCT examinations before and after the use of pilocarpine eye drops. Then, all subjects received 3T surgery and examinations of IOP at baseline, 1 day, 1 week, 1 month, 3 months, and 6 months post-surgery. Phaco-OCT examinations were performed at 3 and 6 months post-surgery, and the measurements were compared and analyzed. (3) Results: The MV of TM before and after the use of pilocarpine eye drops was 21.32 ± 2.63 μm/s and 17.00 ± 2.43 μm/s. The CDisp of TM before and after the use of pilocarpine eye drops was 0.204 ± 0.034 μm and 0.184 ± 0.035 μm. After the use of pilocarpine eye drops, both the MV and CDisp significantly decreased compared to those before use ( < 0.001 and 0.013, respectively). The IOP decreased from baseline at 22.16 ± 5.23 mmHg to 15.85 ± 3.71 mmHg after 3 months post-surgery and from 16.33 ± 2.51 mmHg at 6 months post-surgery, showing statistically significant differences ( < 0.001). The use of glaucoma medication decreased from baseline at 3.63 ± 0.65 to 1.17 ± 1.75 at 3 months and 1.00 ± 1.51 at 6 months post-surgery; the differences were statistically significant ( < 0.001). Additionally, there was no statistically significant difference in the MV between 3 and 6 months after surgery compared to baseline ( = 0.404 and 0.139, respectively). Further, there was no statistically significant difference in the CDisp between 3 and 6 months after surgery compared to baseline ( = 0.560 and 0.576, respectively) (4) Conclusions: After the preliminary study, we found that pilocarpine eye drops can attenuate TM pulsatile motion, and that 3T surgery may reduce IOP without affecting the pulsatile motion status of the TM.
PubMed: 38001932
DOI: 10.3390/biomedicines11112932 -
Pediatric Research Mar 2024Although previous studies show that microRNAs (miRNAs) can potentially be used as diagnostic markers for epilepsy, there are very few analyses of pediatric epilepsy...
BACKGROUND
Although previous studies show that microRNAs (miRNAs) can potentially be used as diagnostic markers for epilepsy, there are very few analyses of pediatric epilepsy patients.
METHODS
miRNA profiles using miRNA-seq was performed on plasma samples from 14 pediatric epileptic patients and 14 healthy children. miRNA miR-27a-3p that were significantly changed between two groups were further evaluated. The potential target genes of miR-27a-3p were screened through unbiased mRNA-seq and further validated using Western blot and immunohistochemistry in HEK-293T cells and in the brains of mice with epilepsy induced by lithium chloride-pilocarpine.
RESULTS
We found 82 upregulated and 76 downregulated miRNAs in the plasma from pediatric patients compared with controls (p < 0.01), of which miR-27a-3p exhibited a very low p value (p < 0.0001) and validated in additional plasma samples. Two genes, GOLM1 and LIMK1, whose mRNA levels were decreased (p < 0.001) with the increase of miR-27a-3p were further validated in both HEK-293T cells and in epileptic mice.
CONCLUSIONS
MiR-27a-3p exhibits potential as a diagnostic and therapeutic marker for epilepsy. We postulate that additional studies on the downstream targets of miR-27a-3p will unravel its roles in epileptogenesis or disease progression.
IMPACT
A total of 158 differentially expressed miRNAs were detected in plasma between epileptic and control children. Plasma miR-27a-3p was one of the miRNAs with a low p value. GOLM1 and LIMK1 were validated as downstream target genes of miR-27a-3p. miR-27a-3p has potential as a diagnostic and therapeutic marker for epilepsy.
Topics: Humans; Mice; Animals; Child; MicroRNAs; Epilepsy; Biomarkers; Brain; RNA, Messenger; Lim Kinases; Membrane Proteins
PubMed: 37884644
DOI: 10.1038/s41390-023-02864-z -
International Journal of Molecular... Oct 2023Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is...
Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is primary brain injury, making prevention of epileptogenesis after the initial event an optimal method of treatment. Despite this, no preventive therapy for epilepsy is currently available. The purpose of this study was to evaluate the effects of anakinra, lamotrigine, and their combination on epileptogenesis using the rat lithium-pilocarpine model of temporal lobe epilepsy. The study showed that there was no significant difference in the number and duration of seizures between treated and untreated animals. However, the severity of seizures was significantly reduced after treatment. Anakinra and lamotrigine, alone or in combination, significantly reduced neuronal loss in the CA1 hippocampus compared to the control group. However, the drugs administered alone were found to be more effective in preventing neuron loss in the hippocampal CA3 field compared to combination treatment. The treatment alleviated the impairments in activity level, exploratory behavior, and anxiety but had a relatively weak effect on TLE-induced impairments in social behavior and memory. The efficacy of the combination treatment did not differ from that of anakinra and lamotrigine monotherapy. These findings suggest that anakinra and lamotrigine, either alone or in combination, may be clinically useful in preventing the development of histopathological and behavioral abnormalities associated with epilepsy.
Topics: Rats; Animals; Epilepsy, Temporal Lobe; Pilocarpine; Lamotrigine; Lithium; Interleukin 1 Receptor Antagonist Protein; Anticonvulsants; Seizures; Hippocampus; Disease Models, Animal
PubMed: 37895080
DOI: 10.3390/ijms242015400 -
Molecular Neurobiology Sep 2023Epilepsy is one of the most common neurological disorders. The pro-epileptic and antiepileptic roles of microglia have recently garnered significant attention....
Epilepsy is one of the most common neurological disorders. The pro-epileptic and antiepileptic roles of microglia have recently garnered significant attention. Interleukin-1 receptor-associated kinase (IRAK)-M, an important kinase in the innate immune response, is mainly expressed in microglia and acts as a negative regulator of the TLR4 signaling pathway that mediates the anti-inflammatory effect. However, whether IRAK-M exerts a protective role in epileptogenesis as well as the molecular and cellular mechanisms underlying these processes are yet to be elucidated. An epilepsy mouse model induced by pilocarpine was used in this study. Real-time quantitative polymerase chain reaction and western blot analysis were used to analyze mRNA and protein expression levels, respectively. Whole-cell voltage-clamp recordings were employed to evaluate the glutamatergic synaptic transmission in hippocampal neurons. Immunofluorescence was utilized to show the glial cell activation and neuronal loss. Furthermore, the proportion of microglia was analyzed using flow cytometry. Seizure dynamics influenced the expression of IRAK-M. Its knockout dramatically exacerbated the seizures and the pathology in epilepsy and increased the N-methyl-d-aspartate receptor (NMDAR) expression, thereby enhancing glutamatergic synaptic transmission in hippocampal CA1 pyramidal neurons in mice. Furthermore, IRAK-M deficiency augmented hippocampal neuronal loss via a possible mechanism of NMDAR-mediated excitotoxicity. IRAK-M deletion promotes microglia toward the M1 phenotype, which resulted in high levels of proinflammatory cytokines and was accompanied by a visible increase in the expressions of key microglial polarization-related proteins, including p-STAT1, TRAF6, and SOCS1. The findings demonstrate that IRAK-M dysfunction contributes to the progression of epilepsy by increasing M1 microglial polarization and glutamatergic synaptic transmission. This is possibly related to NMDARs, particularly Grin2A and Grin2B, which suggests that IRAK-M could serve as a novel therapeutic target for the direct alleviation of epilepsy.
Topics: Mice; Animals; Microglia; Neuroinflammatory Diseases; Interleukin-1 Receptor-Associated Kinases; Status Epilepticus; Seizures; Epilepsy
PubMed: 37277682
DOI: 10.1007/s12035-023-03407-7 -
Clinical & Experimental Optometry Dec 2023Patients prescribed pilocarpine ophthalmic solution are advised to be cautious when driving at night, but studies evaluating the effects of pilocarpine hydrochloride...
CLINICAL RELEVANCE
Patients prescribed pilocarpine ophthalmic solution are advised to be cautious when driving at night, but studies evaluating the effects of pilocarpine hydrochloride ophthalmic solution 1.25% (pilo), approved to treat presbyopia, on driving at night are lacking.
BACKGROUND
This double-masked, crossover, phase 3b study evaluated night-driving performance with pilo or the placebo once daily.
METHODS
Forty-three adults (40-55 years) with presbyopia impacting daily activities and mesopic, high-contrast, binocular distance-corrected near vision 6/12-6/30 were randomised to bilateral treatment with pilo followed by placebo or placebo followed by pilo (with a ≥7-day washout between interventions). Night-driving performance was evaluated at twilight at a closed-circuit course. Primary efficacy endpoint: overall composite night-driving performance Z score at the end of the 7-14-day intervention period, 1 hour post-instillation. Pilo was considered non-inferior if the lower limit of the 95% confidence interval (CI) for the least squares mean difference (LSMD, pilo minus placebo) was >-0.25. Other efficacy endpoints: individual components of the night-driving performance test (hazard avoidance rate; road sign recognition rate and distance; pedestrians recognition distance; overall driving and lane-keeping times) and night-driving experience questionnaire. Safety included treatment-emergent adverse events (TEAEs).
RESULTS
The mean overall composite Z scores were -0.121 (pilo) and 0.118 (placebo). The LSMD (pilo minus placebo) was -0.224 (95% CI, -0.346, -0.103), with 3 of the 7 individual tasks being significantly better with the placebo. The questionnaire did not reveal significant differences between pilo and the placebo. There were no serious or severe TEAEs and no TEAE-related discontinuations. The most common ocular TEAEs were headache and visual impairment with pilo (both 27.9%), and dry eye (7.0%) with the placebo.
CONCLUSION
The overall performance of night driving was inferior with pilo, compared with placebo. The study findings are consistent with the current class labelling and provide evidence to inform regulators and assist clinicians considering prescribing pilo to adults who seek treatment of presbyopia symptoms and drive at night. NCT04837482.
PubMed: 38044272
DOI: 10.1080/08164622.2023.2279189 -
European Archives of... Jul 2024This study aims to investigate the efficacy of lower dose pilocarpine in alleviating late dry mouth symptoms in head and neck cancer patients received radiotherapy.
Does lower dose pilocarpine have a role in radiation-induced xerostomia in the modern radiotherapy era? A single-center experience based on patient-reported outcome measures.
PURPOSE
This study aims to investigate the efficacy of lower dose pilocarpine in alleviating late dry mouth symptoms in head and neck cancer patients received radiotherapy.
METHODS
Eighteen head and neck cancer patients experiencing persistent dry mouth were enrolled in this study. All participants started pilocarpine treatment a median of 6 months post-radiotherapy. Initially, patients received pilocarpine at 5 mg/day, with a gradual increase to the recommended dose of 15 mg/day. A Patient-Reported Outcome Measurement (PROMs) questionnaire assessed symptoms' severity related to hyposalivation.
RESULTS
All patients reported symptomatic dry mouth above grade 2 before starting the medication. Pilocarpine treatment continued based on patients' self-assessment, with a median duration of 12 months (range, 3-36 months). The median daily maintenance dose was 10 mg (range, 5 to 20 mg). Total PROMs scores significantly decreased following medication, from 13 points (range 7-18 points) to 7 points (range 4-13 points) (p = 0.001). Significant improvements were observed in questions related to dry mouth (p < 0.001), water intake during eating (p = 0.01), carrying water (p = 0.01), taste (p < 0.001), and water intake during speech (p < 0.001). Initial and maintenance doses of pilocarpine were lower, and the duration of pilocarpine usage was shorter in patients treated with intensity-modulated radiation therapy compared to conformal radiotherapy (12 months vs. 25 months, p = 0.04).
CONCLUSION
Pilocarpine may be considered at doses lower for late-term dry mouth. With modern radiotherapy techniques effectively preserving the parotid gland, short-term use may be recommended in these patients. Future studies may enhance the development of a more robust patient selection criteria model.
Topics: Humans; Xerostomia; Pilocarpine; Male; Female; Middle Aged; Patient Reported Outcome Measures; Head and Neck Neoplasms; Aged; Muscarinic Agonists; Radiation Injuries; Adult; Treatment Outcome
PubMed: 38573515
DOI: 10.1007/s00405-024-08616-x -
Biology Sep 2023d-serine has been observed in submandibular gland tissue in rats, but its functions remain to be clarified. Oral administration of d-serine, but not l-serine, increased...
d-serine has been observed in submandibular gland tissue in rats, but its functions remain to be clarified. Oral administration of d-serine, but not l-serine, increased its concentrations in the submandibular gland and pilocarpine-induced salivary secretion. In vivo microdialysis was used to collect the d- and l-enantiomers of amino acids from local interstitial fluid in the rat submandibular gland. The proportion of the d-form of serine in interstitial fluid was higher than that in plasma or saliva. Perfusion of the rat submandibular gland with d-serine and l-glutamic acid via the submandibular gland artery resulted in a significant increase in salivary secretion after stimulation of muscarinic receptors with carbachol. In vivo microdialysis applied to the submandibular glands of rats showed that infusion of d-serine along with l-glutamate through the microdialysis probe significantly elevated acetylcholine levels in local interstitial fluids in the submandibular glands of anesthetized rats as compared to that with l-glutamate alone in an -methyl-d-aspartate receptor glycine site antagonist-sensitive manner. These results indicate that d-serine augments salivary secretion by increasing acetylcholine release in the salivary glands.
PubMed: 37759626
DOI: 10.3390/biology12091227