RESUMO
PURPOSE: Secondary tethered cord syndrome (TCS) can be diagnosed with signs of progressive deterioration in urological or neuro-orthopedic systems following primary untethering surgery. Though urological deterioration is a common secondary TCS manifestation, a paucity of diagnostic criteria makes diagnoses challenging. A detailed description of urological deterioration may help diagnose secondary TCS. Thus, the clinical and urodynamic features of the current secondary TCS cases were described. MATERIALS AND METHODS: Fifty-one patients who had undergone reuntethering for secondary TCS experienced improvement or stabilization of progressive problems. Moreover, their clinical and videourodynamic changes were longitudinally described. RESULTS: Loss of postoperative spontaneous voiding was the first urological secondary TCS sign for those who could void spontaneously. Urological problems mostly occurred during elementary school (6-12 years). Major urological presentations were recalcitrant urinary tract infection or urinary incontinence. Follow-up videourodynamic studies revealed typical changes, from acontractile bladder to overactive and low-complaint bladders. While detrusor overactivity did not always occur during the progression, detrusor sphincter dyssynergia was always present in all patients with urological deterioration. All patients postoperatively showed significant urodynamic improvement regardless of preoperative bladder dysfunction. This included four cases of restoring spontaneous voiding. Nine patients experienced newly appearing nonprogressive neuro-orthopedic complications despite their urological improvement. CONCLUSIONS: Urological deterioration should prompt secondary TCS suspicion, and changes in clinical patterns and videourodynamic studies helped diagnose it. However, reuntethering can effectively address urological problems at the cost of some neuro-orthopedic functions in some patients.
Assuntos
Defeitos do Tubo Neural , Incontinência Urinária , Seguimentos , Humanos , Defeitos do Tubo Neural/complicações , Defeitos do Tubo Neural/cirurgia , Bexiga Urinária/cirurgia , UrodinâmicaRESUMO
The fatality of novel coronavirus disease 2019 (COVID-19) is precipitously increased in patients with underlying comorbidities or elderly people. Kidney transplant (KT) recipients are one of the vulnerable populations for infection. COVID-19 infection in KT recipients might be a complicated and awkward situation, but there has been a lack of reports concerning this group. Herein, we demonstrated two distinct cases with different clinical progress. The first case was a 36-year-old man who underwent KT 3 years ago. He was diagnosed with COVID-19 expressing relevant symptoms. Following administration of lopinavir/ritonavir and hydroxychloroquine with reduced immunosuppressant, he recovered from COVID-19. However, the unexpected fluctuations in tacrolimus trough levels needed to be managed because of drug-to-drug interaction. The second case was developed in a 56-year-old man without any symptoms. He received a second KT from an ABO-incompatible donor 8 years ago. He was diagnosed with COVID-19 by screening due to exposure history. During the hospitalization period, the chest infiltrative lesion showed a wax and wane, but he successfully recovered by administration of hydroxychloroquine with azithromycin. These apparently different cases suggest that assertive screening and management could improve the clinical course. In addition, antiviral agents should be used cautiously, especially in patients on calcineurin inhibitors.
Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/terapia , Falência Renal Crônica/complicações , Transplante de Rim , Pneumonia Viral/complicações , Pneumonia Viral/terapia , Transplantados , Adulto , Antivirais/uso terapêutico , Azitromicina/uso terapêutico , Betacoronavirus , COVID-19 , Inibidores de Calcineurina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Combinação de Medicamentos , Interações Medicamentosas , Humanos , Hidroxicloroquina/uso terapêutico , Imunossupressores/uso terapêutico , Falência Renal Crônica/cirurgia , Lopinavir/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pandemias , Ritonavir/uso terapêutico , SARS-CoV-2 , Tacrolimo/uso terapêutico , Tratamento Farmacológico da COVID-19RESUMO
Pediatric multiple sclerosis (MS) is a chronic inflammatory neurologic disease that is challenging to diagnose and treat. Although there are many clinical parallels between pediatric-onset MS and adult-onset MS, there is also accumulating evidence of distinguishing clinical features that may, in part, arise from development-specific, neuroimmune processes governing MS pathogenesis in children. Here the authors describe the clinical features, diagnosis, and treatment of pediatric MS, with a particular focus on describing clinical features and highlighting new developments that promise a better understanding of pediatric MS pathogenesis. An important task that lies ahead for pediatric neurologists is better understanding the early gene-environment interaction that precipitates the first demyelinating event in pediatric MS. This area is of particular importance for understanding the MS etiology and the natural history of pediatric MS. Such understanding should in turn inform new developments in diagnostic tools, long-term therapies, and much-needed biomarkers. Such biomarkers are not only valuable for defining the disease onset, but also for monitoring both the treatment response and a disease evolution that spans multiple decades in children with MS.
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Esclerose Múltipla , Idade de Início , Criança , Humanos , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/etiologia , Esclerose Múltipla/terapiaRESUMO
OBJECTIVE: To evaluate the longitudinal relationship between bone mineral density (BMD) and BMD changes and the progression of knee osteoarthritis (OA), as measured by cartilage outcomes. METHODS: We used observational cohort data from the Vitamin D for Knee Osteoarthritis trial. Bilateral femoral neck BMD values as well as knee magnetic resonance imaging (MRI) scans in each subject were obtained at baseline and subsequently at 12 months and 24 months. The change in total cartilage volume and tibial and femoral cartilage thickness was measured by manual cartilage segmentation of 2 sequential knee MRI scans in each subject. Multivariable linear regression models were used to examine the associations of baseline BMD and BMD change with the cartilage outcomes, adjusting for baseline age, sex, body mass index, malalignment, and vitamin D treatment. Model fit and assumptions were validated. RESULTS: A total of 127 subjects were eligible for analysis. Longitudinal BMD loss was associated with loss of cartilage volume (ß = 1.25 per 0.1 gm/cm(2) , P = 0.02) and loss of tibial cartilage thickness (ß = 0.028, P = 0.03). BMD loss of a magnitude greater than the least significant change (<-4.7%) was associated with 1.02% cartilage volume loss per year (P = 0.005), 0.014 mm femoral cartilage thickness loss (P = 0.04), and 0.021 mm tibial cartilage thickness loss per year (P = 0.009). There were no significant associations between baseline BMD and any of the cartilage outcomes. CONCLUSION: Longitudinal BMD loss is associated with progressive cartilage loss in knees with OA. Further work to clarify the basis of this relationship could reveal novel therapeutic targets for knee OA.
Assuntos
Densidade Óssea , Cartilagem Articular/patologia , Colo do Fêmur/patologia , Articulação do Joelho/patologia , Osteoartrite do Joelho/fisiopatologia , Idoso , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
Caveolae are organelles abundant in the plasma membrane of many specialized cells including endothelial cells (ECs), epithelial cells, and adipocytes, and in these cells, caveolin-1 (Cav-1) is the major coat protein essential for the formation of caveolae. To identify proteins that require Cav-1 for stable incorporation into membrane raft domains, a quantitative proteomics analysis using isobaric tagging for relative and absolute quantification was performed on rafts isolated from wild-type and Cav-1-deficient mice. In three independent experiments, 117 proteins were consistently identified in membrane rafts with the largest differences in the levels of Cav-2 and in the caveola regulatory proteins Cavin-1 and Cavin-2. Because the lung is highly enriched in ECs, we validated and characterized the role of the newly described protein Cavin-1 in several cardiovascular tissues and in ECs. Cavin-1 was highly expressed in ECs lining blood vessels and in cultured ECs. Knockdown of Cavin-1 reduced the levels of Cav-1 and -2 and weakly influenced the formation of high molecular weight oligomers containing Cav-1 and -2. Cavin-1 silencing enhanced basal nitric oxide release from ECs but blocked proangiogenic phenotypes such as EC proliferation, migration, and morphogenesis in vitro. Thus, these data support an important role of Cavin-1 as a regulator of caveola function in ECs.
Assuntos
Caveolina 1/metabolismo , DNA Polimerase I/metabolismo , Proteômica , Animais , Sequência de Bases , Western Blotting , Caveolina 1/genética , Linhagem Celular , Movimento Celular , Proliferação de Células , Cromatografia por Troca Iônica , Inativação Gênica , Humanos , Espectrometria de Massas , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , Óxido Nítrico/metabolismo , RNA Interferente PequenoRESUMO
Myeloperoxidase (MPO) is a pro-inflammatory enzyme abundantly secreted by activated myeloid cells after stroke. We show that when MPO activity is either blocked by the specific inhibitor 4-aminobenzoic acid hydrazide (ABAH) in wildtype (WT) mice or congenitally absent (MPO-/-), there was decreased cell loss, including degenerating neurons and oligodendrocytes, in the ischemic brains compared to vehicle-treated WT mice after stroke. MPO inhibition also reduced the number of activated myeloid cells after ischemia. MPO inhibition increased cytoprotective heat shock protein 70 (Hsp70) by 70% and p-Akt by 60%, while decreased the apoptotic marker p53 level by 62%, compared to vehicle-treated mice after ischemia. Similarly, MPO inhibition increased the number of Hsp70+/NeuN+ cells after stroke by 60%. Notably, MPO inhibition significantly improved neurological outcome compared with the vehicle-treated group after stroke. We further found longer treatment periods resulted in larger reduction of infarct size and greater neurobehavioral improvement from MPO inhibition, even when given days after stroke. Therefore, MPO inhibition with ABAH or MPO deficiency creates a protective environment that decreased inflammatory cell recruitment and increased expression of survival factors to improve functional outcome. MPO inhibition may represent a promising therapeutic target for stroke therapy, possibly even days after stroke has occurred.
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Compostos de Anilina/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Inibidores Enzimáticos/uso terapêutico , Peroxidase/metabolismo , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Deleção de Genes , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroproteção/efeitos dos fármacos , Peroxidase/antagonistas & inibidores , Peroxidase/genéticaRESUMO
BACKGROUND: The incidence of prostate cancer (PC) in Asian countries is increasing for reasons that are not clear. Data describing how PC is diagnosed and treated are fragmented across Asia, with marked intercountry and intracountry differences in outcome and knowledge gaps in clinical diagnostic and treatment practices. To address these knowledge gaps, we have established a PC disease registry with the aim of providing a comprehensive picture of PC diagnosis, prognosis, treatment and outcome, population characteristics, and comorbidities in real-world clinical practice in Asia. METHODS: This is a multinational, multicenter, longitudinal, and observational registry of PC patients presenting to participating tertiary-care hospitals in eight Asian countries (www.clinicaltrials.gov NCT02546908. Registry Identifier: NOPRODPCR4001). Approximately 3500-4000 eligible patients with existing or newly diagnosed high-risk localized PC (cohort 1), nonmetastatic biochemically recurrent PC (cohort 2), or metastatic PC (cohort 3) will be consecutively enrolled and followed-up for 5 years. An enrollment cap of 600 patients each will be applied to cohorts 1 and 2. Disease status is collected at enrollment, and outcome variables captured at 3-monthly intervals include diagnostic/staging, treatments including reason for change, laboratory results, comorbidities, and concomitant medications. Treatments and survival outcomes will be captured real time until study end. Patient-reported quality-of-life will be measured every 6 months, and medical resource utilization summarized at study end. Data analysis will include exploratory analyses of potential associations between multiple risk factors and socioeconomic variables with disease progression and evaluation of various treatments for PC including novel therapies on clinical outcome and health-related quality-of-life outcomes. RESULTS: 3636 men with PC were enrolled until July 2018; 416 in cohort 1, 399 in cohort 2 and 2821 in cohort 3. DISCUSSION: A total of 3636 patients were enrolled until July 2018. The prospective disease registry will provide comprehensive and wide-ranging real-world information on how PC is diagnosed and treated in Asia. Such information can be used to inform policy development for best practice and direct clinical study design evaluating new treatments.
RESUMO
Actin plays crucial roles in the mechanical response of cells to applied forces. For example, during cell adhesion, under the action of forces transmitted through integrins, actin filaments (F-actin) induce intracellular mechanical movements leading to changes in the cell shape. Muscle contraction results from the interaction of F-actin with the molecular motor myosin. Thus, understanding the origin of actin's mechanical flexibility is required to understand the basis of fundamental cellular processes. F-actin results from the polymerization of globular actin (G-actin), which contains one tightly bound nucleotide (ATP or ADP). Experiments revealed that G-actin is more flexible than F-actin, but no molecular-level understanding of this differential behavior exists. To probe the basis of the mechanical behavior of actin, we study the force response of G-actin bound with ATP (G-ATP) or ADP (G-ADP). We investigate the global unfolding of G-actin under forces applied at its ends and its mechanical resistance along the actin-actin and actin-myosin bonds in F-actin. Our study reveals that the nucleotide plays an important role in the global unfolding of actin, leading to multiple unfolding scenarios which emphasize the differences between the G-ATP and G-ADP states. Furthermore, our simulations show that G-ATP is more flexible than G-ADP and that the actin-myosin interaction surface responds faster to force than the actin-actin interaction surface. The deformation of G-actin under tension revealed in our simulations correlates very well with experimental data on G-actin domain flexibility.
Assuntos
Actinas/química , Difosfato de Adenosina/química , Trifosfato de Adenosina/química , Miosinas/química , Ligação Proteica , Desdobramento de ProteínaRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by autoantibodies and preferentially affecting women of childbearing age. Because the offspring of mothers with SLE show a high frequency of learning disorders, we hypothesized that maternally transferred autoantibodies that bind DNA and the N-methyl-D-aspartate receptor (NMDAR) could have a pathogenic role during fetal brain development. Here we describe a maternal SLE mouse model wherein pregnant dams harbored DNA-specific, NMDAR-specific autoantibodies throughout gestation. High titers of these autoantibodies in maternal circulation led to histological abnormalities in fetal brain and subsequent cognitive impairments in adult offspring. These data support a paradigm in which in utero exposure to neurotoxic autoantibodies causes abnormal brain development with long-term consequences. This paradigm may apply to multiple congenital neuropsychiatric disorders.
Assuntos
Autoanticorpos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Malformações do Sistema Nervoso/etiologia , Neurônios/imunologia , Complicações na Gravidez/imunologia , Animais , Anticorpos Antinucleares/imunologia , Autoanticorpos/sangue , Citotoxinas/imunologia , Modelos Animais de Doenças , Feminino , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Troca Materno-Fetal/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Malformações do Sistema Nervoso/imunologia , Neurônios/metabolismo , Gravidez , Complicações na Gravidez/sangue , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Neuropsychiatric systemic lupus erythematosus, which often entails cognitive disturbances and memory loss, has become a major complication for lupus patients. Previously, we developed a murine model of neuropsychiatric lupus based on Abs that cross-react with dsDNA and the NMDA receptor (NMDAR). We showed that these murine Abs impair cognition when they access the CNS through a breach in the blood-brain barrier (BBB) triggered by lipopolysaccharide. Because studies show that lupus patients possess anti-NMDAR Abs in their serum and cerebrospinal fluid, we decided to investigate whether these human Abs contribute to cognitive dysfunction. Here, we show that serum with reactivity to DNA and NMDAR extracted from lupus patients elicited cognitive impairment in mice receiving the serum intravenously and given lipopolysaccharide to compromise the BBB integrity. Brain histopathology showed hippocampal neuron damage, and behavioral testing revealed hippocampus-dependent memory impairment. To determine whether anti-NMDAR Abs exist in the brains of systemic lupus erythematosus patients, we eluted IgG from a patient's brain. The IgG bound DNA and NMDAR and caused neuronal apoptosis when injected into mouse brains. We examined four more brains of patients with neuropsychiatric lupus and found that they displayed endogenous IgG colocalizing with anti-NMDAR Abs. Our results indicate that lupus patients have circulating anti-NMDAR Abs capable of causing neuronal damage and memory deficit, if they breach the BBB, and that the Abs exist within patients' brains. Which aspects of neuropsychiatric lupus may be mediated by anti-NMDAR Abs, how often, and in which patients are now important clinical questions.
Assuntos
Autoanticorpos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Animais , Autoanticorpos/sangue , DNA/imunologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Hipocampo/patologia , Humanos , Lipopolissacarídeos/farmacologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/patologia , Transtornos da Memória/sangue , Transtornos da Memória/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/patologiaRESUMO
INTRODUCTION: We reviewed our experience with the use of gabapentin to treat symptoms of overactive bladder (OAB) and nocturia in patients who have failed conventional anticholinergic therapy. METHODS: Thirty-one patients referred to us with refractory (OAB) and/or nocturia were treated with oral gabapentin. All the patients had tried or remained on antimuscarinic drugs during treatment. Twenty-four of 31 complained of bothersome symptoms during day and night and the other seven had primary complaints of nocturia. Initial gabapentin doses ranged from 100-300 mg at bedtime. Dose was slowly titrated up to 3,000 mg based on patients' symptomatology and tolerability. RESULTS: The mean age was 51 years old (range 27-78). There were 13 men and 18 women. The median steady state dose chosen by the patient after initial titration was 600 mg/day. Fourteen of 31 patients reported subjective improvement of their frequency and 8 have been on the medication for over 12 months with persistent efficacy. For the 14 improved patients, mean frequency/24 hours decreased from 14.1 +/- 2.2 to 10.0 +/- 2.1. Three patients with primary nocturia reported improvement from a mean of 4.0 +/- 1.3 to 1.0 +/- 0.3 episodes/night. Six patients stopped taking the drug within one month due to side effects mostly described as drowsiness or lethargy. CONCLUSIONS: Fourteen of 31 patients with refractory (OAB) and nocturia improved with oral gabapentin. Gabapentin was generally well tolerated and can be considered in selective patients when conventional modalities have failed.
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Aminas/uso terapêutico , Ácidos Cicloexanocarboxílicos/uso terapêutico , Incontinência Urinária/tratamento farmacológico , Transtornos Urinários/tratamento farmacológico , Ácido gama-Aminobutírico/uso terapêutico , Adulto , Idoso , Antimaníacos/uso terapêutico , Antagonistas Colinérgicos/uso terapêutico , Protocolos Clínicos , Feminino , Gabapentina , Humanos , Masculino , Pessoa de Meia-Idade , Falha de TratamentoRESUMO
INTRODUCTION: We reviewed our experience with the use of gabapentin to treat symptoms of overactive bladder (OAB) and nocturia in patients who have failed conventional anticholinergic therapy. METHODS: Thirty-one patients referred to us with refractory (OAB) and/or nocturia were treated with oral gabapentin. All the patients had tried or remained on antimuscarinic drugs during treatment. Twenty-four of 31 complained of bothersome symptoms during day and night and the other seven had primary complaints of nocturia. Initial gabapentin doses ranged from 100-300 mg at bedtime. Dose was slowly titrated up to 3,000 mg based on patients' symptomatology and tolerability. RESULTS:The mean age was 51 years old (range 27-78). There were 13 men and 18 women. The median steady state dose chosen by the patient after initial titration was 600 mg/day. Fourteen of 31 patients reported subjective improvement of their frequency and 8 have been on the medication for over 12 months with persistent efficacy. For the 14 improved patients, mean frequency/24 hours decreased from 14.1 ± 2.2 to10.0 + 2.1. Three patients with primary nocturia reported improvement from a mean of 4.0 ± 1.3 to 1.0 ± 0.3 episodes/night. Six patients stopped taking the drug within one month due to side effects mostly described as drowsiness or lethargy. CONCLUSION: Fourteen of 31 patients with refractory (OAB) and nocturia improved with oral gabapentin. Gabapentin was generally well tolerated and can be considered in selective patients when conventional modalities have failed.