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1.
Nat Commun ; 12(1): 1401, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658516

RESUMO

Effective treatments for patients suffering from heat hypersensitivity are lacking, mostly due to our limited understanding of the pathogenic mechanisms underlying this disorder. In the nervous system, activating transcription factor 4 (ATF4) is involved in the regulation of synaptic plasticity and memory formation. Here, we show that ATF4 plays an important role in heat nociception. Indeed, loss of ATF4 in mouse dorsal root ganglion (DRG) neurons selectively impairs heat sensitivity. Mechanistically, we show that ATF4 interacts with transient receptor potential cation channel subfamily M member-3 (TRPM3) and mediates the membrane trafficking of TRPM3 in DRG neurons in response to heat. Loss of ATF4 also significantly decreases the current and KIF17-mediated trafficking of TRPM3, suggesting that the KIF17/ATF4/TRPM3 complex is required for the neuronal response to heat stimuli. Our findings unveil the non-transcriptional role of ATF4 in the response to heat stimuli in DRG neurons.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Nociceptividade/fisiologia , Células Receptoras Sensoriais/fisiologia , Canais de Cátion TRPM/metabolismo , Fator 4 Ativador da Transcrição/genética , Animais , Membrana Celular/metabolismo , Quimiocina CXCL12/metabolismo , Gânglios Espinais/citologia , Gânglios Espinais/fisiologia , Células HEK293 , Temperatura Alta , Humanos , Injeções Espinhais , Cinesina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Técnicas de Patch-Clamp , Transporte Proteico , Receptores CXCR4/metabolismo , Canais de Cátion TRPM/genética
2.
Am J Phys Med Rehabil ; 100(1): 100-104, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33534219

RESUMO

ABSTRACT: The incidence of leptomeningeal disease (LMD) is believed to be increasing in part because of more effective chemotherapy treatments allowing cancer progression behind the blood-brain barrier. However, little has been published about the rehabilitation of this growing patient population. In this study, impairments and rehabilitation utilization by cytology-proven LMD patients receiving intrathecal chemotherapy at a cancer center are described. A total of 109 consecutive patients with pathology-confirmed LMD who received an intrathecal chemotherapy infusion from January 1, 2017, through October 31, 2017, were retrospectively reviewed. Of the 109 patients, 103 (95%) had impairments described in their medical record that could impact physical function, including 74 of 109 (68%) who had deconditioning or fatigue. Kaplan-Meier median survival from initial LMD diagnosis was 13.1 mos. The median number of hospital admissions and intrathecal chemotherapy administrations was both 8. Of the 109 patients, 43 (39%) had magnetic resonance imaging radiology interpreted LMD. Most LMD patients used rehabilitation services (95/109, 87%) and most were able to forego post-acute inpatient rehabilitation facilities (96/109, 88%). Additional research and education for rehabilitation professionals about this increasingly common syndrome are needed.


Assuntos
Neoplasias Encefálicas/reabilitação , Fadiga/reabilitação , Neoplasias Meníngeas/reabilitação , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/tratamento farmacológico , Fadiga/etiologia , Feminino , Humanos , Injeções Espinhais , Masculino , Neoplasias Meníngeas/complicações , Neoplasias Meníngeas/tratamento farmacológico , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
3.
J Vis Exp ; (168)2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33616092

RESUMO

Mesenchymal stem cells (MSCs) have been studied for the treatment of various diseases. In neurodegenerative diseases involving defects in both the brain and the spinal cord, the route of administration is very important, because MSCs must migrate to both the brain and the spinal cord. This paper describes a method for administering MSCs into the spinal canal (intraspinal cavity injection) that can target the brain and spinal cord in a rat model. One million MSCs were injected into the spinal canals of rats at the level of lumbar vertebrae 2-3. After administration, the rats were euthanized at 0, 6, and 12 h post-injection. Optical imaging and quantitative real-time polymerase chain reaction (qPCR) were used to track the injected MSCs. The results of the present study demonstrated that MSCs administered via the spinal cavity could be detected subsequently in both the brain and spinal cord at 12 h. Intraspinal cavity injection has the advantage of not requiring general anesthesia and has few side effects. However, the drawback of the low migration rate of MSCs to the brain must be overcome.


Assuntos
Encéfalo/metabolismo , Movimento Celular , Rastreamento de Células/métodos , Injeções Espinhais/métodos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Animais , Humanos , Ratos , Ratos Sprague-Dawley
4.
Nucleic Acids Res ; 49(2): 657-673, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33367834

RESUMO

Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.


Assuntos
Sistema Nervoso Central/química , Camundongos/metabolismo , Oligonucleotídeos Antissenso/farmacocinética , Primatas/metabolismo , Ratos/metabolismo , Animais , Sistema Nervoso Central/citologia , Feminino , Hibridização In Situ , Injeções Intraventriculares , Injeções Espinhais , Macaca fascicularis , Masculino , Neuroglia/química , Neurônios/química , Oligonucleotídeos Antissenso/administração & dosagem , Especificidade de Órgãos , RNA Longo não Codificante/análise , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , Ratos Sprague-Dawley , Ribonuclease H , Distribuição Tecidual
5.
BMJ Case Rep ; 13(12)2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33370945

RESUMO

Transient spinal shock is a previously unreported complication of intrathecal contrast. A 63-year-old man presented with the chief complaint of worsening back pain. Computed topography of lumbar spine without contrast showed a lytic lesion. After international normalized ratio (INR) correction, patient was sent for CT myelogram. After intrathecal contrast injection, the patient dropped his blood pressure profoundly and developed clinical manifestations of spinal shock. Emergent intravenous bolus fluids were initiated resulting in improvement in blood pressure. Patient's spinal shock resolved within hours. CT myelogram was normal except previously known lytic lesion. It was concluded that the transient shock was most likely due to contrast injection. We believe that this is the first reported case of transient spinal shock following CT myelogram using water-soluble iodinated non-ionic contrast agent administered intrathecally.


Assuntos
Dor nas Costas/diagnóstico , Meios de Contraste/efeitos adversos , Injeções Espinhais/efeitos adversos , Mielografia/efeitos adversos , Choque/induzido quimicamente , Medula Espinal/efeitos dos fármacos , Meios de Contraste/administração & dosagem , Humanos , Iohexol/administração & dosagem , Iohexol/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mielografia/métodos , Remissão Espontânea , Medula Espinal/fisiopatologia , Tomografia Computadorizada por Raios X
7.
Medicine (Baltimore) ; 99(46): e23000, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181664

RESUMO

BACKGROUND: Both acupoint injection and sacral canal injection are widely adopted in the treatment of lumbar disc herniation (LDH), but there are still doubts about the effectiveness and safety of the 2 methods. Therefore, the objective of the randomized controlled trial is to evaluate the effectiveness and safety of acupoint injection and sacral canal injection in the treatment of LDH. METHOD: This is a prospective randomized controlled trial to study the effectiveness and safety of acupoint injection and sacral canal injection in the treatment of LDH. With the approval by the clinical research ethics committee of our hospital, patients were randomly included into 1 of 2 treatment protocols:Patients, doctors, nurses, and research assistants responsible for collecting data were blinded to group allocation. Main outcome observation indicator: visual analogue scale; secondary outcome observation indicator: Oswestry disability index scores; paresthesia score; adverse reactions. Data were analyzed using the statistical software package SPSS version 25.0 (Chicago, IL). DISCUSSION: The effectiveness and safety of acupoint injection and sacral canal injection in the treatment of LDH were evaluated in this study, and the results of this trial would establish clinical evidence for the adoption of acupoint injection or sacral canal injection to treat LDH. TRIAL REGISTRATION NUMBER: DOI 10.17605 / OSF.IO / VTFUD.


Assuntos
Pontos de Acupuntura , Terapia por Acupuntura/métodos , Injeções Espinhais/métodos , Deslocamento do Disco Intervertebral/terapia , Vértebras Lombares , Adulto , Idoso , Protocolos Clínicos , Avaliação da Deficiência , Feminino , Humanos , Plexo Lombossacral , Masculino , Pessoa de Meia-Idade , Medição da Dor , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-Cego , Resultado do Tratamento , Escala Visual Analógica , Adulto Jovem
8.
Nat Commun ; 11(1): 5074, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033265

RESUMO

Touch and itch sensations are crucial for evoking defensive and emotional responses, and light tactile touch may induce unpleasant itch sensations (mechanical itch or alloknesis). The neural substrate for touch-to-itch conversion in the spinal cord remains elusive. We report that spinal interneurons expressing Tachykinin 2-Cre (Tac2Cre) receive direct Aß low threshold mechanoreceptor (LTMR) input and form monosynaptic connections with GRPR neurons. Ablation or inhibition markedly reduces mechanical but not acute chemical itch nor noxious touch information. Chemogenetic inhibition of Tac2Cre neurons also displays pronounced deficit in chronic dry skin itch, a type of chemical itch in mice. Consistently, ablation of gastrin-releasing peptide receptor (GRPR) neurons, which are essential for transmitting chemical itch, also abolishes mechanical itch. Together, these results suggest that innocuous touch and chemical itch information converge on GRPR neurons and thus map an exquisite spinal circuitry hard-wired for converting innocuous touch to irritating itch.


Assuntos
Rede Nervosa/fisiopatologia , Prurido/fisiopatologia , Tato/fisiologia , Animais , Comportamento Animal , Injeções Espinhais , Luz , Potenciais da Membrana , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Precursores de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores da Bombesina/metabolismo , Pele/patologia , Medula Espinal/fisiopatologia , Sinapses/metabolismo , Taquicininas/metabolismo
9.
Mymensingh Med J ; 29(4): 951-955, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33116101

RESUMO

The incidence of visceral pain among caesarean section can be as high as 50% in sub arachnoid block (SAB) in spite adequate sensory block, which requires conversion to general anesthesia. Different types of adjuvant have been used to augment the effect of local anesthetics but their use is limited due to adverse effects. The effect of intrathecal midazolam along with hyperbaric bupivacaine in sub arachnoid block is less known. So this randomized, double blind study was conducted to evaluate the additive effect of 0.4ml midazolam to 0.5% 3ml bupivacaine on sub arachnoid block in scheduled elective caesarean section. This study demonstrated that the addition of intrathecal 0.4ml midazolam to spinal 0.5% bupivacaine kept all the characteristics of block unaffected, furthermore pain score VAS 3.4±1.3 in Group A and 1.8±1.22 in Group B which is statistically significant, the requirement of intraoperative analgesia and also increased the duration of postoperative analgesia that is 130.3±5.4 minute in Group A, 265.1±3.6 minute in Group B and also statistically significant. Therefore addition of 2.0mg midazolam with 0.5% bupivacaine significantly reduces the VAS score, reduces the intraoperative visceral pain and need of analgesia.


Assuntos
Raquianestesia , Anestésicos Locais , Midazolam , Dor Pós-Operatória , Anestésicos Locais/uso terapêutico , Bupivacaína , Cesárea , Método Duplo-Cego , Feminino , Humanos , Injeções Espinhais , Midazolam/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Gravidez , Estudos Prospectivos
10.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 283-288, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981287

RESUMO

Objective: To introduce a new design needle and a device of microcatheter protection for lumbar intrathecal catheterization in rats,and evaluate its feasibility and effectiveness.Methods: Sixty pathogen-free adult male Sprogue-Dawley rats were randomly divided into two groups(n=30 in each group), the control group (group C) and the modification group(group M). The traditional puncture device, 20G needle, was used in the group C without extemal shielding protection. The new design puncture needle and the microinjection cock were used in the group M. All rats were assessed for motor function on postoperative. The motor function was evaluated 1 day afteroperation. Lidocaine was injected in the catheter at 1st,3rd,7th,14th,21st day post-catheterization, methylene blue was injected in intrathecal at 30th day after operation, and the catheter location was observed. The paw withdrawal threshold(PWT) was measured at 1st,3rd,7th,14th,21st,30th day after operation, open-field test was tested at preoperative and one week postoperative for the purpose of evaluating the autonomous behavior of rats. Results: About motor function:level Ⅰ 75.9%,level Ⅱ 20.7%,level Ⅲ 3.4% in group C, and level Ⅰ 96.7%,level Ⅱ 3.3% in group M, Compared with group C,group M had higher percentage of the level Ⅰ in motor function (P<0.05);Lidocaine test and methylen blue location showed that each one case of catheter was removed on the 14th and 21st day after intubation in group C, and total four cases were removed till the 30th day, while all catheters were in normal location in group M. There was significant difference between two groups in protection of the extemal portion of catheter(P<0.05); The time of intrathecal injection in group M was only 1 minute, and it spent more than 3 minutes in group C. Compared with group C,the time of intrathecal injection is significantly shorter in group M(P<0.01);PWT was reduced to the lowest on the third day after catheterization, and there was significant difference compared with preoperative(P<0.05), PWT recovered on the 7th day and there were no significant difference between two groups; Compared with preoperative, there was no significant difference in the parameters of the group M in the open field test, neither between two groups. Conclusion: The new design puncture needle by its less injury and higher efficiency can be used in intrathecal catheterization. The microinjection cock is reliable and convenient for repeat injection with a perfect protection function of the external portion of catheter, meanwhile it has no impact on rats' autonomous behavior so that it is worthy of further promoting.


Assuntos
Cateterismo , Injeções Espinhais , Agulhas , Animais , Cateterismo/instrumentação , Injeções Espinhais/instrumentação , Masculino , Agulhas/normas , Ratos , Ratos Sprague-Dawley
11.
Medicine (Baltimore) ; 99(36): e21971, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899035

RESUMO

BACKGROUND: The purpose of this meta-analysis was to comprehensively collect randomized controlled trials (RCTs) to assess the clinical efficacy of intrathecal morphine (ITM) versus local infiltration analgesia (LIA) in the treatment of total knee and hip arthroplasty patients. METHODS: Relevant studies were identified from the Embase, PubMed, Cochrane Library, Web of Science, Wanfang, and Chinese National Knowledge Infrastructure (CNKI) databases. We also reviewed the references of all identified articles to identify additional studies. For each study, we assessed the risk ratio (RR), weighted mean difference (WMD), and corresponding 95% confidence interval (95% CI) to synthesize outcomes. Meta-analysis was performed with Stata 12.0 software. RESULTS: We included 13 studies with 942 patients for meta-analysis. LIA significantly decreased the pain value with rest or mobilization until 72 hours (P < .05). LIA significantly decreased cumulative morphine consumption by 13.52 mg. Moreover, the length of hospital stay was lower in the LIA group than in the ITM analgesia group. Finally, LIA significantly reduced morphine-related complications (nausea and vomiting, pruritus, and respiration depression). CONCLUSIONS: LIA was an effective approach for relieving postoperative pain and reducing postoperative consumption of morphine compared with ITM in total knee and hip arthroplasty patients.


Assuntos
Analgesia/métodos , Analgésicos Opioides/administração & dosagem , Artroplastia de Quadril , Artroplastia do Joelho , Morfina/administração & dosagem , Anestesia Local , Humanos , Injeções Espinhais , Tempo de Internação , Dor Pós-Operatória/prevenção & controle
12.
Medicine (Baltimore) ; 99(39): e22335, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991445

RESUMO

INTRODUCTION: Plasmablastic lymphoma (PBL) is an uncommon and aggressive large B-cell lymphoma commonly diagnosed in human immunodeficiency viruses -positive patients. Oral cavity is the most commonly PBL affected site. Most oral PBLs presented as asymptomatic swellings, frequently associated with ulcerations and bleeding. Most cases lacked B-symptoms, suggesting a more local involvement of the disease. No standard treatment is yet for oral PBL. Five-year survival rate recorded no more than 33.5%. PATIENT CONCERNS: A 39-year-old male presented to Dental Clinic with 1 month swelling of the oral cavity, in absence of any other symptoms or signs. He followed antibiotic therapy just on suspicion of an oral abscess and later oral surgical treatment on suspicion of bone neoplasm. DIAGNOSIS: Surgical specimen analysis highlighted a diffuse infiltrate of large-sized atypical cells with plasmablastic appearance and plasma cell phenotype. Oral cavity PBL was diagnosed. Blood tests recorded mild lymphopenia and positive human immunodeficiency viruses serology. INTERVENTIONS: Patient underwent chemotherapy including intrathecal methotrexate prophylaxis, in addition to a highly active antiretroviral therapy. OUTCOMES: At 12 months from diagnosis, patient recorded complete hematological remission. CONCLUSIONS: Oral PBL diagnosis requires a high level of suspicion and awareness both by physicians and pathologists. They should be aware of the extent of such disease which is often mistaken as oral abscess or infected tooth, thus leading to delay the most appropriate diagnostic evaluation. As PBL is an aggressive non-Hodgkin lymphoma, a delayed diagnosis might negatively impact on both treatment and survival.


Assuntos
Antineoplásicos/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Boca/patologia , Linfoma Plasmablástico/tratamento farmacológico , Abscesso/diagnóstico , Abscesso/tratamento farmacológico , Adulto , Assistência ao Convalescente , Antibacterianos/uso terapêutico , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Quimioterapia Combinada , Edema/etiologia , Infecções por HIV/complicações , Soropositividade para HIV/sangue , HIV-1/imunologia , Humanos , Injeções Espinhais , Linfoma não Hodgkin/patologia , Masculino , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Plasmócitos/patologia , Linfoma Plasmablástico/diagnóstico por imagem , Resultado do Tratamento
13.
Medicine (Baltimore) ; 99(39): e22394, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991462

RESUMO

OBJECTIVE: We perform this protocol for randomized controlled trial to compare the efficacy of intrathecal morphine and local infiltration anesthesia (LIA) in the treatment of the postoperative pain after total knee replacement (TKR). METHODS: This is a randomized controlled, single center trial which was performed from March 2019 to March 2020. This trial is conducted according to the SPIRIT Checklist of randomized researches. It is authorized via the Ethics Committee of Beijing Friendship Hospital (2019-P2-050-01). Eighty participants who undergo TKR were randomized into 2 groups. Intrathecal morphine group: 0.1 mg of the morphine was intrathecally injected, and the spinal anesthetic was injected at the same time in the group LIA; In the LIA group: the knee joint was infiltrated with epinephrine, ketorologic acid and ropivacaine in the process of operation, and the identical mixture was injected 2 bolus through the intraarticular catheter after operation. The main outcome variables were the visual analog scale and the consumption amount of opioid every 6-hour interval within 2 days postoperatively. The secondary outcome variables were the side effects associated with opioid, the length of hospital stay, motion range, and the loss of blood collected by the closed suction drainage. All the required analyses were carried out via applying the SPSS for Windows Version 19.0. RESULTS: The clinical outcome variables between groups were shown in . CONCLUSION: This protocol will provide the evidence on which technique can achieve better analgesia after TKR.


Assuntos
Analgésicos Opioides/administração & dosagem , Anestesia Local , Artroplastia do Joelho/efeitos adversos , Morfina/administração & dosagem , Dor Pós-Operatória/prevenção & controle , Humanos , Injeções Espinhais , Dor Pós-Operatória/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Br J Anaesth ; 125(5): 811-817, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32900508

RESUMO

BACKGROUND: Intrathecal morphine prolongs analgesia after surgery, but has been implicated in postoperative respiratory depression or apnoeic episodes. However, this has not been investigated in a prospective trial using respiratory polygraphy. This randomised controlled triple-blinded trial tested the hypothesis that intrathecal morphine increases sleep apnoea severity, measured using respiratory polygraphy. METHODS: Sixty subjects undergoing hip arthroplasty under spinal anaesthesia received either 15 mg isobaric bupivacaine 0.5% with 0.5 ml normal saline 0.9% (control group) or 15 mg isobaric bupivacaine 0.5% with 0.5 ml intrathecal morphine 100 µg (intrathecal morphine group). Respiratory polygraphy was performed before surgery and on the first and third postoperative nights. The primary outcome was the apnoea-hypopnoea index in the supine position (supine AHI) on the first postoperative night. Secondary outcomes included supine AHI on the third postoperative night, oxygen desaturation index (ODI), and ventilatory frequency during the first and third postoperative nights. RESULTS: On the first postoperative night, mean (95% confidence interval) values for supine AHI were 20.6 (13.9-27.3) and 21.2 (12.4-30.0) events h-1 in the control and intrathecal morphine groups, respectively (P=0.90). There were no significant between-group differences for any of the secondary outcomes, except for a significantly higher central and mixed apnoea index preoperatively and significantly lower mean SpO2 on the third postoperative night in the control group. CONCLUSIONS: Intrathecal morphine did not increase sleep apnoea severity when measured using respiratory polygraphy. Of note, all patients had an increased number of apnoeic episodes on the third postoperative night. CLINICAL TRIAL REGISTRATION: NCT02566226.


Assuntos
Analgésicos Opioides/efeitos adversos , Artroplastia de Quadril/métodos , Morfina/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Síndromes da Apneia do Sono/induzido quimicamente , Síndromes da Apneia do Sono/epidemiologia , Idoso , Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Raquianestesia/métodos , Anestésicos Locais , Bupivacaína , Método Duplo-Cego , Feminino , Humanos , Injeções Espinhais , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Morfina/uso terapêutico , Oxigênio/sangue , Polissonografia , Decúbito Dorsal , Resultado do Tratamento
15.
PLoS One ; 15(9): e0239094, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915912

RESUMO

The G protein-gated inwardly rectifying K+ (GIRK) channels play important signaling roles in the central and peripheral nervous systems. However, the role of GIRK channel activation in pain signaling remains unknown mainly due to the lack of potent and selective GIRK channel activators until recently. The present study was designed to determine the effects and mechanisms of ML297, a selective GIRK1/2 activator, on nociception in the spinal cord by using behavioral studies and whole-cell patch-clamp recordings from substantia gelatinosa (SG) neurons. Rats were prepared for chronic lumber catheterization and intrathecal administration of ML297. The nociceptive flexion reflex was tested using an analgesy-meter, and the influence on motor performance was assessed using an accelerating rotarod. We also investigated pre- and post-synaptic actions of ML297 in spinal cord preparations by whole-cell patch-clamp recordings. Intrathecal administration of ML297 increased the mechanical nociceptive threshold without impairing motor function. In voltage-clamp mode of patch-clamp recordings, bath application of ML297 induced outward currents in a dose-dependent manner. The ML297-induced currents demonstrated specific equilibrium potential like other families of potassium channels. At high concentration, ML297 depressed miniature excitatory postsynaptic currents (mEPSCs) but not their amplitude. The ML297-induced outward currents and suppression of mEPSCs were not inhibited by naloxone, a µ-opioid receptor antagonist. These results demonstrated that intrathecal ML297 showed the antinociceptive effect, which was mediated through direct activation of pre- and post-synaptic GIRK channels. Selective GIRK channel activation is a promising strategy for the development of new agents against chronic pain and opioid tolerance.


Assuntos
Analgésicos/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/agonistas , Nociceptividade/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Pirazóis/farmacologia , Substância Gelatinosa/efeitos dos fármacos , Analgésicos/uso terapêutico , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Animais , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Dor Crônica/tratamento farmacológico , Tolerância a Medicamentos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Humanos , Injeções Espinhais , Masculino , Modelos Animais , Naloxona/administração & dosagem , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Nociceptividade/fisiologia , Técnicas de Patch-Clamp , Compostos de Fenilureia/uso terapêutico , Pirazóis/uso terapêutico , Ratos , Substância Gelatinosa/citologia , Substância Gelatinosa/fisiologia
16.
Medicine (Baltimore) ; 99(31): e21435, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756154

RESUMO

INTRODUCTION: The population of obese individuals is increasing worldwide, and as a result, the number of mothers with super morbid obesity undergoing cesarean sections is also increasing. However, little is known about which anesthetic technique is appropriate for cesarean sections of super morbidly obese parturients. PATIENT CONCERNS: A 35-year-old woman with body mass index 61.3 kg/m at a gestational age of 37 weeks. DIAGNOSIS: The patient was super morbidly obese parturient. INTERVENTIONS: Spinal anesthesia was performed. A spinal needle was inserted into the L4-5 interspinous space in the sitting position. After confirmation of cerebrospinal fluid, 0.5% hyperbaric bupivacaine 9 mg and fentanyl 20 µg were injected into the subarachnoid space. OUTCOMES: After the administration of spinal anesthetics, the nerve block to the T8 dermatome level was confirmed, surgery was performed, and the fetus was delivered. The patient's vital signs were stable until the end of the operation. CONCLUSION: There is no established strategy for selecting a method of anesthesia in patients with morbid obesity (body mass index 40 kg/m or more). For this reason and considering the amount of bupivacaine used for spinal anesthesia, we wanted to share our experience with spinal anesthesia for cesarean section in a super morbidly obese parturients.


Assuntos
Anestesia Obstétrica/métodos , Raquianestesia/instrumentação , Cesárea/métodos , Obesidade Mórbida/cirurgia , Adulto , Analgésicos Opioides/administração & dosagem , Anestesia Epidural/métodos , Anestesia Obstétrica/tendências , Raquianestesia/métodos , Anestésicos Locais/administração & dosagem , Índice de Massa Corporal , Bupivacaína/administração & dosagem , Feminino , Fentanila/administração & dosagem , Idade Gestacional , Humanos , Injeções Espinhais , Agulhas , Obesidade Mórbida/epidemiologia , Alta do Paciente/normas , Gravidez
17.
N Engl J Med ; 383(2): 109-119, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640130

RESUMO

BACKGROUND: Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations. METHODS: We conducted a phase 1-2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured. RESULTS: A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture-related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], -18 to 27) for the 20-mg dose, -25 percentage points (95% CI, -40 to -5) for the 40-mg dose, -19 percentage points (95% CI, -35 to 2) for the 60-mg dose, and -33 percentage points (95% CI, -47 to -16) for the 100-mg dose. CONCLUSIONS: In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture-related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.).


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos/administração & dosagem , Superóxido Dismutase-1/líquido cefalorraquidiano , Adulto , Esclerose Amiotrófica Lateral/líquido cefalorraquidiano , Esclerose Amiotrófica Lateral/genética , Progressão da Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Cefaleia/induzido quimicamente , Humanos , Injeções Espinhais/efeitos adversos , Filamentos Intermediários , Leucocitose/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Mutação , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacocinética , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos Antissenso/farmacocinética , Superóxido Dismutase-1/genética , Capacidade Vital
18.
N Engl J Med ; 383(2): 151-158, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640133

RESUMO

Two patients with familial amyotrophic lateral sclerosis (ALS) and mutations in the gene encoding superoxide dismutase 1 (SOD1) were treated with a single intrathecal infusion of adeno-associated virus encoding a microRNA targeting SOD1. In Patient 1, SOD1 levels in spinal cord tissue as analyzed on autopsy were lower than corresponding levels in untreated patients with SOD1-mediated ALS and in healthy controls. Levels of SOD1 in cerebrospinal fluid were transiently and only slightly lower in Patient 1 but were not affected in Patient 2. In Patient 1, meningoradiculitis developed after the infusion; Patient 2 was pretreated with immunosuppressive drugs and did not have this complication. Patient 1 had transient improvement in the strength of his right leg, a measure that had been relatively stable throughout his disease course, but there was no change in his vital capacity. Patient 2 had stable scores on a composite measure of ALS function and a stable vital capacity during a 12-month period. This study showed that intrathecal microRNA can be used as a potential treatment for SOD1-mediated ALS.


Assuntos
Esclerose Amiotrófica Lateral/terapia , MicroRNAs/uso terapêutico , Superóxido Dismutase-1/líquido cefalorraquidiano , Esclerose Amiotrófica Lateral/líquido cefalorraquidiano , Esclerose Amiotrófica Lateral/genética , Dependovirus , Evolução Fatal , Inativação Gênica , Terapia Genética , Vetores Genéticos , Humanos , Injeções Espinhais , Masculino , Meningoencefalite , Pessoa de Meia-Idade , Mutação , Estudo de Prova de Conceito , Medula Espinal/química , Medula Espinal/patologia , Superóxido Dismutase-1/análise , Superóxido Dismutase-1/genética , Capacidade Vital , Adulto Jovem
19.
Neurology ; 95(4): e413-e416, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32665408

RESUMO

OBJECTIVE: To report our experience with adult patients with spinal muscular atrophy (SMA), some of whom were treated with nusinersen. METHODS: We reviewed charts of adult patients with SMA seen in our neuromuscular clinic between 2017 and 2019 and noted their demographics, clinical characteristics, treatment, and side effects. RESULTS: Twenty-two patients were included. Nine had type 2 and 13 type 3 SMA. Median age was 36 years (range 20-71). Most could not walk unassisted. Ten patients had significant respiratory impairment necessitating ventilation and 2 had tracheostomy. Seventeen had severe scoliosis. Ten patients were treated with nusinersen for 6-24 months (median 12 months), 3 of whom required bone laminectomy for intrathecal access. One developed bowel and bladder incontinence following the procedure. In the treated group, on average, % Medical Research Council change was 2.5% at 12 months and 3.9% at 24 months. Most untreated patients remained stable; 3 had slightly declined. Five treated patients reported subjective improvement. Treatment side effects included post lumbar puncture headache in 5 patients, 2 of whom needed blood patch, and 1 bacterial meningitis requiring inpatient treatment. Three patients stopped treatment after 12-24 months due to lack of improvement, recurrent pneumonia, or proteinuria. CONCLUSION: Side effects of nusinersen can be serious. Whereas half of treated patients reported modest improvement in function, there were no significant objective changes, which may point largely to a placebo effect. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for some adult patients with SMA, nusinersen improves subjective function and causes serious adverse effects.


Assuntos
Atrofia Muscular Espinal/tratamento farmacológico , Oligonucleotídeos/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Injeções Espinhais/efeitos adversos , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos/administração & dosagem , Adulto Jovem
20.
Am J Physiol Regul Integr Comp Physiol ; 319(2): R223-R232, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32609538

RESUMO

Purinergic 2X (P2X) receptors on the endings of group III and IV afferents play a role in evoking the exercise pressor reflex. Particular attention has been paid to P2X3 receptors because their blockade in the periphery attenuated this reflex. In contrast, nothing is known about the role played by P2X receptors in the spinal cord in evoking the exercise pressor reflex in rats. P2X7 receptors, in particular, may be especially important in this regard because they are found in abundance on spinal glial cells and may communicate with neurons to effect reflexes controlling cardiovascular function. Consequently, we investigated the role played by spinal P2X7 receptors in evoking the exercise pressor reflex in decerebrated rats. We found that intrathecal injection of the P2X7 antagonist brilliant blue G (BBG) attenuated the exercise pressor reflex (blood pressure index: 294 ± 112 mmHg·s before vs. 7 ± 32 mmHg·s after; P < 0.05). Likewise, intrathecal injection of minocycline, which inhibits microglial cell output, attenuated the reflex. In contrast, intrathecal injection of BBG did not attenuate the pressor response evoked by intracarotid injection of sodium cyanide, a maneuver that stimulated carotid chemoreceptors. Moreover, injections of BBG either into the arterial supply of the contracting hindlimb muscles or into the jugular vein did not attenuate the exercise pressor reflex. Our findings support the hypothesis that P2X7 receptors on microglial cells within the spinal cord play a role in evoking the exercise pressor reflex.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Condicionamento Físico Animal , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Reflexo/efeitos dos fármacos , Corantes de Rosanilina/administração & dosagem , Animais , Estado de Descerebração/fisiopatologia , Injeções Espinhais , Masculino , Minociclina/farmacologia , Ratos , Ratos Sprague-Dawley
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