RESUMEN
Photoexcitation of cyclic ketones leads to the expulsion of carbon monoxide and a mixture of products derived from diradical intermediates. Here we show that synthetic utility of this process is improved if strained heterocyclic ketones are used. Photochemistry of 3-oxetanone and N-Boc-3-azetidinone has not been previously described. Decarbonylation of these 4-membered rings proceeds through a step-wise Norrish typeâ I cleavage of the C-C bond from the singlet excited state. Ylides derived from both compounds are high-energy species that are kinetically stable long enough to undergo [3+2] cycloaddition with a variety of alkenes and produce substituted tetrahydrofurans and pyrrolidines. The reaction has a sufficiently wide scope to produce scaffolds that were either previously inaccessible or difficult to synthesize, thereby providing experimental access to new chemical space.
Asunto(s)
Azetidinas , Cetonas , Análisis Espectral , Cetonas/química , Simulación por ComputadorRESUMEN
We prepared a collection of complex cycloheptatriene-containing azetidine lactones by applying two key photochemical reactions: "aza-Yang" cyclization and Buchner carbene insertion into aromatic rings. While photolysis of phenacyl amines leads to a rapid charge transfer and elimination, we found that a simple protonation of the amine enables the formation of azetidinols as single diastereomers. We provide evidence, through ultrafast spectroscopy, for the electron transfer from free amines in the excited state. Further, we characterize the aza-Yang reaction by establishing the dependence of the initial reaction rates on the rates of photon absorption. An unanticipated change in reactivity in morpholine analogues is explained through interactions with the tosylate anion. The Buchner reaction proceeds with a slight preference for one diastereomer over the other, and successful reaction requires electron-donating carbene-stabilizing substituents. Overall, 16 compounds were prepared over seven steps. Guided by an increase in structural complexity, efforts such as this one extend the reach of chemists into unexplored chemical space and provide useful quantities of new compounds for studies focused on their properties.
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Azetidinas , Lactonas , Ciclización , Aminas/químicaRESUMEN
Force health protection (FHP) is defined as "the prevention of disease and injury in order to protect the strength and capabilities" of any service population. FHP was the foundational principal of the US Public Health Service (USPHS). President John Adams' signing of An Act for Sick and Disabled Seamen on July 16, 1798, marked the first dedication of US federal resources to ensuring the well-being of US civilian sailors and Naval service members. On January 4, 1889, President Cleveland enacted the USPHS Commissioned Corps, creating the world's first (and still only) uniformed service dedicated to promoting, protecting, and advancing the health and safety of the United States and the world. Building on the lessons of the 2014-2015 response to the Ebola virus pandemic, the Corps Care program was formalized in 2017 to establish and implement a uniform and comprehensive strategy to meet the behavioral health, medical, and spiritual needs of all Commissioned Corps officers. Its role was expanded in response to the coronavirus disease 2019 (COVID-19) pandemic, which has placed unprecedented demands on health care workers and spotlighted the need for FHP strategies. We describe the FHP roles of the Corps Care program for the resiliency of Commission Corps officers in general and the Corps' impact during the response to the COVID-19 pandemic. Qualitative analysis of FHP discussions with deployed officers highlights the unique challenges to FHP presented by the pandemic response.
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COVID-19/epidemiología , Personal de Salud/psicología , Fiebre Hemorrágica Ebola/epidemiología , Resiliencia Psicológica , United States Public Health Service , COVID-19/terapia , Fiebre Hemorrágica Ebola/terapia , Estados UnidosRESUMEN
We present six cases of central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO) that we recently treated with hyperbaric oxygen (HBO2). Patients in three of the six cases, including the CRVO case, experienced near to complete restoration of their vision. Another case had marked improvement. Our findings are similar to other case studies with approximately 65-70% improvement in patients treated for CRAO. Physicians should be aware that rapid referral of CRAO and CRVO patients to HBO2 is efficacious. Such patients should be placed on 100% oxygen by non-rebreather mask as soon as the diagnosis is suspected, pending transportation to HBO2.
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Acute hypoxia is experienced in an array of ailments and conditions, including asthma, chronic obstructive pulmonary disease, heart failure, sleep apnea, acute hypotension, and blast lung injury. Classically, infection activates the neuroimmune system, causing loss of interest in the social environment. We report that the non-infectious stimulus acute hypoxia triggers neuroimmune system activation (NSA), causing loss of interest in the social environment, and that recovery from hypoxia-induced NSA is impaired in a mouse model of type 2 diabetes. Importantly, recovery from the behavioral consequences of hypoxia-induced NSA was nearly ablated in MyD88 (myeloid differentiation factor 88) knock-out mice and in mice intracerebroventricularly administered the caspase-1 inhibitor ac-YVAD-CMK (ac-Tyr-Val-Asp-2,6-dimethylbenzoyloxymethylketone). Diabetic mice had prolonged recovery from NSA that could be halved by administration of subcutaneous interleukin-1 (IL-1) receptor antagonist (RA). These results show that acute hypoxia activates the IL-1beta arm of the neuroimmune system, which diabetes exacerbates and treatment with IL-1RA ameliorates.
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Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Hipoxia Encefálica/inmunología , Hipoxia Encefálica/metabolismo , Neuroinmunomodulación/fisiología , Animales , Diabetes Mellitus Tipo 2/fisiopatología , Hipoxia Encefálica/fisiopatología , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Factores de TiempoRESUMEN
Acute hypoxia is experienced by a variety of individuals (neonates to the elderly) and in an assortment of conditions and diseases (terrorist bomb attack to decompensated heart failure). Increasingly, elaboration of inflammatory cytokines appears key to the brain-based response to hypoxia, as evidenced by the biobehaviors of malaise, fatigue, lethargy, and loss of interest in the physical and social environment. These sickness symptoms implicate hypoxia-dependent activation of the neuroimmune system as a key component of acute hypoxia. Type 2 diabetes (T2D) is associated with increased incidence, severity, and delayed recovery from hypoxic events. Why T2D negatively affects acute hypoxia is not well understood. Recent work, however, reveals that anti-inflammatory pathways tied to the interleukin (IL)-1beta arm of the neuroimmune system may be critical. In this review, the authors examine the link between acute hypoxia, T2D, and neuroimmunity.
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Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Diabetes Mellitus Tipo 2/inmunología , Encefalitis/inmunología , Hipoxia Encefálica/inmunología , Neuroinmunomodulación/inmunología , Animales , Enfermedades Autoinmunes del Sistema Nervioso/metabolismo , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Encefalitis/metabolismo , Encefalitis/fisiopatología , Humanos , Hipoxia Encefálica/metabolismo , Hipoxia Encefálica/fisiopatología , Interleucina-1beta/inmunología , Leptina/inmunología , Leptina/metabolismo , Transducción de Señal/inmunologíaRESUMEN
The incidence of type 2 diabetes (T2D) is rapidly expanding. Some of the more obvious pathologies associated with it include: defective glucose metabolism, obesity, cardiovascular disease and an inability to mount an effective immune response to infection by certain pathogenic organisms, leading to sepsis and death. A common tie linking these seemingly disparate complications is chronic inflammation. Today we know that inflammation is regulated locally and systemically by numerous biochemical signals. One of the most important of these signals is a class of molecules called cytokines. Cytokines can be generally classified as proinflammatory or anti-inflammatory and allow an organism to respond rapidly to an immune challenge by coordinating an appropriate immune response. In T2D, the balance between proinflammatory and anti-inflammatory cytokines is shifted toward proinflammation, potentially causing or exacerbating the health complications found in T2D. Over-nutrition has been shown to trigger the innate immune system but activation of the innate immune system, itself, induces hyperglycemia and insulin resistance. In all likelihood, diabetes and chronic inflammation are inseparable and act as a reciprocal feed-forward loop.
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Citocinas/fisiología , Diabetes Mellitus Tipo 2/fisiopatología , Inflamación/fisiopatología , Antiinflamatorios/uso terapéutico , Diabetes Mellitus Tipo 2/epidemiología , Humanos , Incidencia , Inflamación/tratamiento farmacológico , Inflamación/patología , Interleucina-1beta/fisiología , Interleucina-6/fisiología , Leptina/fisiología , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
PURPOSE: Communicating unexpected news of a patient death is rarely encountered in urology. We evaluated resident performance during an unexpected patient death scenario involving high fidelity simulation. We also studied simulation as a tool to teach and assess nontechnical skills in urology. MATERIALS AND METHODS: An unexpected patient death scenario was developed at a simulation center using high fidelity mannequins, urology residents, critical care fellows, nurses, hospital chaplains and actors. Scenario objectives addressed Accreditation Council for Graduate Medical Education core competencies. The 19 urology residents in training years 2 to 6 participated in the scenario. Performance was evaluated using 5-point Likert scale questionnaires and checklists completed by residents, faculty and actors. RESULTS: Overall resident performance was satisfactory in the simulation scenario. Verification of code status was identified as an area requiring improvement. Euphemisms for death were more commonly used in the initial delivery (16 residents or 84.2%) than the preferred words died or death (3 or 15.8%). After completing the scenario the perceived competency of residents increased from 73.7% before to 94.7% after the scenario. In addition, all residents agreed that the simulation experience was useful and overall realistic, and it should be part of the training curriculum. CONCLUSIONS: Evaluation of urology resident performance was possible during an unexpected patient death scenario. Upon completion of the scenario perceived competency of the simulation task was increased. High fidelity simulation was found to be an effective method for teaching and assessing the acquisition of nontechnical skills. All residents agreed that the simulation was useful and should be included in urological training.
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Muerte , Educación Médica/métodos , Internado y Residencia , Revelación de la Verdad , Urología/educación , Humanos , Maniquíes , Simulación de Paciente , Estudios ProspectivosRESUMEN
The idea that type 2 diabetes is associated with augmented innate immune function characterized by increased circulating levels of acute phase reactants and altered macrophage biology is fairly well established, even though the mechanisms involved in this complex interaction still are not entirely clear. To date, the majority of studies investigating innate immune function in type 2 diabetes are limited to the context of wound healing, atherosclerosis, stroke, and other commonly identified comorbidities. Several important recurring themes come out of these data. First, type 2 diabetes is associated with a state of chronic, subclinical inflammation. Second, in macrophages, type 2 diabetic conditions enhance proinflammatory reactions and impair anti-inflammatory responses. Third, after acute activation of the innate immune system in type 2 diabetes, recovery or resolution of inflammation is impaired. The consequences of type 2 diabetes-associated inflammatory alterations on PNI processes have been recognized only recently. Given the impact of diminished emotional well-being on the quality of life in patients who have type 2 diabetes, diabetes-induced exacerbation of PNI responses should be considered a serious complication of type 2 diabetes that warrants further clinical attention.
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Encéfalo/inmunología , Complicaciones de la Diabetes/inmunología , Diabetes Mellitus Tipo 2/inmunología , Inmunidad Innata/inmunología , Proteínas de Fase Aguda/metabolismo , Animales , Barrera Hematoencefálica/inmunología , Citocinas/sangre , Complicaciones de la Diabetes/psicología , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Tipo 2/psicología , Glucocorticoides/fisiología , Humanos , Inmunidad Celular/inmunología , Inflamación/inmunología , Inflamación/psicología , Resistencia a la Insulina/inmunología , Lipopolisacáridos/inmunología , Ratones , Psiconeuroinmunología , Ratas , Rol del EnfermoRESUMEN
Occurrences of pharmaceuticals are evident in aquatic organisms. A reproducible gas chromatography-mass spectrometry (GC-MS) method using selected ion monitoring (SIM) has been used to determine the anti-histamine diphenhydramine (DPH), anti-anxiety diazepam (DZP), anti-seizure carbamazepine (CZP) drugs and their metabolites in grocery stores fish that were homogenized, extracted, pre-concentrated, cleaned up, and examined. Identifications of the compounds in extracts were obtained by comparing similar mass spectral features and retention properties with standards. Among nine frequently detected drugs, only DPH and DZP were observed and ranged from 0.61 to 6.21 and 1.99 to 16.57 ng/g, respectively, in fourteen fish species. These concentration values were lower than the environmental fish. Mean spike recoveries of analytes exceeded 75% with relative standard deviations (RSD)<10%. The statistically-derived method detection limits (MDLs) for nine compounds ranged from 0.13 to 5.56 ng/g. Average surrogate recoveries were 80-85% with 4-9% RSD.
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Peces/metabolismo , Cromatografía de Gases y Espectrometría de Masas/métodos , Animales , Soluciones FarmacéuticasRESUMEN
A sizable body of knowledge has arisen demonstrating that type 2 diabetes (T2D) is associated with alterations in the innate immune system. The resulting proinflammatory-leaning imbalance is implicated in the development of secondary disease complications and comorbidities, such as delayed wound healing, accelerated progress of atherosclerosis, and retinopathy, in people who have T2D. New experimental data and the results of recently published health-related quality-of-life surveys indicate that individuals who have T2D experience diminished feelings of happiness, well being, and satisfaction with life. These emotional and psychological consequences of T2D point to altered neuroimmunity as a previously unappreciated complication of T2D. This article discusses recent data detailing the impact of T2D on a person's PNI response.
RESUMEN
We have previously shown that type 2 diabetes (T2D) in the mouse is associated with increased responsivity to innate immune challenge. Here we demonstrate that in a mouse model of type 1 diabetes (T1D) LPS-dependent suppression of social exploration (SE) is augmented and dependent on hyperglycemia. T1D was induced in mice with intraperitoneal (i.p.) streptozotocin (STZ). After 4d, STZ treated mice had blood glucose levels of 417+/-34mg/dl compared to 160+/-11mg/dl in non-STZ treated mice. When these diabetic mice were challenged with i.p. lipopolysaccharide (LPS), LPS-induced depression of SE was nearly 2.7-fold greater in diabetic mice at 2h than in non-diabetic mice. Examination of peritoneal proinflammatory cytokine levels 2h after LPS administration showed that diabetic mice had 4-, 2.5- and 3.6-fold greater concentrations of IL-1beta, IL-6 and TNF-alpha, respectively, when compared to non-diabetic mice. Control of blood glucose levels with injected insulin in diabetic mice improved 2h post LPS-induced loss of SE by 3.9-fold. Interestingly, insulin given intracerebroventricularly to diabetic mice did not impact LPS-induced loss of SE but did increase basal SE 8, 12 and 24h later. Finally, administration of STZ to hyperglycemic/hyperinsulinemic db/db mice did not alter LPS-induced loss of SE. Taken together these findings indicate that mice with T1D have augmented loss of SE in response to LPS and this is due to hyperglycemia and not to insulin.
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Diabetes Mellitus Tipo 1/inmunología , Conducta Exploratoria/fisiología , Hiperglucemia/inmunología , Inmunidad Innata/fisiología , Conducta Social , Animales , Líquido Ascítico/inmunología , Líquido Ascítico/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/psicología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hiperglucemia/sangre , Hiperglucemia/psicología , Insulina/sangre , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/inmunología , Ratones , Ratones Endogámicos , Ratones Mutantes , Estadísticas no ParamétricasRESUMEN
To the ill patient with diabetes, the behavioral symptoms of sickness such as fatigue and apathy are debilitating and can prevent recuperation. Here we report that peripherally administered insulin-like growth factor 1 (IGF-1) attenuates LPS-dependent depression of social exploration (sickness) in nondiabetic (db/+) but not in diabetic (db/db) mice. We show that the insulin/IGF-1 mimetic vanadyl sulfate (VS) is effective at augmenting recovery from sickness in both db/+ and db/db mice. Specifically, peak illness was reached at 2 h for both VS and control animals injected with LPS, and VS mice recovered 50% faster than non-VS-treated animals. Examination of the mechanism of VS action in db/+ mice showed that VS paradoxically augmented peritoneal macrophage responsivity to LPS, increasing both peritoneal and ex vivo macrophage production of IL-1beta and IL-6 but not TNF-alpha. The effects of VS in promoting recovery from sickness were not restricted to LPS, because they were also observed after direct administration of IL-1beta. To explore the possibility that VS impairs immune-to-brain communication via vagal afferents, the vagally mediated satiety-inducing effects of cholecystokinin 8 were tested in db/+ mice. Cholecystokinin decreased food intake in saline-injected mice but not in VS-treated mice. VS also inhibited LPS-dependent up-regulation of IL-1beta and IL-6 mRNA in the brain, while increasing by 50% the cerebral expression of transcripts of the specific antagonist of IL-1 receptors IL-1RA and IL-1R2. Taken together, these data indicate that VS improves recovery from LPS-induced sickness by blocking vagally mediated immune-to-brain signaling and by up-regulating brain expression of IL-1beta antagonists.