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Theory without relevance for practice in a professional graduate degree has been critiqued by some scholars as a deficit approach when preparing MBA students for the workforce. Scholars and practitioners alike call for more pedagogy in the curriculum with a focus on innovation, creativity, and the involvement of industry practitioners. This paper serves as a case study of a moment in time on Monday, 14 June 2021, when the concept of "pracademics" was realized between two artists and two faculty. Following the transcription of the dialogue between two guest speakers from the Hip Hop world (i.e., Fat Joe and DJ Khaled) and two faculty from the sport management MBA program, the paper analyzes the deeper meaning of their intellectual presence with their expertise in the business of culture (i.e., Hip Hop). Findings reveal how the pairing of Hip Hop artists and faculty in an MBA program can address the innovation gap within global business curricula and models. The broader umbrella of pedagogy and application has implications for other academic disciplines to embrace this concept of pairing academics and industry practitioners.
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Complanadine A and lycodine are representative members of the Lycopodium alkaloids with a characteristic pyridine-containing tetracyclic skeleton. Complanadine A has demonstrated promising neurotrophic activity and potential for persistent pain management. Herein we report a pyrrole strategy enabled by one-carbon insertion and polarity inversion for concise total syntheses of complanadine A and lycodine. The use of a pyrrole as the pyridine precursor allowed the rapid construction of their tetracyclic skeleton via a one-pot Staudinger reduction, amine-ketone condensation, and Mannich-type cyclization. The pyrrole group was then converted to the desired pyridine by the Ciamician-Dennstedt rearrangement via a one-carbon insertion process, which also simultaneously introduced a chloride at C3 for the next C-H arylation. Other key steps include a direct anti-Markovnikov hydroazidation, a Mukaiyama-Michael addition, and a Paal-Knorr pyrrole synthesis. Lycodine and complanadine A were prepared in 8 and 11 steps, respectively, from a readily available known compound.
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Compuestos Heterocíclicos de 4 o más AnillosRESUMEN
OBJECTIVES: To compare participant-reported bleeding and pain with two medication regimens for early pregnancy loss (EPL). STUDY DESIGN: We performed a secondary analysis of a randomized trial in which participants took either mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later or misoprostol alone for medical management of EPL. Participants reported bleeding and pain (Numeric Pain Rating Scale, NPRS, 0-10) with daily paper diaries and at study visits on trial days 3, 8, and 30. We used, Fisher's exact, Pearson chi-square, Wilcoxon rank sum, and Student's t-tests to compare onset, duration, and severity of bleeding and pain symptoms between trial arms after misoprostol administration. RESULTS: Among 291 participants who submitted diary data, 143 received mifepristone pretreatment. A larger proportion of this group reported moderate or heavy bleeding on trial day 2, the day of misoprostol administration, compared with those who did not receive pretreatment (73% vs 47%, p < 0.01). Between days 4 and 8, more mifepristone-pretreatment participants reported mild or no bleeding, compared with the misoprostol-only arm (78% vs 61%, p < 0.01). Average pain score for trial days 2-4 was higher for the pretreatment group compared with the misoprostol-only group (6.9 vs 6.0, p = 0.01), and there was a trend toward shorter total duration of pain (15 vs 19 hours, p = 0.08). These differences remained after controlling for treatment success across arms. CONCLUSIONS: Mifepristone pretreatment increased the severity of pain but not bleeding and resulted in a shorter trajectory of symptoms during medical management of EPL. IMPLICATIONS: Mifepristone pretreatment decreases the duration of heavy bleeding and there was a trend toward decreased duration of pain during medical management of miscarriage, indicating that this medication improves the efficiency, in addition to the efficacy, of this treatment.
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Abortivos no Esteroideos , Abortivos Esteroideos , Aborto Inducido , Aborto Espontáneo , Misoprostol , Femenino , Humanos , Mifepristona , Dolor/tratamiento farmacológico , EmbarazoRESUMEN
Covering: 2000-2018In this review, we highlight recent examples of natural product total syntheses employing transition metal-mediated/catalyzed carbonylative cyclization strategies to build key ring systems. It mainly covers carbonylative cyclizations for the construction of O-heterocycles, N-heterocycles and carbocycles including cyclic ketones and phenols. The reaction types include carbonylation of epoxide to ß-lactones, carbonylative (macro)lactonization/lactamization, the Semmelhack reaction, tandem hydroformylation-cyclization, the Pauson-Khand reaction, carbonylative C-H activation cyclization, the Stille/Suzuki carbonylation, [n + m + 1] carbonylative cycloaddition, the Dötz annulation, and others.
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Productos Biológicos/metabolismo , Ciclización , Lactonas/químicaRESUMEN
Abiespiroside A (1), beshanzuenone C (2), and beshanzuenone D (3) belong to the Abies sesquiterpenoid family. Beshanzuenones C (2) and D (3) are isolated from the critically endangered Chinese fir tree species Abies beshanzuensis and demonstrated weak inhibiting activity against protein tyrosine phosphatase 1B (PTP1B). We describe herein the first total syntheses of these Abies sesquiterpenoids relying on the sustainable and inexpensive chiral pool molecule (+)-carvone. The syntheses feature a palladium-catalyzed hydrocarbonylative lactonization to install the 6,6-fused bicyclic ring system and a Dreiding-Schmidt reaction to build the oxaspirolactone moiety of these target molecules. Our chemical total syntheses of these Abies sesquiterpenoids have enabled (i) the validation of beshanzuenone C's weak PTP1B inhibiting potency, (ii) identification of new synthetic analogs with promising and selective protein tyrosine phosphatase SHP2 inhibiting potency, and (iii) preparation of azide-tagged probe molecules for target identification via a chemoproteomic approach. The latter has resulted in the identification and evaluation of DNA polymerase epsilon subunit 3 (POLE3) as one of the novel cellular targets of these Abies sesquiterpenoids and their analogs. More importantly, via POLE3 inactivation by probe molecule 29 and knockdown experiment, we further demonstrated that targeting POLE3 with small molecules may be a novel strategy for chemosensitization to DNA damaging drugs such as etoposide in cancer.
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Abies/química , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Sesquiterpenos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Ciclización , ADN Polimerasa III/antagonistas & inhibidores , Proteínas de Unión al ADN/antagonistas & inhibidores , Sinergismo Farmacológico , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Etopósido/farmacología , Humanos , Nucleoproteínas/antagonistas & inhibidores , Sesquiterpenos/síntesis química , Sesquiterpenos/químicaRESUMEN
Because molecular mechanisms underlying refractory focal epilepsy are poorly defined, we performed transcriptome analysis on human epileptogenic tissue. Compared with controls, expression of Circadian Locomotor Output Cycles Kaput (CLOCK) is decreased in epileptogenic tissue. To define the function of CLOCK, we generated and tested the Emx-Cre; Clockflox/flox and PV-Cre; Clockflox/flox mouse lines with targeted deletions of the Clock gene in excitatory and parvalbumin (PV)-expressing inhibitory neurons, respectively. The Emx-Cre; Clockflox/flox mouse line alone has decreased seizure thresholds, but no laminar or dendritic defects in the cortex. However, excitatory neurons from the Emx-Cre; Clockflox/flox mouse have spontaneous epileptiform discharges. Both neurons from Emx-Cre; Clockflox/flox mouse and human epileptogenic tissue exhibit decreased spontaneous inhibitory postsynaptic currents. Finally, video-EEG of Emx-Cre; Clockflox/flox mice reveals epileptiform discharges during sleep and also seizures arising from sleep. Altogether, these data show that disruption of CLOCK alters cortical circuits and may lead to generation of focal epilepsy.
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Encéfalo/metabolismo , Proteínas CLOCK/deficiencia , Proteínas CLOCK/genética , Epilepsias Parciales/genética , Epilepsias Parciales/metabolismo , Red Nerviosa/metabolismo , Animales , Encéfalo/patología , Células Cultivadas , Epilepsias Parciales/patología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Red Nerviosa/patología , Estudios ProspectivosRESUMEN
Alterations in the ratio of excitatory to inhibitory transmission are emerging as a common component of many nervous system disorders, including autism spectrum disorders (ASDs). Tonic γ-aminobutyric acidergic (GABAergic) transmission provided by peri- and extrasynaptic GABA type A (GABAA ) receptors powerfully controls neuronal excitability and plasticity and, therefore, provides a rational therapeutic target for normalizing hyperexcitable networks across a variety of disorders, including ASDs. Our previous studies revealed tonic GABAergic deficits in principal excitatory neurons in the basolateral amygdala (BLA) in the Fmr1(-/y) knockout (KO) mouse model fragile X syndrome. To correct amygdala deficits in tonic GABAergic neurotransmission in Fmr1(-/y) KO mice, we developed a novel positive allosteric modulator of GABAA receptors, SGE-872, based on endogenously active neurosteroids. This study shows that SGE-872 is nearly as potent and twice as efficacious for positively modulating GABAA receptors as its parent molecule, allopregnanolone. Furthermore, at submicromolar concentrations (≤1 µM), SGE-872 is selective for tonic, extrasynaptic α4ß3δ-containing GABAA receptors over typical synaptic α1ß2γ2 receptors. We further find that SGE-872 strikingly rescues the tonic GABAergic transmission deficit in principal excitatory neurons in the Fmr1(-/y) KO BLA, a structure heavily implicated in the neuropathology of ASDs. Therefore, the potent and selective action of SGE-872 on tonic GABAA receptors containing α4 subunits may represent a novel and highly useful therapeutic avenue for ASDs and related disorders involving hyperexcitability of neuronal networks.
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Amígdala del Cerebelo/efectos de los fármacos , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/patología , Moduladores del GABA/farmacología , Potenciales de la Membrana/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismo , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/patología , Animales , Animales Recién Nacidos , Células CHO , Cricetulus , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , GABAérgicos/farmacología , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacología , Técnicas In Vitro , Potenciales de la Membrana/genética , Ratones , Ratones Noqueados , Técnicas de Placa-Clamp , Pregnanolona/análogos & derivados , Pregnanolona/química , Pregnanolona/farmacología , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Transfección , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
CONTEXT: Competitive sports are recognized as having unique health benefits and risks, and the effect of sports on life-span health among elite athletes has received increasing attention. However, supporting scientific data are sparse and do not represent modern athletes. OBJECTIVE: To assess holistic life-span health and health-related quality-of-life (HRQL) among current and former National Collegiate Athletic Association student-athletes (SAs). DESIGN: Cross-sectional study. SETTING: A large Division I university. PATIENTS OR OTHER PARTICIPANTS: Population-based sample of 496 university students and alumni (age 17-84 years), including SAs and an age-matched and sex-matched nonathlete (NA) control group. MAIN OUTCOME MEASURE(S): Participants completed anonymous, self-report questionnaires. We measured the Short-Form 12 (SF-12) physical and mental component HRQL scores and cumulative lifetime experience and relative risk of treatment for joint, cardiopulmonary, and psychosocial health concerns. RESULTS: Older alumni (age 43+ years) SAs reported greater joint health concerns than NAs (larger joint summary scores; P = .04; Cohen d = 0.69; probability of clinically important difference [pCID] = 77%; treatment odds ratio [OR] = 14.0, 95% confidence interval [CI] = 1.6, 126). Joint health for current and younger alumni SAs was similar to that for NAs. Older alumni reported greater cardiopulmonary health concerns than younger alumni (summary score P < .001; d = 1.05; pCID = 85%; OR = 5.8, 95% CI = 2.0, 16) and current students (P < .001; d = 2.25; pCID >99.5%; OR = 7.1, 95% CI = 3.3, 15), but the risk was similar for SAs and NAs. Current SAs demonstrated evidence of better psychosocial health (summary score P = .006; d = -0.52; pCID = 40%) and mental component HRQL (P = .008; d = 0.50; pCID = 48%) versus NAs but similar psychosocial treatment odds (OR = 0.87, 95% CI = 0.39, 1.9). Psychosocial health and mental component HRQL were similar between alumni SAs and NAs. No differences were observed between SAs and NAs in physical component HRQL. CONCLUSIONS: The SAs demonstrated significant, clinically meaningful evidence of greater joint health concerns later in life, comparable cardiopulmonary health, and differences in life-span psychosocial health and HRQL profiles compared with NAs. These data provide timely evidence regarding a compelling public issue and highlight the need for further study of life-span health among modern athletes.
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Atletas , Traumatismos en Atletas/psicología , Salud Mental , Calidad de Vida , Estudiantes , Universidades , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Traumatismos en Atletas/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Encuestas y Cuestionarios , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability. Comorbidities of FXS such as autism are increasingly linked to imbalances in excitation and inhibition (E/I) as well as dysfunction in GABAergic transmission in a number of brain regions including the amygdala. However, the link between E/I imbalance and GABAergic transmission deficits in the FXS amygdala is poorly understood. Here we reveal that normal tonic GABAA receptor-mediated neurotransmission in principal neurons (PNs) of the basolateral amygdala (BLA) is comprised of both δ- and α5-subunit-containing GABAA receptors. Furthermore, tonic GABAergic capacity is reduced in these neurons in the Fmr1 knockout (KO) mouse model of FXS (1.5-fold total, 3-fold δ-subunit, and 2-fold α5-subunit mediated) as indicated by application of gabazine (50 µM), 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 1 µM), and α5ia (1.5 µM) in whole cell patch-clamp recordings. Moreover, α5-containing tonic GABAA receptors appear to preferentially modulate nonsomatic compartments of BLA PNs. Examination of evoked feedforward synaptic transmission in these cells surprisingly revealed no differences in overall synaptic conductance or E/I balance between wild-type (WT) and Fmr1 KO mice. Instead, we observed altered feedforward kinetics in Fmr1 KO PNs that supports a subtle yet significant decrease in E/I balance at the peak of excitatory conductance. Blockade of α5-subunit-containing GABAA receptors replicated this condition in WT PNs. Therefore, our data suggest that tonic GABAA receptor-mediated neurotransmission can modulate synaptic E/I balance and timing established by feedforward inhibition and thus may represent a therapeutic target to enhance amygdala function in FXS.
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Amígdala del Cerebelo/metabolismo , Potenciales Postsinápticos Excitadores , Síndrome del Cromosoma X Frágil/metabolismo , Potenciales Postsinápticos Inhibidores , Receptores de GABA-A/metabolismo , Sinapsis/metabolismo , Amígdala del Cerebelo/citología , Amígdala del Cerebelo/fisiología , Animales , Retroalimentación Fisiológica , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Agonistas de Receptores de GABA-A/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/fisiología , Isoxazoles/farmacología , Ratones , Ftalazinas/farmacología , Subunidades de Proteína/metabolismo , Piridazinas/farmacología , Sinapsis/fisiología , Triazoles/farmacologíaRESUMEN
The oligotrophic bacterium Caulobacter crescentus has the ability to metabolize various organic molecules, including plant structural carbohydrates, as a carbon source. The nature of ß-glucosidase (BGL)-mediated gluco-oligosaccharide degradation and nutrient transport across the outer membrane in C. crescentus was investigated. All gluco-oligosaccharides tested (up to celloheptose) supported growth in M2 minimal media but not cellulose or CM-cellulose. The periplasmic and outer membrane fractions showed highest BGL activity, but no significant BGL activity was observed in the cytosol or extracellular medium. Cells grown in cellobiose showed expression of specific BGLs and TonB-dependent receptors (TBDRs). Carbonyl cyanide 3-chlorophenylhydrazone lowered the rate of cell growth in cellobiose but not in glucose, indicating potential cellobiose transport into the cell by a proton motive force-dependent process, such as TBDR-dependent transport, and facilitated diffusion of glucose across the outer membrane via specific porins. These results suggest that C. crescentus acquires carbon from cellulose-derived gluco-oligosaccharides found in the environment by extracellular and periplasmic BGL activity and TBDR-mediated transport. This report on extracellular degradation of gluco-oligosaccharides and methods of nutrient acquisition by C. crescentus supports a broader suite of carbohydrate metabolic capabilities suggested by the C. crescentus genome sequence that until now have not been reported.
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Caulobacter crescentus/metabolismo , Oligosacáridos/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Transporte Biológico , Caulobacter crescentus/genética , Caulobacter crescentus/crecimiento & desarrollo , Celobiosa/metabolismo , Espacio Extracelular/metabolismo , Expresión Génica , Transcripción Genética , beta-Glucosidasa/genética , beta-Glucosidasa/metabolismoRESUMEN
Fragile X syndrome (FXS) is a debilitating neurodevelopmental disorder thought to arise from disrupted synaptic communication in several key brain regions, including the amygdala, a central processing center for information with emotional and social relevance. Recent studies reveal defects in both excitatory and inhibitory neurotransmission in mature amygdala circuits in Fmr1(-/y) mutants, the animal model of FXS. However, whether these defects are the result of altered synaptic development or simply faulty mature circuits remains unknown. Using a combination of electrophysiological and genetic approaches, we show the development of both presynaptic and postsynaptic components of inhibitory neurotransmission in the FXS amygdala is dynamically altered during critical stages of neural circuit formation. Surprisingly, we observe that there is a homeostatic correction of defective inhibition, which, despite transiently restoring inhibitory synaptic efficacy to levels at or beyond those of control, ultimately fails to be maintained. Using inhibitory interneuron-specific conditional knock-out and rescue mice, we further reveal that fragile X mental retardation protein function in amygdala inhibitory microcircuits can be segregated into distinct presynaptic and postsynaptic components. Collectively, these studies reveal a previously unrecognized complexity of disrupted neuronal development in FXS and therefore have direct implications for establishing novel temporal and region-specific targeted therapies to ameliorate core amygdala-based behavioral symptoms.
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Amígdala del Cerebelo/patología , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/fisiopatología , Homeostasis/genética , Red Nerviosa/fisiología , Inhibición Neural/genética , Animales , Diferenciación Celular/genética , Modelos Animales de Enfermedad , Potenciales Postsinápticos Inhibidores/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Técnicas de Cultivo de ÓrganosRESUMEN
Deficits in neuronal plasticity are common hallmarks of many neurodevelopmental disorders. In the case of fragile-X syndrome (FXS), disruption in the function of a single gene, FMR1, results in a variety of neurological consequences directly related to problems with the development, maintenance, and capacity of plastic neuronal networks. In this paper, we discuss current research illustrating the mechanisms underlying plasticity deficits in FXS. These processes include synaptic, cell intrinsic, and homeostatic mechanisms both dependent on and independent of abnormal metabotropic glutamate receptor transmission. We place particular emphasis on how identified deficits may play a role in developmental critical periods to produce neuronal networks with permanently decreased capacity to dynamically respond to changes in activity central to learning, memory, and cognition in patients with FXS. Characterizing early developmental deficits in plasticity is fundamental to develop therapies that not only treat symptoms but also minimize the developmental pathology of the disease.
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Síndrome del Cromosoma X Frágil/patología , Plasticidad Neuronal/fisiología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/fisiología , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Homeostasis/fisiología , Humanos , Red Nerviosa/patología , Receptores de Cannabinoides/genética , Receptores de Cannabinoides/fisiología , Receptores de Glutamato/fisiologíaRESUMEN
Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disability, sensory hypersensitivity, and high incidences of autism spectrum disorders and epilepsy. These phenotypes are suggestive of defects in neural circuit development and imbalances in excitatory glutamatergic and inhibitory GABAergic neurotransmission. While alterations in excitatory synapse function and plasticity are well-established in Fmr1 knockout (KO) mouse models of FXS, a number of recent electrophysiological and molecular studies now identify prominent defects in inhibitory GABAergic transmission in behaviorally relevant forebrain regions such as the amygdala, cortex, and hippocampus. In this review, we summarize evidence for GABAergic system dysfunction in FXS patients and Fmr1 KO mouse models alike. We then discuss some of the known developmental roles of GABAergic signaling, as well as the development and refinement of GABAergic synapses as a framework for understanding potential causes of mature circuit dysfunction. Finally, we highlight the GABAergic system as a relevant target for the treatment of FXS.
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Síndrome del Cromosoma X Frágil/fisiopatología , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Ácido gamma-Aminobutírico/metabolismo , Amígdala del Cerebelo/fisiopatología , Amígdala del Cerebelo/ultraestructura , Animales , Corteza Cerebral/fisiopatología , Corteza Cerebral/ultraestructura , Modelos Animales de Enfermedad , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/terapia , Hipocampo/fisiopatología , Hipocampo/ultraestructura , Humanos , Plasticidad Neuronal/fisiologíaRESUMEN
Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by variable cognitive impairment and behavioral disturbances such as exaggerated fear, anxiety and gaze avoidance. Consistent with this, findings from human brain imaging studies suggest dysfunction of the amygdala. Underlying alterations in amygdala synaptic function in the Fmr1 knock-out (KO) mouse model of FXS, however, remain largely unexplored. Utilizing a combination of approaches, we uncover profound alterations in inhibitory neurotransmission in the amygdala of Fmr1 KO mice. We demonstrate a dramatic reduction in the frequency and amplitude of phasic IPSCs, tonic inhibitory currents, as well as in the number of inhibitory synapses in Fmr1 KO mice. Furthermore, we observe significant alterations in GABA availability, both intracellularly and at the synaptic cleft. Together, these findings identify abnormalities in basal and action potential-dependent inhibitory neurotransmission. Additionally, we reveal a significant neuronal hyperexcitability in principal neurons of the amygdala in Fmr1 KO mice, which is strikingly rescued by pharmacological augmentation of tonic inhibitory tone using the GABA agonist gaboxadol (THIP). Thus, our study reveals relevant inhibitory synaptic abnormalities in the amygdala in the Fmr1 KO brain and supports the notion that pharmacological approaches targeting the GABAergic system may be a viable therapeutic approach toward correcting amygdala-based symptoms in FXS.
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Amígdala del Cerebelo/efectos de los fármacos , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Síndrome del Cromosoma X Frágil/fisiopatología , Agonistas del GABA/farmacología , Isoxazoles/farmacología , Transmisión Sináptica/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Modelos Animales de Enfermedad , Potenciales Evocados , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Glutamato Descarboxilasa/metabolismo , Técnicas In Vitro , Interneuronas/metabolismo , Masculino , Ratones , Ratones Noqueados , Inhibición Neural/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Técnicas de Placa-Clamp , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Inhibitory neurosteroids, molecules generated in glia from circulating steroid hormones and de novo from cholesterol, keep seizures in check in epileptic animals. They can enhance inhibitory transmission mediated by gamma-aminobutyric acid receptors and have anticonvulsant action.
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Epilepsia/metabolismo , Neurotransmisores/metabolismo , Animales , Modelos Animales de Enfermedad , Electroencefalografía/métodos , Inhibidores Enzimáticos/efectos adversos , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Epilepsia/fisiopatología , Femenino , Finasterida/efectos adversos , Gonadotropinas/uso terapéutico , Litio , Neurotransmisores/antagonistas & inhibidores , Pilocarpus , Pregnanolona/uso terapéutico , RatasRESUMEN
PURPOSE: New treatments are needed for status epilepticus (SE) that is refractory to drugs modulating GABA(A) receptors, and NMDA receptor antagonists are candidate drugs. METHODS: Clinically available NMDA receptor antagonist ketamine was tested for effectiveness in terminating prolonged SE induced by a combination of lithium and pilocarpine. Animals were treated 10 min after first grade 5 behavioral seizure (Racine scoring scale) by intraperitoneal administration of ketamine, diazepam, or saline. Seizure termination was determined by electroencephalogram (EEG) recordings from the hippocampus and the cortex. RESULTS: Animals treated with normal saline or either 20 mg/kg diazepam, or 50 mg/kg ketamine continued in SE for the next 300 min. However, combined treatment with diazepam and ketamine rapidly terminated prolonged cholinergic stimulation-induced SE. Detailed study of dose response relationships demonstrated that diazepam enhanced efficacy and potency of ketamine in terminating SE. DISCUSSION: This study demonstrated synergistic action of diazepam and ketamine in terminating SE. It suggests that a ketamine-diazepam combination might be a clinically useful therapeutic option for the treatment of refractory SE.
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Diazepam/uso terapéutico , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Ketamina/farmacología , Compuestos de Litio , Agonistas Muscarínicos , Pilocarpina , Estado Epiléptico/inducido químicamente , Estado Epiléptico/prevención & control , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiopatología , Diazepam/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Electroencefalografía/estadística & datos numéricos , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Ketamina/uso terapéutico , Masculino , Ratas , Ratas Sprague-Dawley , Estado Epiléptico/fisiopatología , Resultado del TratamientoRESUMEN
OBJECTIVE: No clear consensus exists regarding the effect of sustained, heavy drinking on hippocampal volume. Our prior work hypothesized significantly lowered total hippocampus volumes in heavy chronically drinking alcohol-dependent (AD) subjects compared with light-drinking nondependent control subjects matched for age and gender. METHOD: Using a series of applicable exclusion criteria culled from previous published studies, we measured hippocampal volumes from MRI scan data acquired on a 3T scanner and subjected those data to automated volume analysis blind to the drinking history. RESULTS: Comparison with AD test (n=8) and non-AD control (n=8) subjects found significant lessening in total (p=0.020) and left (p=0.010) hippocampal volumes with a near-significant difference on the right (p=0.051). Linear regression demonstrated that neither total brain volume nor intracranial volume affected the hippocampus measures. CONCLUSIONS: These data support the view that heavy drinking exerts a unique and selectively injurious effect on the hippocampus. Further study in larger samples must verify this in a search for possible mechanisms of injury.
Asunto(s)
Alcoholismo/patología , Hipocampo/patología , Adulto , Alcoholismo/psicología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Análisis de Regresión , Cráneo/patologíaRESUMEN
OBJECTIVE: The effects of hypercortisolism on hippocampal volume have not been studied in heavy drinkers. Prior work suggested increased hypothalamic-pituitary-adrenal activity in relation to lowered total hippocampus volume (THV) in heavy-drinking alcohol-dependent (AD) subjects. The present study hypothesized the following: (1) that chronic heavy-drinking subjects would demonstrate significantly higher salivary cortisol concentrations than light-drinking control subjects and (2) that data from the whole sample group would present an inverse relationship between cortisol concentration and THV. METHOD: In carefully selected test and control subject groups matched for age, gender, and ethnicity, we measured salivary cortisol samples at waking, waking + 30 minutes, noon, and 4 PM on the day of magnetic resonance imaging of the brain. We next compared mean cortisol concentrations between groups and assessed the statistical association between cortisol concentration and hippocampus volume measures. RESULTS: Comparison of AD test subjects (n = 8) and non-AD control subjects (n = 8) found significantly higher cortisol concentrations at both morning sampling times (mean [SD] at waking: 0.49 [0.23] vs 0.24 [0.14] microg/dl, p = .012; at waking + 30 minutes: 0.57 [0.37] vs 0.28 [0.11] microg/dl, p = 0.043). Controlling for intracranial volume, there was a significant inverse correlation between waking cortisol concentration and THV (p = .007) in the total sample group (N = 16). However, when analyzed separately, only the control group maintained a strong, inverse association (p = .025). There was no association among the heavy drinking subjects. CONCLUSIONS: These early data in a small sample support the view that chronic heavy drinking results in high salivary cortisol concentrations. What remains unclear is whether hypercortisolism exerts a selectively injurious effect that results in observed hippocampus volume loss. Further research in larger groups using more frequent, monitored sampling must address the following: (1) whether this finding can be replicated and (2) if replicated, whether the lack of an association between low hippocampal volumes and high cortisol levels may indicate an extent of injury beyond which a normal association of the two may be lost.
Asunto(s)
Alcoholismo/complicaciones , Hipocampo/patología , Hidrocortisona/metabolismo , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/etiología , Adulto , Alcoholismo/patología , Humanos , Masculino , Persona de Mediana Edad , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/patología , Saliva/metabolismoRESUMEN
Psychological treatment studies, uncontrolled for ego defense (adaptive) styles, report conflicting survival results. The authors hypothesized that "immature" adaptive styles and frequent depression symptoms would independently predict lower survival rates. This study followed 86 consecutive, mostly late-stage, cancer outpatients for up to 5 years; their survival data were analyzed in relation to the Beck Depression Inventory and the Defense Style Questionnaire scores at study entry. Cumulative survival probability curves contrasted the extreme cases: the most (N=15) to the least (N=21) depressed, and the "immature" (N=14) to the "mature" (N=16) adaptors. Depression did not separate the groups until 30 months after diagnosis. Ego defense style separated them at 8 months; by 18 months, the "immature" survival probability had dropped to 50%, versus 87% for the "mature." At 36 months, survival probabilities were 19% and 57%, respectively. These data direct clinical attention toward ego defense mechanisms as indicators of distress and lowered survival in cancer patients. They further suggest that the maturity of adaptive mechanisms must be controlled for in behavioral-treatment trials of cancer patients.