RESUMEN
BACKGROUND: To date, little is known about the prevalence of itch in multiple sclerosis (MS) and its characteristics. OBJECTIVES: In this cross-sectional study, we assessed the prevalence, intensity and characteristics of chronic pruritus in MS patients and its effect on quality-of-life and association with MS symptoms, clinical signs, comorbidities and MRI findings. METHODS: MS patients presenting to an outpatient neurology clinic were asked about their current symptoms. Those who experienced chronic pruritus were administered the Standardized Itch Questionnaire and Itch Quality of Life forms. All patients' medical records were reviewed. Patients with any medical conditions associated with chronic itch were excluded. RESULTS: Seventy-seven total MS patients were included, and 27 (35%) reported pruritus. The average itch NRS severity was 5.42 (range 0-10). The most affected body parts were the extremities, face or scalp, and trunk. Itch was characterized as acute (74%), paroxysmal (59%) and tingling (55%). Heat (52%) was the most common aggravating factor, while cold temperatures had no effect. Compared with MS patients without itch, itch patients reported more fatigue (77% vs 44%, p = 0.004), heat sensitivity (48% vs 20%, p = 0.0177), cognitive impairment (62% vs 26%, p = 0.0029) and depression or anxiety (48% vs 16%, p = 0.0063). Additionally, itch patients had more T2 hyperintensities in the posterior cervical cord and anterior pons/ventromedial medulla (74.1% vs 46.0%, p = 0.018 and 29.6% vs 8.0%, p = 0.020, respectively). Finally, T2 hyperintensities in the anterior pons/ventromedial medulla were strongly associated with itch localized to the face or scalp (OR 11.3, 95% CI 1.6-78.6, p = 0.025). CONCLUSION: MS patients experience paroxysmal neuropathic pruritus that is most frequently localized to the extremities, face or scalp. Patients with itch were more likely to have MS-related comorbidities and demyelinating lesions in the spinal cord or brainstem.
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Esclerosis Múltiple , Calidad de Vida , Humanos , Estudios Transversales , Esclerosis Múltiple/complicaciones , Índice de Severidad de la Enfermedad , Prurito/epidemiología , Prurito/etiología , Prurito/diagnósticoRESUMEN
BACKGROUND: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS). OBJECTIVE: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion. METHODS: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUCτ) and maximum plasma concentration (Cmax) for Weeks 8-12. B-cell depletion and safety/tolerability were assessed. RESULTS: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUCτ, 487.7 vs 474.1 h × µg/mL (ratio 1.03); Cmax, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated. CONCLUSION: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion.
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Esclerosis Múltiple , Anticuerpos Monoclonales , Anticuerpos Monoclonales Humanizados/efectos adversos , Humanos , Inyecciones Subcutáneas , Esclerosis Múltiple/inducido químicamenteRESUMEN
PURPOSE OF REVIEW: Multiple sclerosis is a heterogeneous disorder. Biomarkers to monitor disease activities are highly desirable especially because of the recent shift toward personalized medicine that coincides with the expansion of disease-modifying therapy. The visual system is highly involved in multiple sclerosis, and the rapid advancement of ophthalmic techniques has boosted the development of potential ocular biomarkers for multiple sclerosis management. RECENT FINDINGS: Recent studies have found that the rapid thinning of the peripapillary retinal nerve fiber layer and ganglion cell-inner plexiform layer (GCIPL) occurs in the progressive stage. Furthermore, the inter-eye thickness difference of the GCIPL could be used in identifying unilateral optic neuritis to facilitate the early diagnosis of multiple sclerosis. Moreover, the retinal microvascular alterations measured as vessel density were found to be related to the disability and visual function, although a standardized protocol to measure retinal microvascular alterations has not been well established. Additionally, aberrant ocular motility, such as fixation microsaccades, can be used to measure disability objectively. SUMMARY: The fast expansion of potential ocular biomarkers measured as retinal microstructural, microvascular, and ocular motility changes may facilitate the diagnosis and management of multiple sclerosis.
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Técnicas de Diagnóstico Oftalmológico/tendencias , Esclerosis Múltiple/diagnóstico , Neuritis Óptica/diagnóstico , Retina/diagnóstico por imagen , Biomarcadores/análisis , Diagnóstico Precoz , Humanos , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/terapia , Evaluación de Necesidades , Neuritis Óptica/epidemiología , Neuritis Óptica/etiología , Neuritis Óptica/terapia , Retina/patología , Retina/fisiopatología , Retina/ultraestructura , Tomografía de Coherencia Óptica/métodos , Tomografía de Coherencia Óptica/tendencias , Pruebas de Visión/métodos , Pruebas de Visión/tendenciasRESUMEN
BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).
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Encéfalo/patología , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Piridinas/uso terapéutico , Adulto , Atrofia/prevención & control , Encéfalo/diagnóstico por imagen , Depresión/inducido químicamente , Imagen de Difusión Tensora , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Cefalea/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/patología , Inhibidores de Fosfodiesterasa/efectos adversos , Piridinas/efectos adversosRESUMEN
Aging is one of the main risk factors for cardiovascular diseases, and oxidative stress is a key element responsible for the development of age-related pathologies. In addition, the alteration of circadian rhythms also contributes to cardiovascular pathology, but the underlying mechanisms are not well defined. We investigated the aging consequences on the temporal patterns of antioxidant defenses, the molecular clock machinery, and the blood pressure, in the heart of male rats maintained under constant darkness (free running) conditions. Male Holtzman rats from young adult (3-month-old) and older (22-month-old) groups were maintained under constant darkness (12-h dark:12-h dark, DD) condition during fifteen days before the experiment. After the DD period, heart ventricle samples were isolated every 4-h throughout a 24-h period. We observed circadian rhythms of catalase (CAT) and glutathione peroxidase (GPx) mRNA expression, as well as ultradian rhythms of Nrf2 mRNA levels, in the heart of young adult rats. We also found circadian oscillations of CAT and GPx enzymatic activities, reduced glutathione (GSH) and BMAL1 protein in the same group. Interestingly, aging abolished the rhythms of CAT and GPx enzymatic activities, phase-shifted the rhythm's acrophases of GSH and BMAL1 protein levels and turned circadian the ultradian oscillation of Nrf2 expression. Moreover, aging phase-shifted the circadian pattern of systolic blood pressure. In conclusion, aging modifies the temporal organization of antioxidant defenses and blood pressure, probably, as a consequence of a disruption in the circadian rhythm of the clock's transcriptional regulator, BMAL1, in heart.
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Antioxidantes , Ritmo Circadiano , Envejecimiento , Animales , Presión Sanguínea , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Fingolimod is a S1P1 receptor modulator that prevents activated lymphocyte egress from lymphoid tissues causing lymphopenia, mainly affecting CD4+ T lymphocytes. Withdrawal from fingolimod can be followed by severe disease reactivation, and this coincides with return of autoreactive lymphocytes into circulation. The CD8+ T cytotoxic population returns prior to the regulatory CD4+ T lymphocytes leading to a state of dysregulation, which may contribute to the rebound and severity of clinical relapses. On the other hand, dimethyl fumarate (DMF) preferentially reduces CD8+ T lymphocytes, has the same efficacy as fingolimod, and therefore, was expected to be a suitable oral alternative to reduce the rebound associated with fingolimod withdrawal. CASE PRESENTATION: We present six patients with relapsing-remitting MS who developed an unexpected increase in disease activity after transitioning from fingolimod to DMF. All patients were clinically and radiologically stable on fingolimod for at least 1 year. The switch in therapy was due to significantly low CD4+ T lymphocyte count ≤65 cells/ul (normal range 490-1740 cells/ul), after discussing the results with the patients and the potential risk for opportunistic infections including cryptococcal infections. DMF was introduced following a washout period of 5 to 11 weeks to allow reconstitution of the immune system and for the absolute lymphocyte count to reach ≥500 cells/ul. Every patient who experienced a relapse had several enhancing lesions in the brain and/or spinal cord between 12 to 23 weeks after cessation of fingolimod and 1 to 18 weeks after starting DMF. All relapses were treated with intravenous methylprednisolone with good clinical responses. CONCLUSION: The anticipated beneficial response of DMF treatment to mitigate rebound after fingolimod therapy cessation was not observed. Our patients experienced rebound disease despite being on treatment with DMF. Additional studies are necessary to understand which treatments are most effective to transition to after discontinuing fingolimod.
Asunto(s)
Dimetilfumarato/uso terapéutico , Sustitución de Medicamentos/efectos adversos , Clorhidrato de Fingolimod/uso terapéutico , Inmunosupresores/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Brote de los Síntomas , Adulto , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/patologíaRESUMEN
BACKGROUND: The steady-state pattern electroretinogram (PERG) is a sensitive measure of retinal ganglion cell (RGC) function that includes within-test progressive changes-adaptation-reflecting RGC autoregulatory dynamics. Comprehensive PERG assessment in patients with multiple sclerosis (MS) (with or without optic neuritis [ON]) may provide unique information about RGC dysfunction and its progression, as well as a comparison between functional loss and structural loss as measured by optical coherence tomography (OCT). The goal of this project was to measure steady-state PERG components and their associations with intraretinal layer thicknesses in MS. METHODS: One hundred forty eyes of 70 patients with relapsing-remitting MS and 126 eyes of 63 age- and sex-matched healthy control subjects (HC) were investigated using a new-generation PERG method and ultrahigh-resolution OCT. Of MS eyes, there were 30 eyes with ON (MSON), 22 non-ON fellow eyes (MSFE), and 88 non-ON MS eyes (MSNON). PERG amplitude, phase (latency), and adaptation of amplitude and phase were measured and correlated with OCT-determined thicknesses of intraretinal layers. RESULTS: The average PERG amplitude in MSON eyes was significantly lower than MSFE (P = 0.007), MSNON (P = 0.002), and HC (P < 0.001). The PERG amplitude in MSFE eyes was also significantly lower than HC (P = 0.039). The PERG latency in MSON eyes was significantly shorter than in MSFE (P = 0.001), MSNON (P = 0.002), and HC (P < 0.001). The PERG latency in MSFE (P = 0.007) and MSNON (P = 0.002) was significantly shorter than in HC. However, no significant differences were found between MSFE and MSNON (P > 0.05). PERG adaptation of amplitude in MSON was significantly lower than that in MSNON (P = 0.039) and HC (P = 0.037). Both the amplitude and latency in the MS eyes were significantly correlated with the thicknesses of the macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (GCIPL). CONCLUSIONS: Shortened PERG latency and impaired autoregulatory dynamics occurred in MS, suggesting preferential dysfunction of small, slower RGC axons and decreased ability of RGC to autoregulate their gain in response to PERG stimulus. The established relations of PERG measurements with intraretinal thickness measurements suggested that PERG losses were primarily associated with GCIPL and mRNFL thinning.
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Esclerosis Múltiple/fisiopatología , Neuritis Óptica/fisiopatología , Células Ganglionares de la Retina/fisiología , Adulto , Axones/fisiología , Electrorretinografía , Femenino , Homeostasis/fisiología , Humanos , Masculino , Persona de Mediana Edad , Reconocimiento Visual de Modelos , Tomografía de Coherencia Óptica , Agudeza Visual/fisiologíaRESUMEN
The aim of the present work was to investigate whether the nitric oxide produced by the nitric oxide/nitric oxide synthase (NO/NOS) system present in the coeliac ganglion modulates the effects of cholinergic innervation on oxidative status, steroidogenesis and apoptotic mechanisms that take place in the rat ovary during the first proestrous. An ex vivo Coeliac Ganglion- Superior Ovarian Nerve- Ovary (CG-SON-O) system was used. Cholinergic stimulation of the CG was achieved by 10-6â¯M Acetylcholine (Ach). Furthermore, 400⯵M Aminoguanidine (AG) - an inhibitor of inducible-NOS was added in the CG compartment in absence and presence of Ach. It was found that Ach in the CG compartment promotes apoptosis in ovarian tissue, probably due to the oxidative stress generated. AG in the CG compartment decreases the release of NO and progesterone, and increases the release of estradiol from the ovary. The CG co-treatment with Ach and AG counteracts the effects of the ganglionic cholinergic agonist on ovarian oxidative stress, increases hormone production and decreases Fas mRNA expression. These results suggest that NO is an endogenous modulator of cholinergic neurotransmission in CG, with implication in ovarian steroidogenesis and the apoptotic mechanisms that take place in the ovary during the preovulatory period in rats.
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Ganglios Simpáticos/metabolismo , Óxido Nítrico/metabolismo , Ovario/fisiología , Animales , Antioxidantes/metabolismo , Enzimas/metabolismo , Estradiol/metabolismo , Femenino , Fase Folicular/fisiología , Ganglios Simpáticos/efectos de los fármacos , Guanidinas/farmacología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ovario/citología , Ovario/efectos de los fármacos , Estrés Oxidativo/fisiología , Carbonilación Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Transmisión Sináptica/fisiología , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
BACKGROUND: The transparent ocular structure enables quantitative analysis of microvasculature of retina, a neuronal tissue affected by multiple sclerosis (MS). OBJECTIVE: The aim of this study was to determine whether the retinal blood flow velocity and flow volume at the macula are impaired in patients with relapsing remitting multiple sclerosis (RRMS). METHODS: A total of 17 RRMS patients and 17 age- and gender-matched healthy subjects were assessed. A retinal function imager was used to measure the blood flow velocity of retinal arterioles and venules and to calculate the total perifoveal blood flow volume. RESULTS: The blood flow velocities of the retinal arterioles (3.34 ± 0.89 mm/s) and venules (2.61 ± 0.6 mm/s) were significantly lower in MS patients than normal subjects (arteriole: 4.10 ± 0.87 mm/s; venule: 3.22 ± 0.65 mm/s, both p = 0.01). In addition, the total perifoveal blood flow volume in arterioles (3.74 ± 1.64 nL/s) and venules (3.81 ± 1.60 nL/s) were significantly lower in MS patients than in normal subjects (arteriole: 4.87 ± 1.41 nL/s, p = 0.02; venule: 4.71 ± 1.64 nL/s, p = 0.04). CONCLUSION: The impaired retinal microcirculation in RRMS patients indicates microvascular dysfunction in MS.
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Velocidad del Flujo Sanguíneo/fisiología , Microcirculación/fisiología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Vasos Retinianos/fisiopatología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Imagen Óptica , Vasos Retinianos/diagnóstico por imagenRESUMEN
An ex-vivo Coeliac Ganglion-Superior Ovarian Nerve-Ovary (CG-SON-O) system from virgin rats in the first proestrous was used to test whether cholinergic stimulation of CG affects oxidative status and steroidogenesis in the ovary. The CG and the O were placed in separate buffered-compartments, connected by the SON, and the CG was stimulated by acetylcholine (Ach). To test a possible role of nitric oxide (NO) in the ovarian response to cholinergic stimulation of CG, aminoguanidine (AG) - an inhibitor of inducible-NO synthase was added to the O compartment. After 180 min incubation, the oxidative status was assessed in O whereas nitrite and steroidogenesis were assessed at 30, 120 and 180 min. Ach in CG decreased the total antioxidant capacity, but increased NO production and protein carbonization in O. Ach stimulation of CG increased estradiol, but decreased progesterone release in O by reducing the mRNAs related to their synthesis and degradation. The addition of AG to the O compartment caused an opposite effect, which was more pronounced in the presence of Ach in the CG compartment than in its absence. These results show that the stimulation of the extrinsic-cholinergic innervation of the O increases the concentration of NO, causes oxidative stress and modulates steroidogenesis in the first rat proestrous.
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Colinérgicos/farmacología , Ganglios Simpáticos/efectos de los fármacos , Óxido Nítrico/metabolismo , Ovario/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Proestro , Progesterona/biosíntesis , Animales , Femenino , Ganglios Simpáticos/fisiología , Óxido Nítrico/biosíntesis , Ovario/inervación , Ovario/metabolismo , Proestro/efectos de los fármacos , Progesterona/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
There is considerable evidence of the neuroendocrine control involved in luteal regression in the rat. In addition, circulating prolactin (PRL), which increases during the night before parturition, may gain access to the coeliac ganglion (CG), indirectly impacting the physiology of the ovary because of the known connection between the CG and the ovary via the superior ovarian nerve (SON). In this work we investigated in the CG-SON-ovary system and whether PRL added to the CG has an impact, indirectly via the SON, on luteal regression on Day 21 of pregnancy. The system was incubated without (control) or with PRL added to the CG. We measured the ovarian release of progesterone (P), oestradiol and prostaglandin F2 alpha (PGF2α) by radioimmunoassay, and nitrites (NO) by the Griess method. Luteal mRNA expression of 3ß-hydroxysteroid dehydrogenase (3ß-HSD), 20α-HSD, aromatase, inducible nitric oxide synthase (iNOS) and apoptosis regulatory factors was analysed by reverse transcription-polymerase chain reaction. P release, the expression of Bcl-2 and the Bcl-2:Bax ratio was lower than control preparations, while the expression of 20α-HSD and the release of NO and PGF2α were higher in the experimental group. In conclusion, PRL acts at the CG and, by a neural pathway, modulates luteal function at the end of pregnancy.
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Cuerpo Lúteo/inervación , Ganglios Simpáticos/efectos de los fármacos , Luteólisis/efectos de los fármacos , Ovario/inervación , Prolactina/farmacología , 20-alfa-Hidroxiesteroide Deshidrogenasa/genética , 20-alfa-Hidroxiesteroide Deshidrogenasa/metabolismo , 3-Hidroxiesteroide Deshidrogenasas/genética , 3-Hidroxiesteroide Deshidrogenasas/metabolismo , Animales , Aromatasa/genética , Aromatasa/metabolismo , Cuerpo Lúteo/enzimología , Cuerpo Lúteo/patología , Dinoprost/metabolismo , Estradiol/metabolismo , Femenino , Ganglios Simpáticos/fisiología , Edad Gestacional , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nitritos/metabolismo , Ovario/metabolismo , Embarazo , Progesterona/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas Sprague-Dawley , Factores de Tiempo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
An ex-vivo Coeliac Ganglion-Superior Ovarian Nerve-Ovary (CG-SON-O) system and an ovary without peripheral neural influence from virgin rats in the first proestrous were used to test whether ovarian extrinsic innervation and nitric oxide (NO) affects steroidogenesis in the ovary. The CG and the ovary were placed in separate buffered-compartments, connected by the SON. Stimulation of the CG was achieved by 10(-6)M acetylcholine (Ach). The ovary without peripheral neural influence was placed alone in a buffered-compartment. To test a possible role of NO in the ovarian response to peripheral neural influence, 100µM sodium nitroprusside (SNP, an NO donor) and 100µM N(G)-nitro-l-arginine methyl ester (l-NAME, an inhibitor of NO synthase) were added to the ovarian compartment separately. In the CG-SON-O system, SNP into the ovarian compartment increased the concentration of NO, reduced the release of progesterone and increased the release of estradiol (E2), increasing the mRNAs related to their synthesis enzyme. The addition of l-NAME to the ovarian compartment caused an opposite effect. In the ovary alone, NO manifested an antisteroidogenic effect on both hormones. These results show that the ovarian extrinsic innervation maintains a direct relationship between NO and E2, both needed at high levels during the follicular phase, allowing the continuity of the estrous cycle.
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Fibras Colinérgicas/fisiología , Óxido Nítrico/fisiología , Ovario/metabolismo , Animales , Femenino , Ovario/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
NEW FINDINGS: What is the central question of this study? The processes involved in luteal involution have not yet been clarified and, in general, have been studied only from a hormonal point of view. We investigated whether progesterone, from the coeliac ganglion through the superior ovarian nerve, is able to modify the luteal regression of late pregnancy in the rat. What is the main finding and its importance? We showed that the luteal regression might be reversed by the neural effect of progesterone and demonstrated the presence of its receptors in the coeliac ganglion. This suggests that the peripheral neural pathway, through neuron-hormone interaction, represents an additional mechanism to control luteal function in addition to the classical endocrine regulation. The corpus luteum (CL) is a transitory endocrine gland that produces progesterone (P). At the end of its useful life, it suffers a process of functional and structural regression until its complete disappearance from the ovary. To investigate whether P is able to regulate the process of luteal regression through the peripheral neural pathway, we used the coeliac ganglion (CG)-superior ovarian nerve-ovary system from rats on day 21 of pregnancy. We stimulated the CG with P and analysed the functional regression through ovarian P release measured by radioimmunoassay, expression by RT-PCR and activity of luteal 3ß- and 20α-hydroxysteroid dehydrogenase (anabolic and catabolic P enzymes, respectively). The luteal structural regression was evaluated through a study of apoptosis measured by TUNEL assay and the expression of apoptotic factors, such as Bcl-2, Bax, Fas and Fas ligand (FasL) by RT-PCR. To explore whether the effects mediated by P on the CL may be associated with P receptors, their presence in the CG was investigated by immunohistochemistry. In the group stimulated with P in the CG, the ovarian P release and the 3ß-hydroxysteroid dehydrogenase activity increased, whereas the expression and activity of 20α-hydroxysteroid dehydrogenase decreased. In addition, a decrease in the number of apoptotic nuclei and a decrease of the expression of FasL were observed. We demonstrated the presence of P receptors in the CG. Overall, our results suggest that the regression of the CL of late pregnancy may be reprogrammed through the peripheral neural pathway, and this effect might be mediated by P bound to its receptor in the CG.
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Cuerpo Lúteo/fisiología , Ganglios Simpáticos/fisiología , Luteólisis/fisiología , Neurotransmisores/farmacología , Progesterona/farmacología , Receptores de Progesterona/fisiología , Animales , Cuerpo Lúteo/efectos de los fármacos , Femenino , Ganglios Simpáticos/efectos de los fármacos , Luteólisis/efectos de los fármacos , Neurotransmisores/fisiología , Técnicas de Cultivo de Órganos , Ovario/efectos de los fármacos , Ovario/fisiología , Embarazo , Progesterona/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de Progesterona/agonistasRESUMEN
An African-American male presented with bilateral visual impairment, gait difficulties, and bladder and bowel incontinence raising concerns for multiple sclerosis (MS) or neuromyelitis optica (NMO). He was identified to be HIV-1 infected with high viral load and low CD4+ counts. Magnetic resonance imaging (MRI) of the brain was abnormal, but atypical for MS. MRI of the cervical and thoracic spinal cord showed multiple areas of myelitis with a longitudinally extensive thoracic transverse myelitis that showed enhancement with gadolinium suggestive of NMO. Cerebrospinal fluid showed oligoclonal IgG bands but did not show reactivity to aquaporin 4. Patient underwent treatment for the acute exacerbation with intravenous corticosteroids and treatment of the HIV infection with highly active antiretroviral therapy (HAART). A year later, his viral load was <20 copies/ml and CD4+ counts were normal. Vision did not significantly improve, but his ambulation improved from a near total non-ambulatory state to ambulating without aids and resolution of the bladder and bowel incontinence. A demyelinating disorder of the central nervous system (CNS) like MS or NMO has been previously reported in the context of HIV infection. The remarkable improvement of symptoms has also been previously reported with HAART, and these observations have led to clinical trials of MS with HAART therapy in the absence of HIV infection. We reviewed the few cases of CNS demyelinating disorders with HIV infection reported in the literature and speculate on the mechanisms of pathogenesis.
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Enfermedades Autoinmunes Desmielinizantes SNC/virología , Infecciones por VIH/complicaciones , Terapia Antirretroviral Altamente Activa , Enfermedades Autoinmunes Desmielinizantes SNC/patología , Enfermedades Autoinmunes Desmielinizantes SNC/fisiopatología , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: Alterations in enzymatic antioxidant defense systems lead to a deficit of cognitive functions and altered hippocampal synaptic plasticity. The objectives of this study were to investigate endogenous rhythms of catalase (CAT) and glutathione peroxidase (GPx) expression and activity, as well as CREB1 mRNA, in the rat hippocampus, and to evaluate to which extent the vitamin A deficiency could affect those temporal patterns. METHODS: Rats from control and vitamin A-deficient (VAD) groups received a diet containing 4000 IU of vitamin A/kg diet, or the same diet devoid of vitamin A, respectively, during 3 months. Rats were maintained under 12-hour-dark conditions, during 10 days before the sacrifice. Circadian rhythms of CAT, GPx, RXRγ, and CREB1 mRNA levels were determined by reverse transcriptrase polymerase chain reaction in hippocampus samples isolated every 4 hours during a 24-hour period. CAT and GPx enzymatic activities were also determined by kinetic assays. Regulatory regions of clock and antioxidant enzymes genes were scanned for E-box, RXRE, and CRE sites. RESULTS: E-box, RXRE, and CRE sites were found on regulatory regions of GPx and CAT genes, which display a circadian expression in the rat hippocampus. VAD phase shifted CAT, GPx, and RXRγ endogenous rhythms without affecting circadian expression of CREB1. DISCUSSION: CAT and GPx expression and enzymatic activity are circadian in the rat hippocampus. The VAD affected the temporal patterns antioxidant genes expression, probably by altering circadian rhythms of its RXR receptors and clock factors; thus, it would impair the temporal orchestration of hippocampal daily cognitive performance.
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Catalasa/metabolismo , Dieta , Glutatión Peroxidasa/metabolismo , Hipocampo/enzimología , Vitamina A/sangre , Animales , Catalasa/genética , Ritmo Circadiano/fisiología , Cognición/fisiología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Glutatión Peroxidasa/genética , Masculino , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor gamma X Retinoide/genética , Receptor gamma X Retinoide/metabolismo , Vitamina A/administración & dosificación , Deficiencia de Vitamina A/sangreRESUMEN
The recent success of anti-CD20 monoclonal antibody therapies in the treatment of multiple sclerosis (MS) has highlighted the role of B cells in the pathogenesis of MS. In people with MS, the inflammatory characteristics of B-cell activity are elevated, leading to increased pro-inflammatory cytokine release, diminished anti-inflammatory cytokine production and an accumulation of pathogenic B cells in the cerebrospinal fluid. Rituximab, ocrelizumab, ofatumumab, ublituximab and BCD-132 are anti-CD20 therapies that are either undergoing clinical development, or have been approved, for the treatment of MS. Despite CD20 being a common target for these therapies, differences have been reported in their mechanistic, pharmacological and clinical characteristics, which may have substantial clinical implications. This narrative review explores key characteristics of these therapies. By using clinical trial data and real-world evidence, we discuss their mechanisms of action, routes of administration, efficacy (in relation to B-cell kinetics), safety, tolerability and convenience of use. Clinicians, alongside patients and their families, should consider the aspects discussed in this review as part of shared decision-making discussions to improve outcomes and health-related quality of life for people living with MS.
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Antineoplásicos , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Calidad de Vida , Anticuerpos Monoclonales/farmacología , Rituximab/uso terapéutico , Antineoplásicos/uso terapéutico , CitocinasRESUMEN
Aging is a major risk factor for cognitive deficits, impaired locomotion, and gait disorders. Although oxidative stress and circadian disruption are involved in both normal aging and the pathogenesis of age-associated diseases, just a very few studies explore the consequences of aging on circadian rhythms in the cerebellum. Here, we investigated age-dependent changes in the circadian organization of the molecular clock, antioxidant defenses and synaptic plasticity-related factors, in the rat cerebellum, and discussed the impact of that altered temporal organization on the cognitive function of this brain area. Particularly, we examined the circadian patterns of Brain and muscle ARNT-like 1 (BMAL1) protein levels, Glutathione peroxidase 4 (GPx4) gene expression, GPx and Catalase (CAT) enzymes activity, reduced glutathione (GSH) levels, and the Brain-derived neurotrophic factor (Bdnf) and its Tyrosine kinase receptor B (TrkB) circadian expression. Endogenously-driven circadian rhythms of BMAL1, GPx4, CAT, GSH, and Bdnf/TrkB factors, were observed in the young rat cerebellum. The rhythms' acrophases show a circadian organization that might be crucial for the daily cerebellar-dependent cognitive functions. Notably, aging disrupted circadian rhythms and the temporal organization of BMAL1, antioxidant defenses, and cognitive Bdnf/TrkB gene expression. Increased oxidative stress and disruption of clock-controlled rhythms during aging, might precede and cause the loss of circadian organization in the aged cerebellum. We expect our results highlight circadian rhythms of the studied factors as new targets for the treatment of age-dependent cerebellar disorders.
RESUMEN
OBJECTIVES: To measure the impact of superimposition methods and the designated comparison area on accuracy analyses of dentate models using an ISO-recommended 3-dimensional (3D) metrology-grade inspection software (Geomagic Control X; 3D Systems; Rock Hill, South Carolina; USA). MATERIALS AND METHODS: A dentate maxillary typodont scanned with a desktop scanner (E4; 3 Shape; Copenhagen; Denmark) and an intraoral scanner (Trios 4; 3 Shape; Copenhagen; Denmark) was used as reference. Eight groups were created based on the core features of each superimposition method: landmark-based alignment (G1); partial area-based alignment (G2); entire tooth area-based alignment (G3); double alignment combining landmark-based alignment with entire tooth area-based alignment (G4); double alignment combining partial area-based alignment with entire tooth area-based alignment (G5); initial automated quick pre-alignment (G6); initial automated precise pre-alignment (G7); and entire model area-based alignment (G8). Diverse variations of each alignment and two regions for accuracy analyses (teeth surface or full model surface) were tested, resulting in a total of thirty-two subgroups (n = 18). The alignment accuracy between experimental and reference meshes was quantified using root mean square (RMS) error as trueness and its repeatability as precision. The descriptive statistics, a factorial repeated measures analysis of variance (ANOVA) and a post hoc Tuckey multiple comparison tests were used to analyze the trueness, and precision (α = 0.05). RESULTS: A total of 576 superimpositions were performed. The unique partial area-based superimposition method demonstrated the least precise alignment and was the sole group to exhibit a significant difference (p<.001). Automated initial pre-alignments demonstrated similar accuracy to other superimposition methods (p>.05). Double alignments did not result in accuracy improvement (p>.05). The designated comparison area displayed differences in both trueness (p<.001) and precision (p<.001), leading to an overall discrepancy of 8 ± 4 µm between selecting the teeth surface or full model surface. CONCLUSIONS: The superimposition method choice within the tested software did not impact accuracy analyses, except when the alignment relies on a unique and reduced area, such as the palatal rugae, a single tooth, or three adjacent teeth on one side. CLINICAL SIGNIFICANCE: The superimposition method choice within the tested ISO-recommended 3D inspection software did not impact accuracy analyses.
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Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Modelos Dentales , Programas Informáticos , Humanos , Imagenología Tridimensional/métodos , Procesamiento de Imagen Asistido por Computador/métodos , Puntos Anatómicos de Referencia , Reproducibilidad de los Resultados , Maxilar/anatomía & histología , Diente/anatomía & histología , Diente/diagnóstico por imagenRESUMEN
BACKGROUND AND OBJECTIVES: Race and ethnicity may influence the efficacy of disease-modifying therapies in patients with multiple sclerosis (MS). Incidence of MS in ethnically diverse groups may be higher; however, these populations are under-represented in MS trials. This post hoc analysis compared the proportion of patients achieving 3-parameter no evidence of disease activity (NEDA-3) with ofatumumab vs teriflunomide in participants with relapsing MS (RMS) enrolled in the ASCLEPIOS I/II trials by race/ethnicity subgroup. METHODS: ASCLEPIOS I/II were identical, double-blind, double-dummy, active-controlled, multicenter, phase 3 trials. Participants were randomized (1:1) to receive ofatumumab 20 mg every 4 weeks or teriflunomide 14 mg once daily for up to 30 months. Pooled data were used to determine the efficacy/safety of ofatumumab vs teriflunomide in participants who self-identified as non-Hispanic Black, non-Hispanic Asian, Hispanic/Latino, or non-Hispanic White. Participants who did not self-identify into one of these groups were classified as other/unknown. RESULTS: Of the 1,882 participants, 64 (3.4%) self-identified as non-Hispanic Black, 71 (3.8%) as non-Hispanic Asian, 145 (7.7%) as Hispanic/Latino, and 1,538 (81.7%) as non-Hispanic White. Baseline participant demographics/characteristics were largely balanced across subgroups, aside from minor variations in sex, disease duration, and MRI lesions. From months 0 to 24, the proportion of ofatumumab vs teriflunomide-treated patients achieving NEDA-3 (odds ratio [95% CI]) was as follows: non-Hispanic Black, 33.3% vs 3.4% (15.9 [1.67-151.71; p = 0.0162]); non-Hispanic Asian, 42.9% vs 21.9% (3.18 [0.95-10.59; p = 0.06]); Hispanic/Latino, 36.6% vs 18.6% (3.21 [1.32-7.79; p = 0.01]); and non-Hispanic White, 37.4% vs 16.6% (3.57 [2.73-4.67; p < 0.0001]). Rates of AEs were generally similar between treatment groups and across race/ethnicity subgroups; no new or unexpected safety signals were identified. DISCUSSION: Ofatumumab was associated with greater proportions of NEDA-3 achievement than teriflunomide across race/ethnicity subgroups in the ASCLEPIOS trials. Within each treatment group, the proportion of patients achieving NEDA-3 from months 0 to 24 was similar across the subgroups and overall pooled population. Both ofatumumab and teriflunomide were well tolerated. Future MS trials should include ethnically diverse groups to better inform treatment decisions and improve real-world patient outcomes. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT02792218 (clinicaltrials.gov/ct2/show/NCT02792218), NCT02792231 (clinicaltrials.gov/ct2/show/NCT02792231). Submission date: June 2, 2016. First enrollment: August 26, 2016. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients aged 18-55 years with RMS, the improvement in NEDA-3 with ofatumumab was comparably better than with teriflunomide among patients self-identified as non-Hispanic Black, non-Hispanic Asian, non-Hispanic White, Hispanic/Latino, and other/unknown.
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Anticuerpos Monoclonales Humanizados , Crotonatos , Hidroxibutiratos , Esclerosis Múltiple Recurrente-Remitente , Nitrilos , Toluidinas , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/uso terapéutico , Crotonatos/uso terapéutico , Método Doble Ciego , Etnicidad , Hispánicos o Latinos , Hidroxibutiratos/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/etnología , Nitrilos/uso terapéutico , Toluidinas/uso terapéutico , Resultado del Tratamiento , Negro o Afroamericano , BlancoRESUMEN
BACKGROUND: Giant pituitary adenomas (GPAs) are defined as tumors with ≥40 mm in any maximum diameter, and these tend to invade multiple intracranial compartments. Hence, treatment remains a surgical challenge. OBJECTIVE: To describe the clinical and surgical outcomes of the endoscopic endonasal approach (EEA) for GPA in a pituitary referral center in Latin America and to analyze associated predictive factors. METHODS: 37 patients with histologically-confirmed GPA treated solely through the EEA between a 2-year period were included. Preoperative and postoperative clinical and neuroimaging findings; surgical morbidity and mortality; and binary logistic regression analysis to assess predictive factors were analyzed. RESULTS: Preoperative visual impairment prevalence was 97.3%. Mean tumor volume was 32 cc and gross total resection rate was 40.5%. Favorable visual acuity and visual fields outcome rate was 75% and 82.9%, respectively. In the multivariate analysis, bilateral cavernous sinus invasion (P = 0.018) and postoperative cerebrospinal fluid (CSF) leak (P = 0.036) were associated with an unfavorable visual acuity outcome, while radiation therapy (P = 0.035) was for visual fields. Similarly, intraoperative CSF leak was a predictive factor for postoperative CSF leak (10.8%) (P = 0.042) and vascular injury (13.5%) (P = 0.048). CONCLUSIONS: In this first Mexican clinical series, we demonstrated that the EEA is a safe and effective technique for GPA, although early diagnosis and prompt intervention may promote further visual function preservation without significant endocrine morbidity.