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1.
Proc Natl Acad Sci U S A ; 119(37): e2203230119, 2022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-36067290

RESUMO

Overwintering success is an important determinant of arthropod populations that must be considered as climate change continues to influence the spatiotemporal population dynamics of agricultural pests. Using a long-term monitoring database and biologically relevant overwintering zones, we modeled the annual and seasonal population dynamics of a common pest, Helicoverpa zea (Boddie), based on three overwintering suitability zones throughout North America using four decades of soil temperatures: the southern range (able to persist through winter), transitional zone (uncertain overwintering survivorship), and northern limits (unable to survive winter). Our model indicates H. zea population dynamics are hierarchically structured with continental-level effects that are partitioned into three geographic zones. Seasonal populations were initially detected in the southern range, where they experienced multiple large population peaks. All three zones experienced a final peak between late July (southern range) and mid-August to mid-September (transitional zone and northern limits). The southern range expanded by 3% since 1981 and is projected to increase by twofold by 2099 but the areas of other zones are expected to decrease in the future. These changes suggest larger populations may persist at higher latitudes in the future due to reduced low-temperature lethal events during winter. Because H. zea is a highly migratory pest, predicting when populations accumulate in one region can inform synchronous or lagged population development in other regions. We show the value of combining long-term datasets, remotely sensed data, and laboratory findings to inform forecasting of insect pests.


Assuntos
Mudança Climática , Mariposas , Estações do Ano , Animais , Dinâmica Populacional , Temperatura
2.
J Hand Surg Am ; 48(6): 626.e1-626.e8, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-35440404

RESUMO

PURPOSE: This study investigated metacarpal fracture occurrences, characteristics, treatments, and return-to-play times for National Football League (NFL) athletes. METHODS: NFL players who sustained metacarpal fractures during the 2012 to 2018 seasons were reviewed. All players on the 32 NFL team active rosters with metacarpal fractures recorded through the NFL Injury Database were included. Player age, time in the league, player position, injury setting, injury mechanism, fractured ray, management, and return-to-play were recorded. RESULTS: There were 208 injury occurrences resulting in 1 or more metacarpal fractures, identified in 205 players. Of these, 81 (39%) injuries were operated. Return-to-play data were available for 173 (83%) injured players. The median return-to-play time for all athletes was 15 days (interquartile range, 1-55 days). Of the injured players, 130 (71%) missed time but returned the same season. Within this 130-player subset, 69 (53%) were treated nonsurgically and 61 (47%) operatively with median return-to-play times of 16 days (interquartile range, 6-30 days) and 20 days (interquartile range, 16-42 days) respectively. Eighteen individuals in this 130-player subgroup sustained a thumb metacarpal fracture. The return-to-play time was slower for patients sustaining thumb metacarpal fractures compared to other metacarpal fractures, and was significantly longer (median, 55 days) following nonsurgical treatment of thumb fractures compared with operative intervention (median, 24 days). A regression analysis revealed no trend or difference in return to football with respect to player age, time in the league, injury setting (practice vs game), injury mechanism, articular involvement, multiple concomitant injuries, or player position. CONCLUSIONS: Most NFL players who sustain metacarpal fractures miss less than 3 weeks and return to play the same season. The only variables that lessen the return-to-play time are involvement of lesser digit metacarpals and operative intervention for treatment of thumb metacarpal fractures. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.


Assuntos
Traumatismos dos Dedos , Futebol Americano , Fraturas Ósseas , Traumatismos da Mão , Ossos Metacarpais , Humanos , Futebol Americano/lesões , Volta ao Esporte , Ossos Metacarpais/lesões , Fraturas Ósseas/etiologia , Fraturas Ósseas/cirurgia , Traumatismos da Mão/epidemiologia , Traumatismos da Mão/etiologia , Traumatismos da Mão/cirurgia
3.
Radiographics ; 42(1): 195-211, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34951835

RESUMO

Injury of the scapholunate ligament (SLL) complex can lead to scapholunate dissociation, characterized by scapholunate interval widening and volar rotary subluxation of the scaphoid. Loss of the mechanical linkage between the scaphoid and lunate results in carpal instability and eventual scapholunate advanced collapse (SLAC) arthropathy. SLL complex injuries vary from acute and traumatic to chronic and degenerative. A staging system can be used to guide treatment options for these injuries on the basis of the reparability of the SLL dorsal band, carpal alignment and malalignment reducibility, and cartilage damage. Preoperative imaging with radiography and MRI is a component of injury staging and aids in planning surgical procedures. If the SLL dorsal band is reparable, then direct primary ligament repair with dorsal capsulodesis or dorsal intercarpal (DIC) ligament transfer can be performed. If the SLL dorsal band is irreparable with normal alignment or reducible malalignment, then reconstruction can be performed. In the setting of irreducible malalignment or SLAC arthropathy, a salvage procedure can be performed. Knowledge of SLL primary repair and various reconstruction techniques is important not only when evaluating postoperative images but also for accurate description of SLL injuries and aiding the surgeon in treatment planning. The authors present the normal anatomy of the SLL complex, a staging classification of SLL injury with radiographic and MRI findings, and common surgical procedures. Special attention is given to the operative techniques and postoperative imaging appearances of primary SLL repair with DIC ligament transfer and modified Brunelli reconstruction. ©RSNA, 2021.


Assuntos
Instabilidade Articular , Osso Semilunar , Osso Escafoide , Humanos , Instabilidade Articular/diagnóstico por imagem , Instabilidade Articular/cirurgia , Ligamentos Articulares/diagnóstico por imagem , Ligamentos Articulares/lesões , Ligamentos Articulares/cirurgia , Osso Semilunar/diagnóstico por imagem , Osso Semilunar/cirurgia , Osso Escafoide/diagnóstico por imagem , Osso Escafoide/cirurgia , Articulação do Punho
4.
Beilstein J Org Chem ; 18: 1332-1337, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36247978

RESUMO

The reduction of nitriles to primary amines is a useful transformation in organic synthesis, however, it often relies upon stoichiometric reagents or transition-metal catalysis. Herein, a borane-catalysed hydroboration of nitriles to give primary amines is reported. Good yields (48-95%) and chemoselectivity (e.g., ester, nitro, sulfone) were observed. DFT calculations and mechanistic studies support the proposal of a double B-N/B-H transborylation mechanism.

5.
Neurobiol Learn Mem ; 185: 107507, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34474155

RESUMO

Our memory for time is a fundamental ability that we use to judge the duration of events, put our experiences into a temporal context, and decide when to initiate actions. The medial entorhinal cortex (MEC), with its direct projections to the hippocampus, has been proposed to be the key source of temporal information for hippocampal time cells. However, the behavioral relevance of such temporal firing patterns remains unclear, as most of the paradigms used for the study of temporal processing and time cells are either spatial tasks or tasks for which MEC function is not required. In this study, we asked whether the MEC is necessary for rats to perform a time duration discrimination task (TDD), in which rats were trained to discriminate between 10-s and 20-s delay intervals. After reaching a 90% performance criterion, the rats were assigned to receive an excitotoxic MEC-lesion or sham-lesion surgery. We found that after recovering from surgery, rats with MEC lesions were impaired on the TDD task in comparison to rats with sham lesions, failing to return to criterion performance. Their impairment, however, was specific to the longer, 20-s delay trials. These results indicate that time processing is dependent on MEC neural computations only for delays that exceed 10 s, perhaps because long-term memory resources are needed to keep track of longer time intervals.


Assuntos
Córtex Entorrinal/fisiologia , Memória Episódica , Percepção do Tempo/fisiologia , Animais , Condicionamento Operante/fisiologia , Aprendizagem por Discriminação , Córtex Entorrinal/lesões , Masculino , Transtornos da Memória/fisiopatologia , Ratos , Ratos Long-Evans
6.
J Insect Sci ; 20(3)2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32365174

RESUMO

Stink bugs (Hemiptera: Pentatomidae) are agricultural pests of increasing significance in the North Central Region of the United States, posing a threat to major crops such as soybean. Biological control can reduce the need for insecticides to manage these pests, but the parasitism of stink bugs by Tachinidae (Diptera) is poorly characterized in this region. The objective of this study was to evaluate the rate of parasitism of stink bugs by tachinids over 2 yr from nine states across the North Central Region. Parasitism was assessed by quantifying tachinid eggs on the integument of stink bug adults. Parasitism rates (i.e., percent of adult stink bugs with tachinid eggs) were compared across stink bug species, states, stink bug sex, and years. The mean percent parasitism of stink bugs by tachinids was about 6% across the region and did not differ among stink bug species. Mean percent parasitism was significantly higher in Missouri than in northern and western states. In addition, male stink bugs had significantly higher mean percent parasitism than females. Stink bug species commonly found in soybean in the region showed some parasitism and are therefore potentially vulnerable to oviposition by these parasitoids. This is the first study to characterize the level of parasitism of stink bugs by tachinids across the North Central Region.


Assuntos
Dípteros/fisiologia , Heterópteros/parasitologia , Interações Hospedeiro-Parasita , Controle de Insetos , Controle Biológico de Vetores , Animais , Produtos Agrícolas/crescimento & desenvolvimento , Feminino , Masculino , Meio-Oeste dos Estados Unidos , Glycine max/crescimento & desenvolvimento
7.
J Insect Sci ; 20(6)2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33159527

RESUMO

Feltia subterranea (Fabricius), commonly known as the granulate cutworm, is a common species of owlet moths (Noctuidae) of major agricultural importance, widely distributed in Nearctic and Neotropical regions. This study was conducted to determine the species biological parameters, gather information about its larval host plants, and assess the agricultural significance of this species in the Americas. The viability of the egg, larval, pupal stages, and prepupal period was 98, 98, and 100%, respectively, under laboratory conditions. The average duration of the egg, larval, pupal stages, and prepupal period was 3, 17, 4, and 13 d, respectively. All laboratory-reared larvae developed through five instars. The growth ratio was 1.93 for females and 1.85 for males. The duration of the larval stage was significantly longer in females than in males from the fourth instar. The duration of the pupal stage was significantly shorter in females than in males. When larval and pupal stage durations were combined, there were no significant differences in total development time as a function of sex. In total, 159 botanical taxa belonging to 41 families were recorded as host species for F. subterranea. The families with the greatest number of host species were Fabaceae (22), Poaceae (19), Asteraceae (16), Brassicaceae (13), Solanaceae (12), Amaranthaceae (7), Cucurbitaceae (7), and Malvaceae (5). It is noteworthy that the large number of native weeds used by F. subterranea as host plants could represent a significant source of infestation of crops in the agricultural landscape.


Assuntos
Distribuição Animal , Meio Ambiente , Características de História de Vida , Mariposas/fisiologia , América , Animais , Feminino , Cadeia Alimentar , Larva/crescimento & desenvolvimento , Larva/fisiologia , Magnoliopsida , Masculino , Mariposas/crescimento & desenvolvimento , Óvulo/crescimento & desenvolvimento , Óvulo/fisiologia , Pupa/crescimento & desenvolvimento , Pupa/fisiologia
8.
J Am Chem Soc ; 141(46): 18600-18611, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31656074

RESUMO

The mechanism of R2BH-catalyzed hydroboration of alkynes by 1,3,2-dioxaborolanes has been investigated by in situ 19F NMR spectroscopy, kinetic simulation, isotope entrainment, single-turnover labeling (10B/2H), and density functional theory (DFT) calculations. For the Cy2BH-catalyzed hydroboration 4-fluorophenylacetylene by pinacolborane, the resting state is the anti-Markovnikov addition product ArCH = CHBCy2. Irreversible and turnover-rate limiting reaction with pinacolborane (k ≈ 7 × 10-3 M-1 s-1) regenerates Cy2BH and releases E-Ar-CH═CHBpin. Two irreversible events proceed in concert with turnover. The first is a Markovnikov hydroboration leading to regioisomeric Ar-C(Bpin)═CH2. This is unreactive to pinacolborane at ambient temperature, resulting in catalyst inhibition every ∼102 turnovers. The second is hydroboration of the alkenylboronate to give ArCH2CH(BCy2)Bpin, again leading to catalyst inhibition. 9-BBN behaves analogously to Cy2BH, but with higher anti-Markovnikov selectivity, a lower barrier to secondary hydroboration, and overall lower efficiency. The key process for turnover is B-H/C-B metathesis, proceeding by stereospecific transfer of the E-alkenyl group within a transient, µ-B-H-B bridged, 2-electron-3-center bonded B-C-B intermediate.

9.
J Insect Sci ; 19(4)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31346626

RESUMO

Striacosta albicosta (Smith) is a key pest of maize and dry beans in North America. It has expanded its distribution from the western Great Plains of the United States to the Great Lakes region in the United States and Canada. There has been limited research on the baseline biological aspects of this insect under controlled conditions. The objective of this study was to detail the biological parameters of S. albicosta feeding on an artificial diet under laboratory conditions. Overall survival from neonate to adult at 26.6 ± 1°C was 36.72% and the total developmental time was approximately 110 d. Survival of the egg, larval, prepupal, and pupal stages were 75.71, 98.50, 51.78, and 95.10%, respectively. Average duration of the egg, larval, prepupal, and pupal stages was 4.64, 28.20, 41.50, and 25.91 d, respectively. During the larval stage, 92.50% of larvae developed through seven instars and the remaining through six instars. Larvae that developed through six and seven instars exhibited a mean growth ratio of 1.60 and 1.47, respectively; however, there was no difference in pupal weight. Eggs laid by field-mated moths showed a fertility of 75.71%, compared with 4.18% from laboratory-reared moths. These data suggest that S. albicosta develop primarily through seven instars and the most vulnerable developmental stage is the prepupa. Laboratory conditions strongly affected fertility success. Information presented here greatly expands our understanding of S. albicosta biology, which can be used to improve the efficiency of laboratory bioassays and management techniques for this critical crop pest.


Assuntos
Características de História de Vida , Mariposas/fisiologia , Ração Animal/análise , Animais , Dieta , Feminino , Larva/crescimento & desenvolvimento , Larva/fisiologia , Mariposas/crescimento & desenvolvimento , Óvulo/crescimento & desenvolvimento , Óvulo/fisiologia , Pupa/crescimento & desenvolvimento , Pupa/fisiologia , Reprodução
10.
J Insect Sci ; 18(2)2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29718501

RESUMO

Bean leaf beetle (BLB), Cerotoma trifurcata (Forster; Coleoptera: Chrysomelidae), exhibits considerable color variation but little is known about the underlying genetic structure and gene flow among color phenotypes. Genetic and morphological variation among four color phenotypes-green with spots (G+S), green without spots (G-S), red with spots (R+S) and red without spots (R-S)-were analyzed using amplified fragment length polymorphisms (AFLP) and morphometrics, respectively. AFLP generated 175 markers that showed ≥80% polymorphism. Analysis of molecular variance (AMOVA) indicated that genetic variation was greatest within phenotypes (82.6-84.0%); gene flow among the four phenotypes was relatively high (Nm = 3.82). The dendrogram and STRUCTURE analysis indicated some population divergence of G-S from the other phenotypes. Morphological parameters were similar among phenotypes except that R+S showed significant differences in weight and body-length. Canonical variables 1 and 2, based on average morphometric characters, accounted for 98% of the total variation; some divergence was indicated between G+S and R+S from each other and from the G-S/R-S BLB color morphs. The pattern of genetic variation indicated potential divergence of G-S and G+S from each other and from R-S and R+S. Although these results indicate that the four different color morphs are not genetically or reproductively isolated, there is some genetic differentiation/structure and morphological dissimilarity suggesting weak/incomplete isolation.


Assuntos
Besouros/genética , Pigmentação/genética , Animais , Besouros/anatomia & histologia , Fluxo Gênico
11.
Am J Med Genet C Semin Med Genet ; 172C(1): 41-3, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26867035

RESUMO

Focal dermal hypoplasia (FDH), also known as Goltz syndrome, is a rare condition in which congenital anomalies result in a multitude of defects that affect many systems of the body. These defects can involve the eyes, skin, teeth, and cardiovascular, skeletal, and gastrointestinal systems. There have been many associated abnormalities reported in the literature. An appreciation of the clinical presentation of Goltz syndrome is important because physicians rely heavily on recognition of key physical characteristics in order to help make a diagnosis. In this report, we summarize the clinical findings observed when we were afforded the unique opportunity to interview and physically examine 19 patients, the largest group of individuals with Goltz syndrome brought together in one place to date. The findings are intended to characterize the orthopedic phenotypic manifestations of Goltz syndrome. This collection of data revealed that the most common orthopedic findings were syndactyly (68%), ectrodactyly (68%), leg length discrepancy (57%), and reduction defects of long bones (52%). Nail irregularities were present in 89% of the patients seen.


Assuntos
Hipoplasia Dérmica Focal/diagnóstico , Fenótipo , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Anormalidades Musculoesqueléticas/diagnóstico , Adulto Jovem
12.
J Hand Surg Am ; 40(10): 2032-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26253601

RESUMO

PURPOSE: To determine biomechanical differences between a fixed-angle locking volar titanium plate (VariAx; Stryker, Kalamazoo, MI) and a fixed-angle compression locking volar stainless steel plate (CoverLoc Volar Plate; Tornier, Amsterdam, Netherlands) in the fixation of simulated AO C3 distal radius fractures. METHODS: Eighteen cadaveric upper extremities (9 matched pairs) with an average age of 54 years were tested. A 4-part AO C3 fracture pattern was created in each specimen. The fractures were reduced under direct vision and fixed with either the fixed-angle locking volar titanium plate or the fixed-angle compression locking volar stainless steel plate. Motion tracking analysis was then performed while the specimens underwent cyclic loading. Changes in displacement, rotation, load to failure, and mode of failure were recorded. RESULTS: The fragments, when secured with the fixed-angle compression locking stainless steel construct, demonstrated less displacement and rotation than the fragments secured with the fixed-angle locking titanium plate under physiological loading conditions. In the fixed-angle compression locking stainless steel group, aggregate displacement and rotation of fracture fragments were 5 mm and 3° less, respectively, than those for the fixed-angle locking titanium group. The differences between axial loads at mechanical failure and stiffness were not statistically significant. The compression locking stainless steel group showed no trend in mode of failure, and the locking titanium plate group failed most often by articular fixation failure (5 of 9 specimens). CONCLUSIONS: The fixed-angle compression locking stainless steel volar plate may result in less displacement and rotation of fracture fragments in the fixation of AO C3 distal radius fractures than fixation by the fixed-angle locking volar titanium plate. However, there were no differences between the plates in mechanical load to failure and stiffness. CLINICAL RELEVANCE: Fixation of distal radius AO C3 fracture patterns with the fixed-angle compression locking stainless steel plate may provide improved stability of fracture fragments.


Assuntos
Placas Ósseas , Fixação Interna de Fraturas/instrumentação , Placa Palmar/cirurgia , Fraturas do Rádio/cirurgia , Traumatismos do Punho/cirurgia , Adulto , Idoso , Fenômenos Biomecânicos , Cadáver , Força Compressiva , Desenho de Equipamento , Feminino , Fixação Interna de Fraturas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Radiografia , Fraturas do Rádio/diagnóstico por imagem , Sensibilidade e Especificidade , Aço Inoxidável , Titânio , Traumatismos do Punho/diagnóstico por imagem
13.
J Insect Sci ; 14: 62, 2014 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-25373209

RESUMO

Bean leaf beetle, Cerotoma trifurcata (Forster) (Coleoptera: Chrysomelidae), is a common pest of soybean in the Midwest United States. However, there are currently no reports on the genetic variability of C. trifurcata. This study examined 15-30 individuals from 25 sample locations to estimate genetic variability and gene flow within and among C. trifurcata from across the Mid- west. Amplified fragment length polymorphism generated 175 markers for analyses. Results from analysis of molecular variance (AMOVA) indicated that the majority of genetic variation was from within samples; only a small amount of the total variation was attributed to the variation among the samples. The GST for the entire C. trifurcata population indicated that the majority of genetic variation was found within the samples, further supporting the AMOVA results. The estimated average gene flow among the C. trifurcata samples was 1.83. The Mantel test revealed no indication of correlation between geographical and genetic distance for all the C. trifurcata samples. These findings show that C. trifurcata in the Midwest are genetically heterogeneous and part of a large, interbreeding population.


Assuntos
Distribuição Animal , Besouros/genética , Besouros/fisiologia , Fluxo Gênico , Variação Genética , Animais , Meio-Oeste dos Estados Unidos
14.
Percept Mot Skills ; 119(3): 741-57, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25387037

RESUMO

This paper presents a methodology to control construction task complexity and examined the relationships between construction performance and spatial and mathematical abilities in children. The study included three groups of children (N = 96); ages 7-8, 10-11, and 13-14 years. Each group constructed seven pre-specified objects. The study replicated and extended previous findings that indicated that the extent of component symmetry and variety, and the number of components for each object and available for selection, significantly predicted construction task difficulty. Results showed that this methodology is a valid and reliable technique for assessing and predicting construction play task difficulty. Furthermore, construction play performance predicted mathematical attainment independently of spatial ability.


Assuntos
Cognição/fisiologia , Matemática/métodos , Percepção Espacial/fisiologia , Análise e Desempenho de Tarefas , Adolescente , Criança , Feminino , Humanos , Masculino , Reino Unido
15.
FEBS Lett ; 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-39043619

RESUMO

(Poly)phenols are a group of naturally occurring phytochemicals present in high amounts in plant food and beverages with various structures and activities. The impact of (poly)phenols on brain function has gained significant attention due to the growing interest in the potential benefits of these dietary bioactive molecules for cognitive health and neuroprotection. This review will therefore summarise the current knowledge related to the impact of (poly)phenols on brain health presenting evidence from both epidemiological and clinical studies. Cellular and molecular mechanisms in relation to the observed effects will also be described, including their impact on the gut microbiota through the modulation of the gut-brain axis. Although (poly)phenols have the potential to modulate the gut-brain axis regulation and influence cognitive function and decline through their interactions with gut microbiota, anti-inflammatory and antioxidant properties, further research, including randomised controlled trials and mechanistic studies, is needed to better understand the underlying mechanisms and establish causal relationships between (poly)phenol intake and brain health.

16.
Ecol Evol ; 14(8): e11691, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39114178

RESUMO

Understanding interactions within and between species is crucial to ecological research. However, for cetaceans such interactions can be difficult to observe in the field. Photographs offer an opportunity to study intra- and inter-specific interactions, by capturing 'snapshots' of their occurrence over space and time. At-surface and underwater photographs of bottlenose dolphins (Tursiops aduncus) inhabiting Ponta do Ouro Partial Marine Reserve (PPMR), Mozambique, were used to examine evidence of interactions with other dolphins, predators and ectoparasites. Intra-specific scarring levels significantly differed by sex and age class, with males displaying more scarring than females. Similarly, adults had more scarring than juveniles or calves. Shark bites significantly differed in their distribution across dolphin body areas, with the dorsal side being more frequently wounded than the ventral side. The presence of barnacles was exclusive to fluke, dorsal and pectoral fins, and showed strong seasonal trends. Overall, this study demonstrates the value of photographs for examining marine ecological interactions. It provides the first insights regarding dolphin social behaviour, predation risk and health for this population. These in turn will support future research into the population dynamics and conservation of the PPMR dolphins, which is urgently required in the face of locally increasing anthropogenic pressures.

17.
Clin Transl Sci ; 17(9): e70033, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39300734

RESUMO

Chronic pain represents a significant unmet medical need, affecting one-fifth of the U.S. population. EC5026 is a small molecule inhibitor of the enzyme soluble epoxide hydrolase (sEH) which is being developed as a novel non-opioid, non-NSAID analgesic. EC5026 prolongs the action of epoxy fatty acids, endogenous analgesic lipid mediators that are rapidly metabolized by sEH. We evaluated the safety and pharmacokinetic profile of EC5026 in two phase I trials, a single-ascending dose (SAD) study and a fed-fasted study. The SAD study evaluated EC5026 doses ranging from 0.5 to 24 mg in healthy volunteers. EC5026 was well tolerated. No treatment-emergent adverse events were considered related to EC5026. No apparent treatment- or dose-related trends in laboratory results, vital signs, physical examinations, or electrocardiograms were observed. A linear, near-dose-proportional increase in exposure was observed with progressive doses in the SAD study; plasma exposure was below or near the lower limit of quantification after 0.5-2 mg doses. Mean half-lives ranged from 41.8 to 59.1 h. for doses of 8-24 mg, supporting a once-daily dosing regimen. In the fed-fasted study using 8 mg EC5026 tablets, higher peak concentrations (66%) and total exposures (53%) were observed under the fed condition. Plasma concentrations declined in a monoexponential manner with mean half-lives of 59.5 h. in the fed state and 66.9 h. in the fasted state. Future clinical trials using EC5026 for the treatment of pain are justified based on the favorable outcomes from both clinical trials along with preclinical evidence of analgesic activity.


Assuntos
Interações Alimento-Droga , Voluntários Saudáveis , Humanos , Adulto , Masculino , Método Duplo-Cego , Feminino , Adulto Jovem , Pessoa de Meia-Idade , Relação Dose-Resposta a Droga , Epóxido Hidrolases/antagonistas & inibidores , Jejum/sangue , Adolescente , Administração Oral , Meia-Vida
18.
J Med Chem ; 67(4): 3090-3111, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38306388

RESUMO

The inhibition of ataxia-telangiectasia mutated (ATM) has been shown to chemo- and radio-sensitize human glioma cells in vitro and therefore might provide an exciting new paradigm in the treatment of glioblastoma multiforme (GBM). The effective treatment of GBM will likely require a compound with the potential to efficiently cross the blood-brain barrier (BBB). Starting from clinical candidate AZD0156, 4, we investigated the imidazoquinolin-2-one scaffold with the goal of improving likely CNS exposure in humans. Strategies aimed at reducing hydrogen bonding, basicity, and flexibility of the molecule were explored alongside modulating lipophilicity. These studies identified compound 24 (AZD1390) as an exceptionally potent and selective inhibitor of ATM with a good preclinical pharmacokinetic profile. 24 showed an absence of human transporter efflux in MDCKII-MDR1-BCRP studies (efflux ratio <2), significant BBB penetrance in nonhuman primate PET studies (Kp,uu 0.33) and was deemed suitable for development as a clinical candidate to explore the radiosensitizing effects of ATM in intracranial malignancies.


Assuntos
Ataxia Telangiectasia , Glioblastoma , Piridinas , Quinolonas , Animais , Humanos , Barreira Hematoencefálica/metabolismo , Ataxia Telangiectasia/tratamento farmacológico , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Glioblastoma/tratamento farmacológico
19.
ACS Med Chem Lett ; 15(7): 1151-1158, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-39015284

RESUMO

MUS81 is a structure-selective endonuclease that cleaves various branched DNA structures arising from natural physiological processes such as homologous recombination and mitosis. Due to this, MUS81 is able to relieve replication stress, and its function has been reported to be critical to the survival of many cancers, particularly those with dysfunctional DNA-repair machinery. There is therefore interest in MUS81 as a cancer drug target, yet there are currently few small molecule inhibitors of this enzyme reported, and no liganded crystal structures are available to guide hit optimization. Here we report the fragment-based discovery of novel small molecule MUS81 inhibitors with sub-µM biochemical activity. These inhibitors were used to develop a novel crystal system, providing the first structural insight into the inhibition of MUS81 with small molecules.

20.
BMC Anesthesiol ; 13: 6, 2013 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-23497277

RESUMO

BACKGROUND: Varied and fragmented care plans undertaken by different practitioners currently expose surgical patients to lapses in expected care, increase the chance for operational mistakes and accidents, and often result in unnecessary care. The Perioperative Surgical Home has thus been proposed by the American Society of Anesthesiologists and other stakeholders as an innovative, patient-centered, surgical continuity of care model that incorporates shared decision making. Topics central to the debate about an anesthesiology-based Perioperative Surgical Home include: holding the gains made in anesthesia-related patient safety; impacting surgical morbidity and mortality, including failure-to-rescue; achieving healthcare outcome metrics; assimilating comparative effectiveness research into the model; establishing necessary audit and data collection; a comparison with the hospitalist model of perioperative care; the perspective of the surgeon; the benefits of the Perioperative Surgical Home to the specialty of anesthesiology; and its associated healthcare economic advantages. DISCUSSION: Improving surgical morbidity and mortality mandates a more comprehensive and integrated approach to the management of surgical patients. In their expanded capacity as the surgical patient's "perioperativist," anesthesiologists can play a key role in compliance with broader set of process measures, thus becoming a more vital and valuable provider from the patient, administrator, and payer perspective. The robust perioperative databases created within the Perioperative Surgical Home present new opportunities for health services and population-level research. The Perioperative Surgical Home is not intended to replace the surgeon's patient care responsibility, but rather leverage the abilities of the entire perioperative care team in the service of the patient. To achieve this goal, it will be necessary to expand the core knowledge, skills, and experience of anesthesiologists. Anesthesiologists will need to view becoming perioperative physicians as an expansion of the specialty, rather than an abdication of their traditional intraoperative role. The Perioperative Surgical Home will need to create strategic added value for a health system and payers. This added value will strengthen the position of anesthesiologists as they navigate and negotiate in the face of finite, if not decreasing fiscal resources. SUMMARY: Broadening the anesthesiologist's scope of practice via the Perioperative Surgical Home may promote standardization and improve clinical outcomes and decrease resource utilization by providing greater patient-centered continuity of care throughout the preoperative, intraoperative, and postoperative periods.

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