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1.
Optom Vis Sci ; 99(8): 632-634, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35848990

RESUMO

SIGNIFICANCE: The clinical utility of ophthalmic pilocarpine-induced pupil constriction to help overcome image blur of close-up targets in patients with failing accommodation is examined.Pilocarpine in low-concentration ophthalmic solution eye drops constricts the pupil to approximately 2 mm and thus reduces defocus blur. To gain regulatory approval of this drug for the treatment of presbyopia, clinical trials were conducted with 1.25% pilocarpine. Near vision was improved in a modest proportion of early presbyopes: between 12 and 22% more patients reached criterion near visual acuity than with a placebo, depending on conditions. The drug is well tolerated, and its effect has onset of only minutes and lasts several hours. Small pupils will cause diminished night vision and may have an impact on distance acuity to which possible minor drug-induced accommodative spasms could contribute. The therapy has a role for patients who want to postpone or briefly pause dioptric supplementation of their failing accommodation. No convincing case has been made for one version of ophthalmic pilocarpine over another.


Assuntos
Presbiopia , Acomodação Ocular , Humanos , Miose/induzido quimicamente , Miose/tratamento farmacológico , Soluções Oftálmicas , Pilocarpina , Pupila
2.
Int J Mol Sci ; 23(13)2022 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-35805973

RESUMO

Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) form a clinical continuum associating progressive muscle weakness with additional multi-systemic anomalies of the bones, skin, spleen, and platelets. TAM/STRMK arises from excessive extracellular Ca2+ entry due to gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1. Currently, no treatment is available. Here we assessed the therapeutic potential of ORAI1 downregulation to anticipate and reverse disease development in a faithful mouse model carrying the most common TAM/STRMK mutation and recapitulating the main signs of the human disorder. To this aim, we crossed Stim1R304W/+ mice with Orai1+/- mice expressing 50% of ORAI1. Systematic phenotyping of the offspring revealed that the Stim1R304W/+Orai1+/- mice were born with a normalized ratio and showed improved postnatal growth, bone architecture, and partly ameliorated muscle function and structure compared with their Stim1R304W/+ littermates. We also produced AAV particles containing Orai1-specific shRNAs, and intramuscular injections of Stim1R304W/+ mice improved the skeletal muscle contraction and relaxation properties, while muscle histology remained unchanged. Altogether, we provide the proof-of-concept that Orai1 silencing partially prevents the development of the multi-systemic TAM/STRMK phenotype in mice, and we also established an approach to target Orai1 expression in postnatal tissues.


Assuntos
Transtornos Plaquetários , Dislexia , Ictiose , Miopatias Congênitas Estruturais , Proteína ORAI1 , Animais , Transtornos Plaquetários/genética , Transtornos Plaquetários/metabolismo , Cálcio/metabolismo , Dislexia/genética , Dislexia/metabolismo , Eritrócitos Anormais , Ictiose/genética , Ictiose/metabolismo , Camundongos , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/metabolismo , Miose , Fadiga Muscular , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/metabolismo , Miopatias Congênitas Estruturais/patologia , Proteína ORAI1/genética , Proteína ORAI1/metabolismo , Fenótipo , Baço/anormalidades , Baço/metabolismo , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo
3.
Front Immunol ; 13: 917601, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35812399

RESUMO

Gain-of-function (GOF) mutations in STIM1 are responsible for tubular aggregate myopathy and Stormorken syndrome (TAM/STRMK), a clinically overlapping multisystemic disease characterised by muscle weakness, miosis, thrombocytopaenia, hyposplenism, ichthyosis, dyslexia, and short stature. Several mutations have been reported as responsible for the disease. Herein, we describe a patient with TAM/STRMK due to a novel L303P STIM1 mutation, who not only presented clinical manifestations characteristic of TAM/STRMK but also manifested immunological involvement with respiratory infections since childhood, with chronic cough and chronic bronchiectasis. Despite the seemingly normal main immunological parameters, immune cells revealed GOF in calcium signalling compared with healthy donors. The calcium flux dysregulation in the immune cells could be responsible for our patient's immune involvement. The patient's mother carried the mutation but did not exhibit TAM/STRMK, manifesting an incomplete penetrance of the mutation. More cases and evidence are necessary to clarify the dual role of STIM1 in immune system dysregulation and myopathy.


Assuntos
Dislexia , Ictiose , Miopatias Congênitas Estruturais , Transtornos Plaquetários , Cálcio/metabolismo , Criança , Dislexia/genética , Eritrócitos Anormais , Mutação com Ganho de Função , Humanos , Ictiose/genética , Transtornos de Enxaqueca , Miose/genética , Fadiga Muscular , Mutação , Miopatias Congênitas Estruturais/genética , Proteínas de Neoplasias/genética , Baço/anormalidades , Molécula 1 de Interação Estromal/genética
4.
Cell Calcium ; 105: 102605, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35636153

RESUMO

Gain-of-function mutations on STIM1 and ORAI1 genes are responsible for an increased store-operated calcium entry, and underlie the characteristic symptoms of three overlapping ultra-rare genetic disorders (i.e tubular aggregate myopathy, Stormorken syndrome, York platelet syndrome) that can be grouped as tubular aggregate myopathies. These mutations lead to a wide spectrum of defects, which usually include muscle weakness and cramps. Negative modulators of store-operated Ca2+-entry targeting wild-type STIM1 and ORAI1 have entered clinical trials for a different array of disorders, including pancreatitis, COVID-19, cancer, and autoimmune disorders and, while efficacy data is awaited, safety data indicates tolerability of this STIM1/ORAI1 mutations are amenable to pharmacological intervention. If this were so, given that there are no approved treatments or clinical trials ongoing for these rare disorders, it could be envisaged that these agents could also rehabilitate tubular aggregate myopathy patients. In the present contribution we characterized the Ca2+-entry patterns induced by eleven STIM1 and three ORAI1 mutations in heterologous systems or in patient-derived cells, i.e. fibroblasts and myotubes, and evaluated the effect of CIC-37 and CIC-39, two novel store-operated calcium entry modulators. Our data show that all STIM1 and ORAI1 gain-of-function mutations tested, with the possible exception of the R304Q STIM1 mutation, are amenable to inhibition, albeit with slightly different sensitivities, paving the way to the development of SOCE modulators in tubular aggregate myopathies.


Assuntos
COVID-19 , Miopatias Congênitas Estruturais , Transtornos Plaquetários , Cálcio/metabolismo , Dislexia , Eritrócitos Anormais , Humanos , Ictiose , Transtornos de Enxaqueca , Miose , Fadiga Muscular , Mutação/genética , Miopatias Congênitas Estruturais/genética , Proteínas de Neoplasias/genética , Proteína ORAI1/genética , Baço/anormalidades , Molécula 1 de Interação Estromal/genética
5.
Rom J Ophthalmol ; 66(1): 61-68, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35531448

RESUMO

Objective: To analyze the utility and the nuances of implanting the B-HEX® Pupil Expander (Med Invent Devices, India) at various stages in small pupil phacoemulsification. Methods: This prospective interventional case series was undertaken to assess the utility of B-Hex in small pupil phacoemulsification under topical anesthesia. Our series comprised of 50 cataract cases with small pupils of various etiologies, operated by a single surgeon at our private practice, beginning February 2018. Cataract cases with pharmacological dilation of < 4 mm underwent phacoemulsification with B-Hex implantation. It was employed at the outset or interim, whenever the need arose. Results: The B-Hex ring is extremely handy and useful in small pupil phacoemulsification. The average age of our study cohort was 62 years. In 38 cases B-Hex was employed before making a capsulorhexis. Progressive pupillary constriction during nuclear disassembly warranted the utilization of the device in 9 cases, while the remaining 3 cases had a retained epi-nuclear plate or significant cortex and the ring was placed after nucleus removal. No significant complication was noted. Postoperatively, the pupil dimensions, notably the architecture, were maintained. No significant AC reaction was noted. Intraocular pressure was not high. Conclusion: Our experience showed that B-Hex is secure and easy to use under topical anesthesia. The learning curve is shallow and the technique is precise. B-Hex is truly an ace up the sleeve.


Assuntos
Extração de Catarata , Catarata , Facoemulsificação , Humanos , Pessoa de Meia-Idade , Miose/cirurgia , Facoemulsificação/métodos , Estudos Prospectivos
6.
BMC Ophthalmol ; 22(1): 201, 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35501768

RESUMO

BACKGROUND: Congenital anomalies of the pupil are quite varied, including abnormal size, shape, color, response to stimulus, and function. We are here reporting an unusual case presented with the absence of pupillary opening with folds of iris tissue at the center. Only an extremely small pupil (diameter < 0.5 mm) could be observed during the operation. CASE PRESENTATION: A 15-year-old male patient visited our outpatient clinic due to vision difficulty in his right eye for more than ten years. The best-corrected visual acuity was 2.0 logMAR and 0 logMAR for the right and left eye, respectively. There were amblyopia, astigmatism and constant exotropia in his right eye. Ophthalmic examination of the right eye showed flat iris root, minimal iris pigmentation, and the pupil area was entirely covered by iris tissue. Lens status and fundus evaluation could not be commented. The left eye was found to be within normal limit. Based on ophthalmic examination, the admission diagnosis was given as acorea. Pupilloplasty was performed on the right eye due to the situation that the iris tissue blocked the visual axis, which led to visual impairment and stimulus deprivation amblyopia. However, an extremely small pupil at the center of his pupillary area was observed during the operation. The postoperative course was favorable, and a normal pupil was secured. Hospital discharge diagnosis was given as microcoria, and amblyopia treatment was followed. CONCLUSIONS: We report a rare case of congenital pupillary abnormality. The further diagnosis was given as microcoria, which should be differentiated from acorea. For this kind of pupil disorder which blocks the visual axis, early diagnosis and treatment can help prevent the development of stimulus deprivation amblyopia.


Assuntos
Ambliopia , Doenças da Íris , Distúrbios Pupilares , Adolescente , Ambliopia/complicações , Ambliopia/diagnóstico , Anormalidades do Olho , Humanos , Doenças da Íris/complicações , Masculino , Miose/complicações , Pupila , Distúrbios Pupilares/etiologia
7.
BMC Ophthalmol ; 22(1): 173, 2022 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-35436870

RESUMO

PURPOSE: To compare 6 methods for intraoperative pupil dilatation in eyes with insufficient pupil size during phacoemulsification. METHODS: This was a prospective case-control study. 99 microcoria cataract patients (120 eyes) were collected and were divided into 6 groups(20 eyes each group), and their pupils were dilated by bimanual stretching pupil (group I), pupil radial cut open(group II), mechanical pupil dilatation with iris-retractor hooks (group III), OASIS iris expander (group IV), and Malyguin-ring (Microsurgical company, America) (group V), B-HEX Pupil Expander (Med Invent Devics, India)(group VI),respectively. 3.0 mm clear corneal incision were used in phacoemulsification. All cases were followed up at 1 week and 1, 3, 6 months after the surgery. The best corrected visual acuity (BCVA), intraocular pressure(IOP), corneal endothelium cell density(ECD), pupil diameter(PD) of before and after surgery were compared. RESULTS: One same doctor finished all cataract surgeries successfully. The eyes' condition before surgery and at 6 months after surgery were compared. There were no significant statistical differences for the conditions of the eyes before surgery among six groups. The ECDs were better at 6 months postoperatively in group III and V, median values: 2114/mm2, 1961/mm2. PD was largest in group II (median value: 5.5 mm), which was significantly larger than other groups (Padjusted < 0.05). CONCLUSIONS: All 6 methods used in this study were effective for the mechanical dilatation of small pupils and didn't affect the postoperative visual acuity and intraocular pressure in microcoria cataract phacoemulsification. Iris-retractor hooks and the Malyugin Ring can reduce intraoperative corneal endothelium cell loss. Postoperative PD is larger when the iris was cut open radially.


Assuntos
Catarata , Doenças da Íris , Midríase , Facoemulsificação , Distúrbios Pupilares , Estudos de Casos e Controles , Dilatação , Anormalidades do Olho , Humanos , Doenças da Íris/cirurgia , Implante de Lente Intraocular/métodos , Miose/cirurgia , Facoemulsificação/métodos , Distúrbios Pupilares/cirurgia
8.
Int Ophthalmol ; 42(2): 489-496, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34655377

RESUMO

PURPOSE: The aim of this study was to evaluate the effectiveness of a disposable uniplanar pupil expansion device in small-pupil cataract surgery. METHODS: This is a feasibility study carried out at the Rothschild Foundation, Paris, France. Patients undergoing routine cataract surgery with a dilated pupil size < 6 mm, and who agreed to participate in the study were included. The trial enrolled 25 patients, of whom 21 proceeded to cataract surgery using the pupil expansion device to be evaluated. The pupil diameter was measured at defined stages during the cataract surgery, which was performed by a single surgeon, in a single center setting. The 1st generation Bhattacharjee pupil expansion ring was used if the preoperative pupil size was < 6 mm. Intraoperative and postoperative adverse events were recorded. RESULTS: Pupil size immediately after the Bhattacharjee ring implantation was ≥ 6 mm for 15 eyes (71.4%). The mean dilated pupil size before ring insertion was 4.5 ± 0.8 mm (range 2.5-5.8 mm), and the mean pupil size after ring insertion was 6.1 ± 0.3 mm (range 5.9-6.8 mm). Mean pupil size following removal of the ring was 4.2 ± 0.8 mm (range 2.5-5.4 mm). Two adverse events occurred during the surgeries: 1 Bhattacharjee ring broke prior to implantation, and 1 implanted Bhattacharjee ring was unstable and removed before the end of the surgery. No postoperative adverse event was recorded. CONCLUSIONS: The Bhattacharjee ring is an effective pupil expansion device, which facilitates stable pupil expansion during cataract surgery. This study was registered as a clinical trial at clinicaltrials.gov under the number NCT02434588.


Assuntos
Extração de Catarata , Catarata , Facoemulsificação , Estudos de Viabilidade , Humanos , Miose/cirurgia , Pupila
10.
Int Ophthalmol ; 42(4): 1175-1182, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34761336

RESUMO

PURPOSE: To describe a technique for cataract surgery in eyes with small pupils that combines the use of the femtosecond laser and an iris expansion device, but without the use of corneal sutures and an ophthalmic viscosurgical device (OVD) at the time of laser application. METHODS: A retrospective case series of three eyes with small pupils were operated by the same surgeon without a corneal suture and with removal of anterior chamber OVD prior to laser application. RESULTS: Corrected distance visual acuity (CDVA) for 1 eye in a 70 year-old patient was 20/70 preoperatively and 20/20 thirty days postoperatively. CDVA for a second patient was 20/50 and 20/200 in the two eyes, which improved to 20/25 two months postoperatively in both eyes. There were no complications observed and the intraocular lens were well-centered. CONCLUSION: The use of mechanical pupil expander rings is safe and practical in setting small pupils during femtosecond laser-assisted cataract surgery.


Assuntos
Extração de Catarata , Catarata , Terapia a Laser , Facoemulsificação , Idoso , Catarata/complicações , Extração de Catarata/métodos , Humanos , Terapia a Laser/métodos , Lasers , Implante de Lente Intraocular , Miose , Facoemulsificação/métodos , Pupila , Estudos Retrospectivos , Suturas
11.
Pharmacol Biochem Behav ; 211: 173295, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34742948

RESUMO

BACKGROUND: Regular alcohol consumption is on the rise among older adults and has the potential of altering the subjective experience of pain and response to pain medications. This study examined the cognitive, analgesic and side effect response to oxycodone in middle age and older adults with elevated levels of customary alcohol consumption in a human laboratory setting. METHODS: After refraining from alcohol for one day, eligible participants underwent baseline assessment cognition and side effects by means of questionnaires that were repeated at three time points (90 min, 5 and 8 h) following administration of a 10 mg oral dose of oxycodone. Response to pain stimulus (Cold Pressor Test (CPT)), pupil size, and plasma oxycodone were also measured. RESULTS: One hundred twenty-eight adults (age 35-85) completed the study day. Compared to those with lower customary alcohol consumption, participants with elevated alcohol consumption showed attenuated opioid-induced pupil constriction and cognitive decline on objective measures of working memory, sustained attention, inhibitory control, coordination on a simulated driving task, and subjective dysphoric effects with enhanced subjective euphoric effects. Oxycodone pharmacokinetics, pain tolerance to CPT, and Berg balance were impacted comparably between alcohol consumption groups. Women endorsed greater negative drug effects, whereas men endorsed positive drug effects. CONCLUSION: Independent of subject's age, elevated customary alcohol consumption attenuates opioid central effects (i.e., pupil miosis, impaired cognition) and gender influences subjective drug effects. Clinicians should consider alcohol consumption and gender when prescribing opioid medications.


Assuntos
Consumo de Bebidas Alcoólicas , Etanol/administração & dosagem , Oxicodona/administração & dosagem , Dor/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/administração & dosagem , Atenção/efeitos dos fármacos , Condução de Veículo , Cognição/efeitos dos fármacos , Feminino , Humanos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Pessoa de Meia-Idade , Miose/etiologia , Oxicodona/efeitos adversos , Fatores Sexuais , Inquéritos e Questionários
12.
Sci Rep ; 11(1): 19901, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615946

RESUMO

The kinase haspin phosphorylates histone H3 at threonine-3 (H3T3ph) during mitosis. H3T3ph provides a docking site for the Chromosomal Passenger Complex at the centromere, enabling correction of erratic microtubule-chromosome contacts. Although this mechanism is operational in all dividing cells, haspin-null mice do not exhibit developmental anomalies, apart from aberrant testis architecture. Investigating this problem, we show here that mouse embryonic stem cells that lack or overexpress haspin, albeit prone to chromosome misalignment during metaphase, can still divide, expand and differentiate. RNA sequencing reveals that haspin dosage affects severely the expression levels of several genes that are involved in male gametogenesis. Consistent with a role in testis-specific expression, H3T3ph is detected not only in mitotic spermatogonia and meiotic spermatocytes, but also in non-dividing cells, such as haploid spermatids. Similarly to somatic cells, the mark is erased in the end of meiotic divisions, but re-installed during spermatid maturation, subsequent to methylation of histone H3 at lysine-4 (H3K4me3) and arginine-8 (H3R8me2). These serial modifications are particularly enriched in chromatin domains containing histone H3 trimethylated at lysine-27 (H3K27me3), but devoid of histone H3 trimethylated at lysine-9 (H3K9me3). The unique spatio-temporal pattern of histone H3 modifications implicates haspin in the epigenetic control of spermiogenesis.


Assuntos
Divisão Celular/genética , Gametogênese/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Aurora Quinase B/metabolismo , Diferenciação Celular , Autorrenovação Celular/genética , Centrômero/genética , Centrômero/metabolismo , Dosagem de Genes , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Histonas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Miose/genética , Mitose , Modelos Biológicos , Ligação Proteica , /metabolismo
13.
Vestn Oftalmol ; 137(5. Vyp. 2): 175-180, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34669325

RESUMO

Studying the possibilities of hybrid (femtosecond laser-assisted) phacoemulsification in complicated situations is a relevant problem in cataract surgery. PURPOSE: To develop a technique for hybrid (femtosecond laser-assisted) phacoemulsification in patients with a combination of hypermature cataract, small pupil and lens subluxation. MATERIAL AND METHODS: Hybrid (femtosecond laser-assisted) phacoemulsification of hypermature cataracts was performed in 36 patients (36 eyes) aged 63 to 78 years with grade I-II lens subluxation in combination with small pupil. The initial circular femtolaser capsulotomy was performed within the small pupil using the VICTUS system (Technolas Perfect Vision, Germany). After dilating the pupil with retractor hooks, the capsulorhexis was manually expanded to the required diameter. RESULTS: In all cases, the resulting capsulorhexis had a regular round shape with a smooth edge, without radial ruptures. This made it possible to apply modern methods of fixation and centration of the capsular bag in case of lens subluxation and to perform intracapsular implantation of an intraocular lens (IOL). Complete intracapsular fixation of the IOL with optics edge fully covered by the edge of the capsulorhexis in the postoperative period was achieved in 34 (94.4%) cases. In 2 (5.6%) cases in the postoperative period, the edge of the capsulorhexis exceeded the edge of the IOL optics. The loss of corneal endothelial cells 3 months after surgery was 8.8±1.9%. CONCLUSION: The use of the proposed combined technique of capsulorhexis made it possible to perform the most physiologically appropriate intracapsular IOL implantation in all patients with hypermature cataract, small pupil and lens subluxation.


Assuntos
Catarata , Subluxação do Cristalino , Facoemulsificação , Idoso , Capsulorrexe , Catarata/complicações , Catarata/diagnóstico , Células Endoteliais , Humanos , Implante de Lente Intraocular , Subluxação do Cristalino/complicações , Subluxação do Cristalino/diagnóstico , Pessoa de Meia-Idade , Miose , Facoemulsificação/efeitos adversos
15.
Indian J Ophthalmol ; 69(10): 2688-2693, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34571616

RESUMO

PURPOSE: To evaluate the efficacy and safety of a hinged pupil expansion device (PED) in eyes with small pupils undergoing phacoemulsification. METHODS: In this prospective, multicenter, interventional case series of 57 eyes with suboptimal pharmacologic pupil dilation (<5 mm diameter), a hinged PED (I-Ring, Beaver-Visitec International, Waltham, MA) was applied to facilitate surgical visualization during cataract surgery. The pupil diameters (PD) were measured at different stages of the procedure and at the 1-month follow-up visit. Rate of successful intraoperative PED deployment, pupil size, and shape were assessed. RESULTS: The mean patient age was 70.5 ± 12.1 years. The I-Ring PED was successfully applied in all eyes. The mean PD at various stages were 4.1 ± 1.1 mm (dilation with eye drops only preoperatively), 4.3 ± 1.1 mm (dilation after intracameral epinephrine and ophthalmic viscoelastic device), 6.80 ± 0.00 mm (with PED applied), and 5.7 ± 1.1 mm (end of surgery). A statistically significant difference (P < 0.001) was observed between the mean PD with intracameral medications and with PED application. Postoperative circular pupil was observed in 54 of 57 eyes (94.7%) and the mean eccentricity index (n = 57 eyes) was 0.11 ± 0.22. No significant adverse events were observed. CONCLUSION: The I-Ring PED safely and effectively provided and maintained adequate pupil expansion and surgical visualization in eyes with small pupils undergoing cataract surgery. Postoperatively 95% of eyes attained circular pupils. This hinged PED is an additional instrumentation option for the safe and effective expansion of inadequately sized pupils during cataract surgery.


Assuntos
Extração de Catarata , Catarata , Facoemulsificação , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Miose , Midriáticos , Estudos Prospectivos
16.
Muscle Nerve ; 64(5): 567-575, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34368974

RESUMO

INTRODUCTION/AIMS: Stromal interaction molecule 1 (STIM1) is a reticular Ca2+ sensor composed of a luminal and a cytosolic domain. Autosomal dominant mutations in STIM1 cause tubular aggregate myopathy and Stormorken syndrome or its variant York platelet syndrome. In this study we aimed to expand the features related to new variants in STIM1. METHODS: We performed a cross-sectional study of individuals harboring monoallelic STIM1 variants recruited at five tertiary centers involved in a study of inherited myopathies analyzed with a multigene-targeted panel. RESULTS: We identified seven individuals (age range, 26-57 years) harboring variants in STIM1, including five novel changes: three located in the EF-hand domain, one in the sterile α motif (SAM) domain, and one in the cytoplasmatic region of the protein. Functional evaluation of the pathogenic variants using a heterologous expression system and measuring store-operated calcium entry demonstrated their causative role and suggested a link of new variants with the clinical phenotype. Muscle contractures, found in three individuals, showed variability in body distribution and in the number of joints involved. Three patients showed cardiac and respiratory involvement. Short stature, hyposplenism, sensorineural hearing loss, hypothyroidism, and Gilbert syndrome were variably observed among the patients. Laboratory tests revealed hyperCKemia in six patients, thrombocytopenia in two patients, and hypocalcemia in one patient. Muscle biopsy showed the presence of tubular aggregates in three patients, type I fiber atrophy in one patient, and nonspecific myopathic changes in two patients. DISCUSSION: Our clinical, histological, and molecular data expand the genetic and clinical spectrum of STIM1-related diseases.


Assuntos
Transtornos Plaquetários , Miopatias Congênitas Estruturais , Transtornos Plaquetários/genética , Transtornos Plaquetários/metabolismo , Transtornos Plaquetários/patologia , Cálcio/metabolismo , Estudos Transversais , Humanos , Miose/genética , Miose/metabolismo , Miose/patologia , Miopatias Congênitas Estruturais/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo
17.
Neurology ; 97(2): e145-e155, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-33947782

RESUMO

OBJECTIVE: To determine the molecular basis of a new monogenetic recessive disorder that results in familial autonomic ganglionopathy with diffuse autonomic failure. METHODS: Two adult siblings from one family (I-4 and I-5) and another participant from a second family (II-3) presented with severe neurogenic orthostatic hypotension (nOH), small nonreactive pupils, and constipation. All 3 affected members had low norepinephrine levels and diffuse panautonomic failure. RESULTS: Whole exome sequencing of DNA from I-4 and I-5 showed compound heterozygosity for c.907_908delCT (p.L303Dfs*115)/c.688 G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, α3 subunit gene (CHRNA3). II-3 from the second family was homozygous for the same frameshift (fs) variant (p.L303Dfs*115//p.L303Dfs*115). CHRNA3 encodes a critical subunit of the nicotinic acetylcholine receptors (nAChRs) responsible for fast synaptic transmission in the autonomic ganglia. The fs variant is clearly pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). The p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits based on structural modeling and is predicted to destabilize the nAChR pentameric complex. CONCLUSIONS: We report a novel genetic disease that affected 3 individuals from 2 unrelated families who presented with severe nOH, miosis, and constipation. These patients had rare pathologic variants in the CHRNA3 gene that cosegregate with and are predicted to be the likely cause of their diffuse panautonomic failure.


Assuntos
Doenças do Sistema Nervoso Autônomo/genética , Mutação , Receptores Nicotínicos/genética , Adolescente , Adulto , Constipação Intestinal/genética , Feminino , Genes Recessivos , Humanos , Hipotensão Ortostática/genética , Masculino , Miose/genética , Linhagem , Sequenciamento Completo do Exoma
18.
Minerva Dent Oral Sci ; 70(6): 233-238, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33908745

RESUMO

BACKGROUND: There is increasing evidence of the influence of the oropharyngeal stimulations on the autonomic nervous system and an easy approach to evaluate the balance between parasympathetic and sympathetic system is the measurement of the pupil diameter. The aim of this analytic observational study is to define the effects of clenching and swallowing on pupil diameter, and how an oral appliance can affect the outcome of these tasks, to establish their influence on the sympathetic-parasympathetic balance. METHODS: We measured the pupil diameter in 30 healthy subjects during clenching and swallowing, both with and without oral appliance. We compared the results with the mandibular rest position. The respective positions with and without oral appliance were also compared. RESULTS: Pupillometry showed a mydriatic effect of swallowing (rest 6.94 mm, swallowing 7.26 mm, P=0.04) and oral appliance, more relevant in scotopic conditions. On the contrary, clenching seemed to enhance miosis, especially in intense brightness condition (rest 3.95 mm, clenching 3.83 mm, P=0.02). CONCLUSIONS: Swallowing and oral appliance facilitate the sympathetic system, while clenching activates the parasympathetic branch. We argue that probably the locus coeruleus is the main hub. These results could have practical implications in bruxism physiology, because it could be an attempt to counteract the activation of the sympathetic system.


Assuntos
Bruxismo , Pupila , Sistema Nervoso Autônomo , Humanos , Locus Cerúleo , Miose
19.
Clin Toxicol (Phila) ; 59(8): 727-733, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33475438

RESUMO

OBJECTIVE: To compare accidental pediatric poisoning from methadone vs. buprenorphine in terms of clinical indicators and in-hospital morbidity. METHODS: A matched observational study conducted on children aged ≤12 years admitted to our center between March 2018 and March 2019 with acute poisoning from methadone or buprenorphine. Data were extracted from the electronic patient files of the pediatric methadone poisoning cases, and buprenorphine poisoning cases were followed from ED, during the study period. Cases were compared regarding rates of bradypnea/apnea (primary outcome), the need for antidote therapy and intubation, duration of hospital stay, miosis, loss of consciousness, blood gas analyses, and mortality (secondary outcomes). RESULTS: A total of 90 methadone- and 30 buprenorphine-poisoned children were evaluated. Methadone cases had significantly higher rates of apnea (20/90 methadone vs. 0/30 buprenorphine; OR = 17.7, 95% CI 1.1, 302.8; p = 0.047), but there was no group difference in bradypnea (39/90 methadone vs. 10/30 buprenorphine; p = ns). 28 (31%) methadone and 3 buprenorphine (10%) cases had been referred to as fully awake (p = 0.013). Methadone cases required higher median naloxone doses for initial bolus (0.4 vs. 0.02 mg; p = 0.014) and maintenance infusion (14.4 vs. 2.4 mg; p < 0.001). 20 apnea cases (all from the methadone group) had miotic pupils, and miotic pupils were seen in 44 (90%) cases with bradypnea (OR = 3.2, 95% CI 1.1, 9.3; p = 0.026). Intubation was needed in only 5 methadone cases (5.5%; p = ns). All patients survived. CONCLUSION: Compared to children poisoned with methadone, buprenorphine cases had higher rates of loss of consciousness on admission but subsequently experienced fewer complications during hospital treatment, which is likely due to the buprenorphine partial antagonist effect. Our findings suggest that methadone exposure is more toxic than buprenorphine in pediatric populations.


Assuntos
Buprenorfina/envenenamento , Metadona/envenenamento , Naloxona/uso terapêutico , Intoxicação/terapia , Apneia/induzido quimicamente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Intubação , Tempo de Internação , Masculino , Miose/induzido quimicamente , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/uso terapêutico , Intoxicação/etiologia , Intoxicação/mortalidade , Resultado do Tratamento
20.
Am J Case Rep ; 22: e927556, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33431787

RESUMO

BACKGROUND Fibrosing mediastinitis is a rarely seen, progressive disease. It results from an excessive fibrotic reaction in the mediastinum. We describe a presentation of fibrosing mediastinitis that, to our knowledge, has never been seen before. CASE REPORT A 30-year-old female Colombian flight attendant presented with a right eyelid droop. Examination revealed partial right-sided ptosis and miosis but no anhidrosis. An ill-defined firm swelling was palpable at the root of the neck. Chest radiography revealed a widened mediastinum, and computerized tomography (CT) showed a right paratracheal mass without calcification extending to the thoracic inlet, encasing multiple blood vessels. All basic blood tests, magnetic resonance imaging of the head, and ultrasound Doppler of the neck vessels were normal. History and work up for infections including fungal diseases, granulomatous diseases, vasculitis, and autoimmune diseases were negative. Positron emission tomography (PET) showed significant FDG uptake in the mediastinum. Mediastinal biopsy was histologically consistent with fibrosing mediastinitis. All relevant immunohistochemistry and microbiological studies were negative. Subsequently, the patient developed signs of superior vena cava compression; this was managed by balloon angioplasty, which resulted in improvement of symptoms. However, over time, her symptoms worsened progressively, resulting in a left-sided ptosis and radiological progression of the mass on CT. She received treatment with rituximab and concomitant steroids, which yielded excellent results: the treatment led to both resolution of her symptoms and regression of the mass and its metabolic activity on PET scan. CONCLUSIONS Fibrosing mediastinitis can present with an incomplete Horner's syndrome. Treatment with rituximab and steroids shows promising results in select cases of metabolically active idiopathic fibrosing mediastinitis.


Assuntos
Blefaroptose/etiologia , Mediastinite/complicações , Mediastinite/diagnóstico , Miose/etiologia , Esclerose/complicações , Esclerose/diagnóstico , Adulto , Feminino , Humanos , Mediastinite/terapia , Esclerose/terapia
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