RESUMEN
Movement is an important component of animal behavior and determines how an organism interacts with its environment. The speed at which an animal moves through its environment can be constrained by internal (e.g., physiological state) and external factors (e.g., habitat complexity). When foraging, animals should move at speeds that maximize prey capture while minimizing mistakes (i.e., missing prey, slipping). We used experimental arenas containing obstacles spaced in different arrays to test how variation in habitat complexity influenced attack distance, prey capture speed, and foraging success in the Prairie Lizard. Obstacles spaced uniformly across arenas resulted in 15% slower prey capture speed and 30-38% shorter attack distance compared to arenas with no obstacles or with obstacles clustered in opposite corners of the arena. Prey capture probability was not influenced by arena type or capture speed, but declined with increasing attack distance. Similarly, the probability of prey consumption declined with attack distance across arena types. However, prey consumption probability declined with increasing prey capture speed in more open arenas but not in the cluttered arena. Foraging accuracy declined with increasing speed in more open arenas, and remained relatively constant when obstacles were in closer proximity. Foraging success was primarily constrained by intrinsic properties (speed-maneuverability tradeoff) when ample space was available, but environmental conditions had a greater impact on foraging success in "cluttered" habitats. This empirical test of theoretical predictions about optimal movement speeds in animals provides a step forward in understanding how animals select speeds in nature.
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Sugammadex is a novel reversal agent for aminosteroid neuromuscular blocking drugs, especially rocuronium. Given its renal excretion, sugammadex is not recommended for patients with end-stage renal disease; however, reports exist of its use in this group of patients. This two-institutional retrospective observational study aimed to review the safety profile and effectiveness of sugammadex in surgical patients with end-stage renal disease who required pre-operative renal replacement therapy. Adult surgical patients with end-stage renal disease requiring pre-operative renal replacement therapy, who received sugammadex between April 2016 and January 2019, were studied. The primary outcome was the incidence of postoperative tracheal re-intubation within 48 h. The secondary outcome was the incidence of deferred tracheal extubation in the operating theatre. One hundred and fifty-eight patients were identified from 125,653 surgical patients: 48 patients (30%) underwent renal transplantation and 110 (70%) underwent non-renal transplantation procedures. There were 22 instances (14%) of deferred tracheal extubation due to surgical and/or pre-existing medical conditions. Out of the 136 patients who had the tracheal tube removed at the end of the procedure, three patients had their trachea re-intubated within 48 h: two patients developed pulmonary oedema resulting from volume overload; and one patient had worsening sepsis. No incidence of recurrence of neuromuscular blockade was observed. Of note, 24 (18%) patients were found to have incomplete neuromuscular blockade reversal with neostigmine but administration of sugammadex led to successful tracheal extubation. In conclusion, sugammadex appears to be safe and effective in adult patients with end-stage renal disease receiving pre-operative renal replacement therapy.
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Fallo Renal Crónico/complicaciones , Sugammadex/efectos adversos , Sugammadex/uso terapéutico , Adulto , Anciano , Extubación Traqueal , Femenino , Humanos , Incidencia , Intubación Intratraqueal , Fallo Renal Crónico/fisiopatología , Trasplante de Riñón/métodos , Masculino , Persona de Mediana Edad , Bloqueo Neuromuscular , Complicaciones Posoperatorias/epidemiología , Cuidados Preoperatorios , Terapia de Reemplazo Renal , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Disrupted in schizophrenia 1 (DISC1) is a multi-functional scaffolding protein that has been associated with neuropsychiatric disease. The role of DISC1 is to assemble protein complexes that promote neural development and signaling, hence tight control of the concentration of cellular DISC1 in neurons is vital to brain function. Using structural and biochemical techniques, we show for we believe the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the F-Box protein, FBXW7. We present the structure of FBXW7 bound to the DISC1 phosphodegron motif and exploit this information to prove that disruption of the FBXW7-DISC1 complex results in a stabilization of DISC1. This action can counteract DISC1 deficiencies observed in neural progenitor cells derived from induced pluripotent stem cells from schizophrenia patients with a DISC1 frameshift mutation. Thus manipulation of DISC1 levels via the UPS may provide a novel method to explore DISC1 function.
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Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo , Células Cultivadas , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Células HEK293 , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Modelos Moleculares , Proteínas del Tejido Nervioso/genética , Células-Madre Neurales/metabolismo , Neurogénesis , Neuronas/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Unión Proteica , Esquizofrenia/metabolismo , Transducción de Señal , Ubiquitina/genética , UbiquitinaciónRESUMEN
Mitochondrial aminoacyl-tRNA synthetases (mtARSs) are essential, ubiquitously expressed enzymes that covalently attach amino acids to their corresponding tRNA molecules during translation of mitochondrial genes. Deleterious variants in the mtARS genes cause a diverse array of phenotypes, many of which involve the nervous system. Moreover, distinct mutations in mtARSs often cause different clinical manifestations. Recently, the gene encoding mitochondrial tryptophanyl tRNA synthetase (WARS2) was reported to cause 2 different neurological phenotypes, a form of autosomal recessive intellectual disability and a syndrome of severe infantile-onset leukoencephalopathy. Here, we report the case of a 17-year-old boy with compound heterozygous mutations in WARS2 (p.Trp13Gly, p.Ser228Trp) who presented with infantile-onset, Levodopa-responsive Parkinsonism at the age of 2 years. Analysis of patient-derived dermal fibroblasts revealed decreased steady-state WARS2 protein and normal OXPHOS content. Muscle mitochondrial studies suggested mitochondrial proliferation without obvious respiratory chain deficiencies at the age of 9 years. This case expands the phenotypic spectrum of WARS2 deficiency and emphasizes the importance of mitochondrial protein synthesis in the pathogenesis of Parkinsonism.
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Alelos , Mutación , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/genética , Triptófano-ARNt Ligasa/genética , Adolescente , Edad de Inicio , Biopsia , Análisis Mutacional de ADN , Fibroblastos/metabolismo , Estudios de Asociación Genética , Genotipo , Humanos , Levodopa/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Trastornos Parkinsonianos/tratamiento farmacológico , Fenotipo , Polimorfismo de Nucleótido Simple , Medicina de PrecisiónRESUMEN
BACKGROUND: Bilateral infarcts confined to the globus pallidus are unusual and occur in conjunction with only a few disorders, including isolated methylmalonic acidemia, a heterogeneous inborn error of metabolism. On the basis of neuroradiographic features of metabolic strokes observed in a large cohort of patients with methylmalonic acidemia, we have devised a staging system for methylmalonic acidemia-related globus pallidus infarcts. MATERIALS AND METHODS: Forty patients with isolated methylmalonic acidemia and neurologic symptoms underwent clinical brain MR imaging studies, which included 3D-T1WI. Infarcted globus pallidus segments were neuroanatomically characterized, and infarct volumes were measured. RESULTS: Globus pallidus infarcts were present in 19 patients; all were bilateral, and most were left-dominant. A neuroanatomic scoring system based on the infarct patterns was devised; this revealed a 5-stage hierarchical susceptibility to metabolic infarct, with the posterior portion of the globus pallidus externa being the most vulnerable. Globus pallidus infarct prevalence by methylmalonic acidemia class was the following: cblA (5/7, 71%), cblB (3/7, 43%), mut(o) (10/22, 45%), and mut- (1/4, 25%). Tiny lacunar infarcts in the pars reticulata of the substantia nigra, previously unrecognized in methylmalonic acidemia, were found in 17 patients, 13 of whom also had a globus pallidus infarct. CONCLUSIONS: The staged pattern of globus pallidus infarcts in isolated methylmalonic acidemia suggests a nonuniform, regionally specific cellular susceptibility to metabolic injury, even for patients having milder biochemical phenotypes. In support of this hypothesis, the delineation of lacunar infarcts in the pars reticulata of the substantia nigra, a tissue functionally and histologically identical to the globus pallidus interna, supports the concept of cell-specific pathology.
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Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Infarto Encefálico/etiología , Infarto Encefálico/patología , Globo Pálido/patología , Estudios de Cohortes , Femenino , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.
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Enfermedad , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Guías como Asunto , Reacciones Falso Positivas , Genes/genética , Humanos , Difusión de la Información , Edición , Reproducibilidad de los Resultados , Proyectos de Investigación , Investigación Biomédica Traslacional/normasRESUMEN
The small heat shock protein HSP20 is known to be cardioprotective during times of stress and the mechanism underlying its protective abilities depends on its phosphorylation on Ser16 by PKA (protein kinase A). Although the external stimuli that trigger Ser16 phosphorylation have been well studied, the events that modulate spatial and temporal control of this modification remain to be clarified. Here, we report that inhibition of cAMP phosphodiesterase-4 (PDE4) induces the phosphorylation of HSP20 in resting cardiac myocytes and augments its phosphorylation by PKA following ß-adrenergic stimulation. Moreover, using peptide array technology, in vitro binding studies, co-immunoprecipitation techniques and immunocytochemistry, we show that HSP20 binds directly to PDE4 within a region of the conserved catalytic domain. We also show that FRET-based, genetically-encoded cAMP reporters anchored to HSP20 exhibit a larger response to PDE4 inhibition compared to free cytosolic cAMP reporters, suggesting that the interaction with PDE4 is crucial in modulating the highly localised pool of cAMP to which HSP20 is exposed. Using information gleaned from peptide array analyses, we developed a cell-permeable peptide that serves to inhibit the interaction of PDE4 with HSP20. Disruption of the HSP20-PDE4 complex, using this peptide, suffices to induce phosphorylation of HSP20 by PKA and to protect against the hypertrophic response measured in neonatal cardiac myocytes following chronic ß-adrenergic stimulation.
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Agonistas Adrenérgicos beta/farmacología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Proteínas del Choque Térmico HSP20/metabolismo , Animales , Western Blotting , Línea Celular , Células Cultivadas , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Ensayo de Inmunoadsorción Enzimática , Proteínas del Choque Térmico HSP20/genética , Humanos , Inmunoprecipitación , Isoproterenol/farmacología , Mutagénesis Sitio-Dirigida , Fosforilación/efectos de los fármacos , Reacción en Cadena de la Polimerasa , Unión Proteica , Ratas/anomalías , Ratas Sprague-DawleyRESUMEN
In order to identify new metabolic abnormalities in patients with complex neurodegenerative disorders of unknown aetiology, we performed high resolution in vitro proton nuclear magnetic resonance spectroscopy on patient cerebrospinal fluid (CSF) samples. We identified five adult patients, including two sisters, with significantly elevated free sialic acid in the CSF compared to both the cohort of patients with diseases of unknown aetiology (n = 144; P < 0.001) and a control group of patients with well-defined diseases (n = 91; P < 0.001). All five patients displayed cerebellar ataxia, with peripheral neuropathy and cognitive decline or noteworthy behavioural changes. Cerebral MRI showed mild to moderate cerebellar atrophy (5/5) as well as white matter abnormalities in the cerebellum including the peridentate region (4/5), and at the periventricular level (3/5). Two-dimensional gel analyses revealed significant hyposialylation of transferrin in CSF of all patients compared to age-matched controls (P < 0.001)--a finding not present in the CSF of patients with Salla disease, the most common free sialic acid storage disorder. Free sialic acid content was normal in patients' urine and cultured fibroblasts as were plasma glycosylation patterns of transferrin. Analysis of the ganglioside profile in peripheral nerve biopsies of two out of five patients was also normal. Sequencing of four candidate genes in the free sialic acid biosynthetic pathway did not reveal any mutation. We therefore identified a new free sialic acid syndrome in which cerebellar ataxia is the leading symptom. The term CAFSA is suggested (cerebellar ataxia with free sialic acid).
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Ataxia Cerebelosa/líquido cefalorraquídeo , Ácido N-Acetilneuramínico/líquido cefalorraquídeo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Atrofia/líquido cefalorraquídeo , Células Cultivadas , Ataxia Cerebelosa/patología , Cerebelo/patología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Transferrina/líquido cefalorraquídeoRESUMEN
Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3', 2':4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT(2C) receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties.
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Pirazinas/química , Pirazinas/farmacología , Pirroles/química , Agonistas del Receptor de Serotonina 5-HT2 , Animales , Células CHO , Cricetinae , Humanos , Hidroxilación , Estructura Molecular , Fosfolípidos/farmacología , Pirazinas/síntesis química , Receptor de Serotonina 5-HT2C/genética , Receptor de Serotonina 5-HT2C/metabolismo , Relación Estructura-ActividadRESUMEN
Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists.
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Ingestión de Alimentos/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/farmacología , Animales , Indoles/síntesis química , Indoles/farmacología , Inyecciones Subcutáneas , Pirazinas/síntesis química , Pirazinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Ratas Wistar , Agonistas de Receptores de Serotonina/síntesis química , Relación Estructura-ActividadRESUMEN
A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for all of the compounds at 5-HT(2) receptor subtypes are reported. A number of compounds were found to reduce food intake in rats after oral administration.
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Fármacos Antiobesidad/farmacología , Indoles/farmacología , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/farmacología , Animales , Fármacos Antiobesidad/química , Indoles/química , RatasAsunto(s)
Bismuto/efectos adversos , Reflujo Gastroesofágico/complicaciones , Compuestos Organometálicos/efectos adversos , Salicilatos/efectos adversos , Enfermedades de la Lengua/inducido químicamente , Enfermedades de la Lengua/diagnóstico , Asma/complicaciones , Femenino , Reflujo Gastroesofágico/tratamiento farmacológico , Humanos , Lupus Eritematoso Sistémico/complicaciones , Persona de Mediana EdadRESUMEN
Characterizing human immunodeficiency virus (HIV) expression in semen during primary infection remains essential to understanding the risk of sexual transmission. This investigation represents the first systematic evaluation of male genital tract shedding to use a nonhuman primate model, including the impact of exposure route and viral virulence. Male macaques were inoculated with either a chronic disease-causing virus (HIV-2(GB122); n=4 intravenous; n=4 intrarectal) or an acutely pathogenic simian/HIV strain (SHIV(89.6P); n=2 intravenous). All macaques were systemically infected, and seminal plasma virion-associated RNA (vRNA) levels were approximately 10-fold lower than those in blood. In HIV-2(GB122) infection, seminal virus was delayed by 1-2 weeks compared with that in blood. Intrarectal inoculation resulted in a shorter duration of seminal vRNA expression and intermittent seminal cell provirus. No delays, higher peaks ( approximately 50-fold), or longer durations in seminal virus expression were noted for SHIV(89.6P) infection. This novel model definitively establishes that virus dissemination results in early peak seminal levels and provides a basis for evaluating interventions targeting male genital tract expression.
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Infecciones por VIH/virología , VIH-2/aislamiento & purificación , Provirus/aislamiento & purificación , Virus Reordenados/aislamiento & purificación , Semen/virología , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Esparcimiento de Virus , Animales , Modelos Animales de Enfermedad , Infecciones por VIH/transmisión , VIH-2/genética , Humanos , Macaca nemestrina , Masculino , ARN Viral/análisis , Virus Reordenados/genética , Virus de la Inmunodeficiencia de los Simios/genética , ViremiaRESUMEN
Postexposure prophylaxis (PEP) after intravaginal exposure to human immunodeficiency virus (HIV) was investigated using the HIV type 2 (HIV-2)/pig-tailed macaque transmission model. PEP for 28 days with the reverse transcriptase inhibitor (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA; tenofovir) was initiated 12 to 72 h following HIV-2 exposure. Systemic infection was not evident in the 12- and 36-h groups, as defined by plasma viremia, cell-associated provirus, antibody responses, and lymph node virus. Breakthrough infection in the 72-h group was detected at week 16 post-virus exposure. These results demonstrate for the first time using a vaginal transmission model that early intervention after high-risk sexual exposures may prevent infection.
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Síndrome de Inmunodeficiencia Adquirida/prevención & control , Adenina/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , VIH-2/aislamiento & purificación , Organofosfonatos , Compuestos Organofosforados/uso terapéutico , Vagina/virología , Síndrome de Inmunodeficiencia Adquirida/transmisión , Adenina/uso terapéutico , Animales , Femenino , Humanos , Macaca nemestrina , ARN Viral/análisis , TenofovirRESUMEN
Topical delivery systems can provide prolonged delivery of antibodies to the vaginal mucosal surface for long-term protection against infectious diseases. We examined the biodistribution of antibodies during 30 days of vaginal antibody delivery in mice. Different antibody preparations (including monoclonal IgG and IgM, as well as several different (125)I-labeled IgGs) were administered by polymer vaginal rings, which were designed to provide continuous antibody delivery. Antibody concentrations remained high in the vaginal secretions for up to 30 days after disk insertion; radiolabeled antibody was also found, at approximately 100 times lower concentration, in the blood and other tissues. The measured concentrations agreed reasonably well with a simple pharmacokinetic model, which was used to calculate mucosal and systemic concentrations as a function of antibody delivery and elimination rates. Results from the model were consistent with previously reported antibody pharmacokinetic measurements: the half-life for antibody elimination for the vagina was approximately 3 h; the half-life for IgG(1) clearance from the blood was >1 day; and the overall permeability constant for vaginal uptake of IgG was approximately 0.01 to 0.03 h(-1). These results provide important information for the design of controlled antibody delivery devices for vaginal use, and suggest that high-dose, long-term vaginal administration of antibodies may be a reasonable approach for achieving sustained mucosal and systemic antibody levels.
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Anticuerpos Monoclonales/farmacocinética , Sistemas de Liberación de Medicamentos/métodos , Vagina , Administración Intravaginal , Administración Oral , Administración Tópica , Animales , Líquidos Corporales , Preparaciones de Acción Retardada , Femenino , Humanos , Inmunoglobulina G/farmacología , Inmunoglobulina M/farmacología , Radioisótopos de Yodo , Membranas Artificiales , Ratones , Ratones Endogámicos C57BL , Membrana Mucosa , Polímeros , Distribución Tisular , Enfermedades Vaginales/inmunología , Enfermedades Vaginales/prevención & controlRESUMEN
PURPOSE: This report describes our experience with the use of self-expanding metallic stents (SEMS) in the management of obstructing colorectal cancer. METHODS: A retrospective chart review of all patients undergoing placement of SEMS between May 1997 and January 2000 was performed. RESULTS: Insertion of SEMS was attempted in 12 patients. Successful stent placement was achieved in 10 of the 12 patients. The locations of lesions were hepatic flexure (2), splenic flexure (1), left colon (1), sigmoid colon (4) and rectum (4). The intended uses of SEMS were for palliation in 3 patients and as a bridge to elective surgery in 9. In the latter group, SEMS placement allowed for preoperative bowel preparation in 4 patients and administration of neoadjuvant therapy prior to elective surgery in 2 patients. One patient died prior to definitive surgery. Stent placement was unsuccessful in 2 patients. Three SEMS-related complications occurred; 1 stent migrated and 1 stent obstructed secondary to tumor ingrowth. One patient died 13 days after stent placement and colonic decompression. CONCLUSION: SEMS represent a useful tool in the management of obstructing colorectal neoplasms. As a bridge to surgery, SEMS provide time for a complete preoperative evaluation and a mechanical bowel preparation and may obviate the need for fecal diversion or on-table lavage. It may also allow for time to administer neoadjuvant therapy when indicated. As a palliative measure, SEMS can eliminate the need for an operation.
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Neoplasias Colorrectales/terapia , Stents , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cuidados Paliativos , Diseño de Prótesis , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Speech errors follow the phonotactics of the language being spoken. For example, in English, if [n] is mispronounced as [n], the [n] will always appear in a syllable coda. The authors created an analogue to this phenomenon by having participants recite lists of consonant-vowel-consonant syllables in 4 sessions on different days. In the first 2 experiments, some consonants were always onsets, some were always codas, and some could be both. In a third experiment, the set of possible onsets and codas depended on vowel identity. In all 3 studies, the production errors that occurred respected the "phonotactics" of the experiment. The results illustrate the implicit learning of the sequential constraints present in the stimuli and show that the language production system adapts to recent experience.
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Aprendizaje , Habla , Adolescente , Adulto , Femenino , Humanos , Masculino , Memoria , FonéticaRESUMEN
1. The goal of this study was to characterize the agonist pharmacology of human 5-HT2A, 5-HT2B and 5-HT2C (VSV) receptors expressed in CHO-K1 (Chinese hamster ovary) cells. 2. We used a fluorometric imaging plate reader (FLIPR) which allows rapid detection of rises in intracellular calcium levels upon the addition of agonists. 3. Stimulation of all three receptors by 5-HT caused a robust concentration dependent increase in intracellular calcium levels. No such effect was observed from non-transfected control CHO-K1 cells. 4. The rank order of potency of agonists at the different receptor subtypes varied. Tryptamines, BW-723C86, d-norfenfluramine, Ro 60-0175 and LSD exhibited the following rank order of potency; 5-HT2B>5-HT2C>5-HT2A. Piperazines such as m-Chlorophenylpiperazine (mCPP), ORG-12962, MK-212 and also ORG-37684 exhibited a rank order of potency of 5-HT2C>5-HT2B>5-HT2A. The phenylisopropylamines DOI and DOB had a rank order of 5-HT2A>5-HT2B>5-HT2C. 5. Many agonists tested had partial agonist actions when compared to 5-HT, and a wide range of relative efficacies were exhibited, which was cell line dependent. For example, mCPP had a relative efficacy of 65% at 5-HT2C receptors but <25% at either 5-HT2A or 5-HT2B receptors. 6. Interpretation of literature values of functional assays using different cell lines, different receptor expression levels and different receptor isoforms, is complex. Species differences and the previous use of antagonist radioligands to characterize agonist potency in binding assays emphasizes the importance of studying agonists in the same experiment using the same assay conditions and parental cell lines.
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Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Animales , Células CHO , Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Cricetinae , Relación Dosis-Respuesta a Droga , Colorantes Fluorescentes , Humanos , Receptor de Serotonina 5-HT2A , Receptor de Serotonina 5-HT2B , Receptor de Serotonina 5-HT2C , Receptores de Serotonina/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Agonistas de Receptores de Serotonina/química , Factores de Tiempo , TransfecciónRESUMEN
PURPOSE: This study compared characteristics of colorectal cancer between families with dominant breast cancer inheritance and the general population. The cumulative incidence of colorectal cancer was also studied in genetically determined breast cancer syndrome subjects with BRCA1 and BRCA2 mutations and compared with the general population. METHODS: Subjects included 42 patients with colorectal cancer from 32 clinically determined hereditary breast cancer kindreds based on the autosomal dominant inheritance of breast cancers and early age of onset. The general population colorectal cancer cohort was composed of 755 patients from a tumor registry. Lifetime risk of colorectal cancer was determined in 164 BRCA1 and 88 BRCA2 gene mutation carriers and compared with the general population. Mean age of colorectal cancer onset, anatomic site distribution, histologic stage at presentation, and five year stage-stratified survival rates were compared between clinically determined hereditary breast cancer family members and the general population. RESULTS: The lifetime risk of colorectal cancer in male BRCA1 and BRCA2 mutation carriers was 5.6 percent, which was not different from 6 percent in males from the general population. Likewise, the lifetime colorectal cancer risk in female BRCA1 and BRCA2 mutation carriers was 3.2 percent, which was not different from 5.9 percent in females from the general population. Mean age of onset +/- standard error for patients with colorectal cancer was 60 +/- 2 years for hereditary breast cancer kindreds compared with 67 +/- 0.4 years for the general population (P = 0.0004). Colorectal cancer site distribution did not vary between hereditary breast cancer and the general population. Overall colorectal cancer stage distribution was significantly different, with more Stage I and fewer Stage IV cancers in subjects with hereditary breast cancer compared with the general population (P = 0.01). Overall five year stage-stratified colorectal cancer survival rate +/- standard error was 66 +/- 8 percent for hereditary breast cancer kindreds and 46 +/- 2 percent for the general population (P = 0.023). CONCLUSION: Lifetime cumulative colorectal cancer incidence in subjects with BRCA1 and BRCA2 gene mutations was not different from the general population. However, significant differences in colorectal cancer were noted between hereditary breast cancer family members and the general population. Hereditary breast cancer-associated colorectal cancer had an earlier age of onset, lower tumor stage, and better survival rate than the general population. Except for age of onset, colorectal cancer in hereditary breast cancer kindreds exhibited more favorable characteristics than colorectal cancer in the general population.
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Neoplasias de la Mama/genética , Neoplasias Colorrectales/genética , Genes BRCA1/genética , Proteínas de Neoplasias/genética , Factores de Transcripción/genética , Adulto , Edad de Inicio , Anciano , Proteína BRCA2 , Neoplasias de la Mama/complicaciones , Neoplasias Colorrectales/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pronóstico , Medición de RiesgoRESUMEN
The potential to establish dual retroviral infections was investigated in this study. Groups of macaques infected with human immunodeficiency virus type 2 (HIV-2) isolate (either GB122 or CDC77618) were exposed to the other virus at 2, 4, 8, 12, 14, or 72 weeks after primary inoculation. Dual infections were established in macaques simultaneously exposed to both viruses. In other groups, secondary infections were observed only if challenge occurred at early intervals after primary infection but before a full seroconversion. Polymerase chain reaction and virus-isolation data demonstrated that challenges at 8, 12, 14, or 72 weeks after infection with the initial isolate failed to result in a dual infection. Anti-HIV-2 serologic titers, CD4 levels, virus burden, and the ability to superinfect peripheral blood mononuclear cells in vitro were not correlated with susceptibility to or protection from secondary challenges in this investigation. These findings demonstrate a window period for susceptibility to dual infection and indicate that protection from retroviral infection may be achievable.