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This review provides an in-depth analysis of recent advances and strategies employed in the Pd-catalysed asymmetric allylic alkylation (Pd-AAA) of nucleophilic prochiral heterocycles. The review is divided into sections each focused on a specific family of heterocycle, where optimisation data and reaction scope have been carefully analysed in order to bring forward specific reactivity and selectivity trends. The review eventually opens on how computer-based technologies could be used to predict an ideally matched catalytic system for any given substrate. This user-guide targets chemists from all horizons interested in running a Pd-AAA reaction for the preparation of highly enantioenriched heterocyclic compounds.
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Intralesional corticosteroids are associated with various, uncommon, local adverse events [1]. Atrophy and hypopigmentation most commonlyremain localized to sites of injection. However, outward radiation in a linear, streaky pattern has been reported and is termed "perilesional/perilymphatic hypopigmentation or atrophy [2]." We report a case of this rare adverse event.
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Glucocorticoides/efectos adversos , Hipopigmentación/inducido químicamente , Piel/patología , Triamcinolona Acetonida/efectos adversos , Anciano , Atrofia/inducido químicamente , Glucocorticoides/administración & dosificación , Humanos , Inyecciones Intralesiones/efectos adversos , Masculino , Codo de Tenista/tratamiento farmacológico , Triamcinolona Acetonida/administración & dosificaciónRESUMEN
Lipedematous alopecia is a rare, non-androgenic form of alopecia that is challenging to diagnose, often requiring clinical-pathological correlation. The condition has been reported predominantly in African-American females, but more recently has been described in a broader demographic [1,2]. We describe a rare case of a young Caucasian man with isolated lipedematous alopecia who presented with a boggy, erythematous plaque with alopecia of the occipital scalp and subcutaneous thickening with lymphocytic dermal infiltrate and decreased anagen hairs on histology.
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Tejido Adiposo/patología , Alopecia/patología , Cuero Cabelludo/patología , Adulto , Humanos , Linfocitos , Masculino , Tejido Subcutáneo/patología , Población BlancaAsunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Receptores Quiméricos de Antígenos , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Receptores Quiméricos de Antígenos/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Masculino , Inmunoterapia Adoptiva/métodos , FemeninoRESUMEN
It is known that eosinophilic fasciitis can be associated with monoclonal gammopathy. There is clinical similarity between eosinophilic fasciitis and morphea profunda, but it is unclear whether morphea profunda might be associated with monoclonal gammopathy. The temporal quantification of gammopathy in morphea profunda has not been well characterized. We describe four patients with morphea profunda that were associated with monoclonal gammopathy. Three were associated with monoclonal IgG protein and one with IgM. No patients in our series developed myeloma. In conclusion, the association of monoclonal gammopathy is not unique to eosinophilic fasciitis and scleromyxedema. Further studies are necessary to characterize further the relationship between the two conditions.
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Gammopatía Monoclonal de Relevancia Indeterminada/complicaciones , Esclerodermia Localizada/complicaciones , Adulto , Anciano , Femenino , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/inmunología , Esclerodermia Localizada/patología , Piel/patologíaRESUMEN
Importance: Cellulitis is misdiagnosed in up to 30% of cases due to mimic conditions termed pseudocellulitis. The resulting overuse of antibiotics is a threat to patient safety and public health. Surface thermal imaging and the ALT-70 (asymmetry, leukocytosis, tachycardia, and age ≥70 years) prediction model have been proposed as tools to help differentiate cellulitis from pseudocellulitis. Objectives: To validate differences in skin surface temperatures between patients with cellulitis and patients with pseudocellulitis, assess the optimal temperature measure and cut point for differentiating cellulitis from pseudocellulitis, and compare the performance of skin surface temperature and the ALT-70 prediction model in differentiating cellulitis from pseudocellulitis. Design, Setting, and Participants: This prospective diagnostic validation study was conducted among patients who presented to the emergency department with acute dermatologic lower extremity symptoms from October 11, 2018, through March 11, 2020. Statistical analysis was performed from July 2020 to March 2021 with additional work conducted in September 2023. Main Outcomes and Measures: Temperature measures for affected and unaffected skin were obtained. Cellulitis vs pseudocellulitis was assessed by a 6-physician, independent consensus review. Differences in temperature measures were compared using the t test. Logistic regression was used to identify the temperature measure and associated cut point with the optimal performance for discriminating between cellulitis and pseudocellulitis. Diagnostic performance characteristics for the ALT-70 prediction model, surface skin temperature, and both combined were also assessed. Results: The final sample included 204 participants (mean [SD] age, 56.6 [16.5] years; 121 men [59.3%]), 92 (45.1%) of whom had a consensus diagnosis of cellulitis. There were statistically significant differences in all skin surface temperature measures (mean temperature, maximum temperature, and gradients) between cellulitis and pseudocellulitis. The maximum temperature of the affected limb for patients with cellulitis was 33.2 °C compared with 31.2 °C for those with pseudocellulitis (difference, 2.0 °C [95% CI, 1.3-2.7 °C]; P < .001). The maximum temperature was the optimal temperature measure with a cut point of 31.2 °C in the affected skin, yielding a mean (SD) negative predictive value of 93.5% (4.7%) and a sensitivity of 96.8% (2.3%). The sensitivity of all 3 measures remained above 90%, while specificity varied considerably (ALT-70, 22.0% [95% CI, 15.8%-28.1%]; maximum temperature of the affected limb, 38.4% [95% CI, 31.7%-45.1%]; combination measure, 53.9% [95% CI, 46.5%-61.2%]). Conclusions and Relevance: In this large diagnostic validation study, significant differences in skin surface temperature measures were observed between cases of cellulitis and cases of pseudocellulitis. Thermal imaging and the ALT-70 both demonstrated high sensitivity, but specificity was improved by combining the 2 measures. These findings support the potential of thermal imaging, alone or in combination with the ALT-70 prediction model, as a diagnostic adjunct that may reduce overdiagnosis of cellulitis.
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Celulitis (Flemón) , Termografía , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Celulitis (Flemón)/diagnóstico , Diagnóstico Diferencial , Servicio de Urgencia en Hospital , Leucocitosis/diagnóstico , Valor Predictivo de las Pruebas , Estudios Prospectivos , Temperatura Cutánea , Termografía/métodosRESUMEN
Stereoselective carbon-carbon bond formation via palladium-catalyzed asymmetric allylic alkylation is a crucial strategy to access chiral natural products and active pharmaceutical ingredients. However, catalysts based on the privileged Trost and Pfaltz-Helmchen-Williams PHOX ligands often require high loadings, specific preactivation protocols, and excess chiral ligand. This makes these reactions uneconomical, often unreproducible, and thus unsustainable. Here we report several chiral single-component Pd(0) precatalysts that are active and practically-applicable in a variety of asymmetric allylic alkylation reactions. Despite the decades-long history and widespread use of Trost-type ligands, the precatalysts in this work are the only reported examples of stable, isolable Pd(0) complexes with these ligands. Evaluating these precatalysts across nine asymmetric allylic alkylation reactions reveals high reactivity and selectivity at low Pd loading. Importantly, we also report an unprecedented Pd-catalyzed enantioselective allylation of a hydantoin, achieved on gram scale in high yield and enantioselectivity with only 0.2 mol% catalyst.
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A highly efficient, cost-effective, and environmentally friendly protocol is reported for the C5-selective alkylation of hydantoins under phase-transfer catalysis. The reactions are scalable and only require a catalytic amount of tetrabutylammonium bromide (TBAB) to achieve high yields under mild reaction conditions. Moreover, the method is applicable to a wide range of electrophiles, including alkyl-, allyl-, propargyl-, and benzyl halides, as well as acrylates and dibromoalkanes, but also to virtually any hydantoin precursor. We also highlight the potential for an enantioselective adaptation using a chiral phase-transfer catalyst.
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Objective: To compare clinical documentation of skin warmth to patient report and quantitative skin surface temperatures of patients diagnosed with cellulitis in the emergency department (ED). Methods: Adult patients (≥18 years) presenting to the ED with an acute complaint involving visible erythema of the lower extremity were prospectively enrolled. Those diagnosed with cellulitis were included in this analysis. Participant report of skin warmth was recorded and skin surface temperature values were obtained from the affected and corresponding unaffected area of skin using thermal cameras. Average temperature (Tavg) was extracted from each image and the difference in Tavg between the affected and unaffected limb was calculated (Tgradient). Clinical documentation of skin warmth was compared to patient report and measured skin warmth (Tgradient >0°C). Results: Among 126 participants diagnosed with cellulitis, 110 (87%) exhibited objective warmth (Tgradient >0°C) and 58 (53%) of these cases had warmth documented in the physical examination. Of those with objective warmth, 86 (78%) self-reported warmth and 7 (6%) had warmth documented in their history of present illness (HPI) (difference = 72%, 95% confidence interval [CI]: 62%-82%; P < 0.001). A significant difference was observed for Tavg affected when warmth was documented (32.1°C) versus not documented (31.0°C) in the physical examination (difference = 1.1°C, 95% CI: 0.29-1.94; P = 0.0083). No association was found between Tgradient and patient-reported or HPI-documented warmth. Conclusions: The majority of ED-diagnosed cellulitis exhibited objective warmth, yet significant discordance was observed between patient-reported, clinician-documented, and measured warmth. This raises concerns over inadequate documentation practices and/or the poor sensitivity of touch as a reliable means to assess skin surface temperature. Introduction of objective temperature measurement tools could reduce subjectivity in the assessment of warmth in patients with suspected cellulitis.
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During inflammation neutrophils rapidly migrate to the site of tissue damage or infection by following complex gradients of bacterial peptides and host-derived chemokines. The efficiency and speed of neutrophil migration is critically dependent upon the ability of neutrophils to sense new gradients and utilize only those that provide the most direct path to the damaged or infected site. Receptor desensitization plays an important role in migration efficiency and is most commonly studied using bath application of chemotactic factor solutions instead of presenting cells with gradients analogous to those they would experience in vivo. Here we describe a new method for examining gradient-induced neutrophil desensitization using a previously-developed open-chamber microfluidic gradient generator.
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Factores Quimiotácticos/química , Quimiotaxis/fisiología , Técnicas Analíticas Microfluídicas/métodos , Infiltración Neutrófila/fisiología , Neutrófilos/citología , Células Cultivadas , Colorantes Fluorescentes/química , Humanos , Técnicas Analíticas Microfluídicas/instrumentación , Neutrófilos/fisiologíaRESUMEN
The authors present the case of a patient who developed an Aspergillosis flavus (A flavus) superficial cutaneous infection which was identified at the time of cast removal, 2 weeks after immobilization of a closed distal third humerus fracture. Clinical and microbiological findings, as well as the treatment of this patient, are reported. An otherwise healthy 27-year-old male presented to the orthopaedic surgery clinic 2 weeks after a closed distal humerus fracture, which was initially immobilized with a functional removable brace. Upon cast removal, the patient was noted to have significant brown hyperkeratotic patches and plaques, studded with pustules in an annular configuration on his left posterior and lateral arm. Fungal culture later grew A flavus. The patient was started on both oral and topical antifungals and operative management of the displaced fracture was delayed until skin lesions resolved. Once clinical examination and negative repeat bedside potassium hydroxide were confirmed, open reduction and internal fixation was performed. The fracture healed uneventfully, and the patient did not develop any signs or symptoms of postoperative infection.
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Biomolecule gradients have been shown to play roles in a wide range of biological processes including development, inflammation, wound healing, and cancer metastasis. Elucidation of these phenomena requires the ability to expose cells to biomolecule gradients that are quantifiable, controllable, and mimic those that are present in vivo. Here we review the major biological phenomena in which biomolecule gradients are employed, traditional in vitro gradient-generating methods developed over the past 50 years, and new microfluidic devices for generating gradients. Microfluidic gradient generators offer greater levels of precision, quantitation, and spatiotemporal gradient control than traditional methods, and may greatly enhance our understanding of many biological phenomena. For each method, we outline the salient features, capabilities, and applications.
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Factores Biológicos/metabolismo , Factores Biológicos/farmacología , Técnicas de Cultivo de Célula/métodos , Fenómenos Fisiológicos Celulares/efectos de los fármacos , Animales , Técnicas de Cultivo de Célula/instrumentación , Técnicas Analíticas Microfluídicas/métodos , Especificidad por Sustrato , Factores de TiempoRESUMEN
This study compared the psychological and physical functioning of 12 children in each of three groups: mothers with chronic pain, fathers with chronic pain and a control, pain-free parents. Parents completed a number of questionnaires including the RAND-36 Health Status Inventory, a child health scale and the Child Behavior Checklist. Children completed the Revised Child Manifest Anxiety Scale and a scale measuring pain and sickness behaviour. Children of mothers with chronic pain reported the most physical and psychological problems, followed by children of fathers with chronic pain and children from the control group. Pain reports between children and parents with chronic pain were significantly correlated, suggesting support for a familial pain model. Social learning may explain the concordance between parent and child health in families experiencing parental chronic pain.
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Relaciones Padre-Hijo , Salud Mental , Relaciones Madre-Hijo , Dolor/psicología , Psicología Infantil , Adulto , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Responsabilidad Parental/psicología , Proyectos Piloto , Factores Sexuales , Estadísticas no ParamétricasRESUMEN
We describe a novel chemotaxis assay based on the microvalve-actuated release of a chemoattractant from a cell-free microchamber into a cell-containing microchamber. The microvalve chemotaxis device (microVCD) was placed on the stage of a conventional inverted microscope to obtain time-lapse micrographs of neutrophils migrating in a radially-symmetric evolving gradient of the chemotactic factor CXCL8/Interleukin-8. A fluorescent tracer was added to the CXCL8 solution to visualize the evolution of the gradient profile, so that at each time point the cell positions could be assigned CXCL8 concentration values. Tracking of individual neutrophils for 90 minutes showed that (a) the neutrophil migratory response is, on average, radially directed towards the CXCL8 source; (b) significant non-radial displacements occur frequently; and (c) there is considerable heterogeneity in the migration speeds and directions amongst the neutrophil population. A custom-made imaging analysis tool was used to extract measurements of migratory behavior such as speed, velocity along the gradient's radial axis, and the cosine of the turning angle as a function of CXCL8 concentration. The microVCD can be easily adapted to study the migratory behavior of cultured cells other than neutrophils.
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Quimiotaxis de Leucocito , Interleucina-8/farmacología , Técnicas Analíticas Microfluídicas/métodos , Neutrófilos/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Interleucina-8/química , Técnicas Analíticas Microfluídicas/instrumentación , Microscopía Fluorescente/métodos , Neutrófilos/citología , Neutrófilos/inmunologíaRESUMEN
The isolation and purification of axon guidance molecules has enabled in vitro studies of the effects of axon guidance molecule gradients on numerous neuronal cell types. In a typical experiment, cultured neurons are exposed to a chemotactic gradient and their growth is recorded by manual identification of the axon tip position from two or more micrographs. Detailed and statistically valid quantification of axon growth requires evaluation of a large number of neurons at closely spaced time points (e.g. using a time-lapse microscopy setup). However, manual tracing becomes increasingly impractical for recording axon growth as the number of time points and/or neurons increases. We present a software tool that automatically identifies and records the axon tip position in each phase-contrast image of a time-lapse series with minimal user involvement. The software outputs several quantitative measures of axon growth, and allows users to develop custom measurements. For, example analysis of growth velocity for a dissociated E13 mouse cortical neuron revealed frequent extension and retraction events with an average growth velocity of 0.05 +/- 0.14 microm/min. Comparison of software-identified axon tip positions with manually identified axon tip positions shows that the software's performance is indistinguishable from that of skilled human users.
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Inteligencia Artificial , Conos de Crecimiento/fisiología , Conos de Crecimiento/ultraestructura , Interpretación de Imagen Asistida por Computador/métodos , Microscopía de Contraste de Fase/métodos , Microscopía por Video/métodos , Reconocimiento de Normas Patrones Automatizadas/métodos , Animales , Axones/fisiología , Axones/ultraestructura , Aumento de la Célula , Células Cultivadas , Ratones , Técnica de SustracciónRESUMEN
UNLABELLED: The role of parenting in the relationship between maternal chronic pain and negative child outcomes, including internalizing, externalizing, and social and health problems, was investigated. Parenting strategies used by mothers with chronic pain were compared to parenting strategies used by a control group of mothers without pain. Thirty-nine mothers experiencing chronic pain, their 55 children, 35 pain-free mothers, and their 48 children participated in the study. The results showed that for mothers with chronic pain, dysfunctional parenting strategies and the quality of the mother-child relationship were related to negative child outcomes. Mothers with chronic pain were more likely to engage in lax parenting and report reduced relationship quality with children than were control mothers. For the chronic pain group, over-reactive parenting was found to mediate the relationship between maternal physical functioning and child adjustment. Dysfunctional parenting strategies may constitute part of the risk that maternal chronic pain poses for children. The similarities between the impact of maternal chronic pain on child adjustment and that of other maternal stressors, such as depression, are discussed. PERSPECTIVE: In mothers with chronic pain, poor maternal physical functioning was associated with increased maternal over-reactive behavior that was in turn related to poor child adjustment. Maternal over-reactive behavior did not, however, differ in chronic pain and control mothers.
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Desarrollo Infantil , Crianza del Niño/psicología , Conducta Materna/psicología , Relaciones Madre-Hijo , Dolor/psicología , Desarrollo de la Personalidad , Adaptación Psicológica , Adulto , Estudios de Casos y Controles , Niño , Enfermedad Crónica , Femenino , Humanos , Masculino , Conducta VerbalRESUMEN
The cream or fat fraction of milk consists of fat droplets composed primarily of triacylglycerols that are surrounded by cellular membranes. In this review we discuss what is known about how these droplets are formed in and secreted by mammary epithelial cells during lactation. This secretion mechanism, which appears to be unique, is unlike the exocytotic mechanism used by other cell types to secrete lipids. Milk fat globules originate as small, triacylglycerol-rich, droplets that are formed on or in endoplasmic reticulum membranes. These droplets are released from endoplasmic reticulum into the cytosol as microlipid droplets coated by proteins and polar lipids. Microlipid droplets can fuse with each other to form larger cytoplasmic lipid droplets. Droplets of all sizes appear to be unidirectionally transported to apical cell regions by as yet unknown mechanisms that may involve cytoskeletal elements. These lipid droplets appear to be secreted from the cell in which they were formed by being progressively enveloped in differentiated regions of apical plasma membrane. While plasma membrane envelopment appears to be the primary mechanism by which lipid droplets are released from the cell, a mechanism involving exocytosis of lipid droplets from cytoplasmic vacuoles also has been described. As discussed herein, while we have a general overview of the steps leading to the fat globules of milk, virtually nothing is known about the molecular mechanisms involved in milk fat globule formation, intracellular transit, and secretion.
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Glucolípidos/metabolismo , Glicoproteínas/metabolismo , Glándulas Mamarias Animales/metabolismo , Animales , Bovinos , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/ultraestructura , Femenino , Gotas Lipídicas , Glándulas Mamarias Animales/ultraestructura , RatasRESUMEN
Entrainment in solution of an oscillating activity with a temperature compensated period of 24 min is described for a NADH oxidase (NOX) activity of the bovine milk fat globule membrane, a derivative of the mammary epithelial cell plasma membrane. The period of 24 min remained unchanged at 17 degrees C, 27 degrees C and 37 degrees C whereas the amplitude approximately doubled with each 10 degree C rise in temperature (Q(10)congruent with 2). The periodicity was observed with both intact milk fat globule membranes and with detergent-solubilized membranes, demonstrating that the oscillations did not require an association with membranes. The periodicity was not the result of instrument variation or of chemical interactions among reactants in solution. Preparations with different periodicities entrained (autosynchronized) when mixed. Upon mixing, the preparations exhibited two oscillatory patterns but eventually a single pattern representing the mean of the farthest separated maxima of the two preparations analyzed separately emerged. The cell surface NOX protein is the first reported example of an entrainable biochemical entity with a temperature-compensated periodicity potentially capable of functioning as an ultradian or circadian clock driver.