Diabetes is a common comorbidity in cystic fibrosis (CF) that worsens prognosis. The lack of an animal model for CF-related diabetes (CFRD) has made it difficult to dissect how the onset of ...pancreatic pathology influences the emergence of CFRD. We evaluated the structure and function of the neonatal CF endocrine pancreas using a new CFTR-knockout ferret model. Although CF kits are born with only mild exocrine pancreas disease, progressive exocrine and endocrine pancreatic loss during the first months of life was associated with pancreatic inflammation, spontaneous hyperglycemia, and glucose intolerance. Interestingly, prior to major exocrine pancreas disease, CF kits demonstrated significant abnormalities in blood glucose and insulin regulation, including diminished first-phase and accentuated peak insulin secretion in response to glucose, elevated peak glucose levels following glucose challenge, and variably elevated insulin and C-peptide levels in the nonfasted state. Although there was no difference in lobular insulin and glucagon expression between genotypes at birth, significant alterations in the frequencies of small and large islets were observed. Newborn cultured CF islets demonstrated dysregulated glucose-dependent insulin secretion in comparison to controls, suggesting intrinsic abnormalities in CF islets. These findings demonstrate that early abnormalities exist in the regulation of insulin secretion by the CF endocrine pancreas.
Objective This study sought to assess clinical outcomes in patients receiving gamma knife radiosurgery (GK) for treatment of brain metastases from melanoma and evaluate for potential predictive ...factors. Methods We reviewed 188 GK procedures in 129 consecutive patients that were treated for brain metastases from melanoma. The population consisted of 84 males and 45 females with a median age of 57 years. Fifty-five patients (43%) had a single metastasis. Seventy-one patients (55%) received chemotherapy, 58 patients (45%) received biologic agents, and 36 patients (28%) received prior whole brain radiation therapy (WBRT). The median marginal dose was 18.8 Gy (range 12 to 24 Gy). Results Actuarial survival was 52%, 26%, and 13% at 6, 12, and 24 months, respectively. The median survival time was 6.7 months. Local tumor control was 95%, 81% 53% at 6, 12, and 24 months, respectively. The median time to LBF was 25.2 months. Freedom from distant brain failure was 40%, 29%, and 10% at 6, 12, and 24 months, and the median time to DBF was 4.6 months. At the time of data analysis, 108 patients (84%) had died. Fifty-eight patients (52%) died from neurologic death. The median time to neurologic death from GK treatment was 7.9 months. Multivariate analysis revealed that hemorrhage of metastases prior to GK ( P = .02) and LBF ( P = .03) were the dominant predictors of neurologic death. Conclusions GK achieves excellent local control and may improve outcomes as a component of a multidisciplinary treatment strategy. Distant brain failure and neurologic demise remain problematic and prospective trials are necessary.
Abstract
Nanostructured one-dimensional multiwall-carbon nanotubes have a variety of advantageous properties including good electrical conductivity and mechanical strength, and thus have been widely ...investigated for use in lithium-ion battery electrodes as conductive and microstructural additives, though they also possess some electrochemical activity. Their application to sodium-ion batteries has been less extensively researched, and therefore a greater understanding of the electrochemical reaction with sodium, and effects of slurry composition and electrolyte formulation is warranted, especially as these are likely components in future Na-ion electrode formulations. Here, we report the fabrication of aqueous and organic multi-wall carbon nanotube (MWCNT) negative electrodes processed by ball milling. The binder of choice is noted to greatly affect the electrochemical performance, both in terms of capacity retention and rate capability over a range of current densities from 25 to 500 mA g
−1
. Switching from a carbonate- to diglyme-based electrolyte considerably improves initial coulombic efficiencies (∼10%–60%), attributed to less extensive formation of solid electrolyte interphase, and enables a reversible mechanism with capacities up to 150 mAh g
−1
over 100 cycles depending upon the binder used.
Ex-situ
characterization of the discharged and cycled carbon nanotubes by powder x-ray diffraction, transmission electron microscopy and Raman spectroscopy provide an insight into how MWCNTs undergo sodiation and demonstrate a partially reversible structural transformation during cycling when using the diglyme-based electrolyte. This work lays the foundation for a better understanding of these versatile materials, especially when used in the most promising alternative energy storage technology to lithium ion.
Deep brain stimulation (DBS) lead placement is increasingly performed with the patient under general anesthesia by surgeons using intraoperative MRI (iMRI) guidance without microelectrode recording ...(MER) or macrostimulation. The authors assessed the accuracy of lead placement, safety, and motor outcomes in patients with Parkinson disease (PD) undergoing DBS lead placement into the globus pallidus internus (GPi) using iMRI or MER guidance.
The authors identified all patients with PD who underwent either MER- or iMRI-guided GPi-DBS lead placement at Emory University between July 2007 and August 2016. Lead placement accuracy and adverse events were determined for all patients. Clinical outcomes were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) part III motor scores for patients completing 12 months of follow-up. The authors also assessed the levodopa-equivalent daily dose (LEDD) and stimulation parameters.
Seventy-seven patients were identified (MER, n = 28; iMRI, n = 49), in whom 131 leads were placed. The stereotactic accuracy of the surgical procedure with respect to the planned lead location was 1.94 ± 0.21 mm (mean ± SEM) (95% CI 1.54-2.34) with frame-based MER and 0.84 ± 0.007 mm (95% CI 0.69-0.98) with iMRI. The rate of serious complications was similar, at 6.9% for MER-guided DBS lead placement and 9.4% for iMRI-guided DBS lead placement (RR 0.71 95% CI 0.13%-3.9%; p = 0.695). Fifty-seven patients were included in clinical outcome analyses (MER, n = 16; iMRI, n = 41). Both groups had similar characteristics at baseline, although patients undergoing MER-guided DBS had a lower response on their baseline levodopa challenge (44.8% ± 5.4% 95% CI 33.2%-56.4% vs 61.6% ± 2.1% 95% CI 57.4%-65.8%; t = 3.558, p = 0.001). Greater improvement was seen following iMRI-guided lead placement (43.2% ± 3.5% 95% CI 36.2%-50.3%) versus MER-guided lead placement (25.5% ± 6.7% 95% CI 11.1%-39.8%; F = 5.835, p = 0.019). When UPDRS III motor scores were assessed only in the contralateral hemibody (per-lead analyses), the improvements remained significantly different (37.1% ± 7.2% 95% CI 22.2%-51.9% and 50.0% ± 3.5% 95% CI 43.1%-56.9% for MER- and iMRI-guided DBS lead placement, respectively). Both groups exhibited similar reductions in LEDDs (21.2% and 20.9%, respectively; F = 0.221, p = 0.640). The locations of all active contacts and the 2D radial distance from these to consensus coordinates for GPi-DBS lead placement (x, ±20; y, +2; and z, -4) did not differ statistically by type of surgery.
iMRI-guided GPi-DBS lead placement in PD patients was associated with significant improvement in clinical outcomes, comparable to those observed following MER-guided DBS lead placement. Furthermore, iMRI-guided DBS implantation produced a similar safety profile to that of the MER-guided procedure. As such, iMRI guidance is an alternative to MER guidance for patients undergoing GPi-DBS implantation for PD.
Chronic bacterial lung infections in cystic fibrosis (CF) are caused by defects in the CF transmembrane conductance regulator chloride channel. Previously, we described that newborn CF transmembrane ...conductance regulator-knockout ferrets rapidly develop lung infections within the first week of life. Here, we report a more slowly progressing lung bacterial colonization phenotype observed in juvenile to adult CF ferrets reared on a layered antibiotic regimen. Even on antibiotics, CF ferrets were still very susceptible to bacterial lung infection. The severity of lung histopathology ranged from mild to severe, and variably included mucus obstruction of the airways and submucosal glands, air trapping, atelectasis, bronchopneumonia, and interstitial pneumonia. In all CF lungs, significant numbers of bacteria were detected and impaired tracheal mucociliary clearance was observed. Although Streptococcus, Staphylococcus, and Enterococcus were observed most frequently in the lungs of CF animals, each animal displayed a predominant bacterial species that accounted for over 50% of the culturable bacteria, with no one bacterial taxon predominating in all animals. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry fingerprinting was used to quantify lung bacteria in 10 CF animals and demonstrated Streptococcus, Staphylococcus, Enterococcus, or Escherichia as the most abundant genera. Interestingly, there was significant overlap in the types of bacteria observed in the lung and intestine of a given CF animal, including bacterial taxa unique to the lung and gut of each CF animal analyzed. These findings demonstrate that CF ferrets develop lung disease during the juvenile and adult stages that is similar to patients with CF, and suggest that enteric bacterial flora may seed the lung of CF ferrets.
The auroral footprint of Enceladus on Saturn PRYOR, Wayne R; RYMER, Abigail M; COATES, Andrew J ...
Nature (London),
04/2011, Letnik:
472, Številka:
7343
Journal Article, Web Resource
Recenzirano
Although there are substantial differences between the magnetospheres of Jupiter and Saturn, it has been suggested that cryovolcanic activity at Enceladus could lead to electrodynamic coupling ...between Enceladus and Saturn like that which links Jupiter with Io, Europa and Ganymede. Powerful field-aligned electron beams associated with the Io-Jupiter coupling, for example, create an auroral footprint in Jupiter's ionosphere. Auroral ultraviolet emission associated with Enceladus-Saturn coupling is anticipated to be just a few tenths of a kilorayleigh (ref. 12), about an order of magnitude dimmer than Io's footprint and below the observable threshold, consistent with its non-detection. Here we report the detection of magnetic-field-aligned ion and electron beams (offset several moon radii downstream from Enceladus) with sufficient power to stimulate detectable aurora, and the subsequent discovery of Enceladus-associated aurora in a few per cent of the scans of the moon's footprint. The footprint varies in emission magnitude more than can plausibly be explained by changes in magnetospheric parameters--and as such is probably indicative of variable plume activity.
Rotavirus is the leading global cause of diarrheal mortality for unvaccinated children under 5 years of age. The outer capsid of rotavirus virions consists of VP7 and VP4 proteins, which determine ...viral G and P types, respectively, and are primary targets of neutralizing antibodies. Successful vaccination depends upon generating broadly protective immune responses following exposure to rotaviruses presenting a limited number of G- and P-type antigens. Vaccine introduction resulted in decreased rotavirus disease burden but also coincided with the emergence of uncommon G and P genotypes, including G12. To gain insight into the recent predominance of G12P8 rotaviruses in the United States, we evaluated 142 complete rotavirus genome sequences and metadata from 151 clinical specimens collected in Nashville, TN, from 2011 to 2013 through the New Vaccine Surveillance Network. Circulating G12P8 strains were found to share many segments with other locally circulating strains but to have distinct constellations. Phylogenetic analyses of G12 sequences and their geographic sources provided evidence for multiple separate introductions of G12 segments into Nashville, TN. Antigenic epitopes of VP7 proteins of G12P8 strains circulating in Nashville, TN, differ markedly from those of vaccine strains. Fully vaccinated children were found to be infected with G12P8 strains more frequently than with other rotavirus genotypes. Multiple introductions and significant antigenic mismatch may in part explain the recent predominance of G12P8 strains in the United States and emphasize the need for continued monitoring of rotavirus vaccine efficacy against emerging rotavirus genotypes.
Rotavirus is an important cause of childhood diarrheal disease worldwide. Two immunodominant proteins of rotavirus, VP7 and VP4, determine G and P genotypes, respectively. Recently, G12P8 rotaviruses have become increasingly predominant. By analyzing rotavirus genome sequences from stool specimens obtained in Nashville, TN, from 2011 to 2013 and globally circulating rotaviruses, we found evidence of multiple introductions of G12 genes into the area. Based on sequence polymorphisms, VP7 proteins of these viruses are predicted to present themselves to the immune system very differently than those of vaccine strains. Many of the sick children with G12P8 rotavirus in their diarrheal stools also were fully vaccinated. Our findings emphasize the need for continued monitoring of circulating rotaviruses and the effectiveness of the vaccines against strains with emerging G and P genotypes.
Transcriptional regulation by the glucocorticoid receptor (GR) is mediated by hormone binding, receptor dimerization, and coactivator recruitment. Here, we report the crystal structure of the human ...GR ligand binding domain (LBD) bound to dexamethasone and a coactivator motif derived from the transcriptional intermediary factor 2. Despite structural similarity to other steroid receptors, the GR LBD adopts a surprising dimer configuration involving formation of an intermolecular β sheet. Functional studies demonstrate that the novel dimer interface is important for GR-mediated activation. The structure also reveals an additional charge clamp that determines the binding selectivity of a coactivator and a distinct ligand binding pocket that explains its selectivity for endogenous steroid hormones. These results establish a framework for understanding the roles of protein-hormone and protein-protein interactions in GR signaling pathways.
The literature on abusive supervision largely presumes that employees respond to abuse in a relatively straightforward way: When abuse is present, outcomes are unfavorable, and when abuse is absent, ...outcomes are favorable (or, at least less unfavorable). Yet despite the recognition that abusive supervision can vary over time, little consideration has been given to how past experiences of abuse may impact the ways employees react to it (or, its absence) in the present. This is a notable oversight, as it is widely acknowledged that past experiences create a context against which experiences in the present are compared. By applying a temporal lens to the experience of abusive supervision, we identify abusive supervision inconsistency as a phenomenon that may have different outcomes than would otherwise be predicted by the current consensus in this literature. We draw from theories on time and stress appraisal to develop a model that explains when, why, and for which employees, inconsistent abusive supervision may have negative outcomes (specifically, identifying anxiety as a proximal outcome of abusive supervision inconsistency that has downstream effects on turnover intentions). Moreover, the aforementioned theoretical perspectives dovetail in identifying employee workplace status as a moderator that may buffer employees from the stressful consequences of inconsistent abusive supervision. We test our model using two experience sampling studies with polynomial regression and response surface analyses. Our research makes important theoretical and practical contributions to the abusive supervision literature, as well as the literature on time.
Increased hospitalization is a major component of dementia impact on individuals and cost, but has rarely been studied in dementia with Lewy bodies (DLB). Our aim was to describe the risk and ...duration of hospital admissions in patients with DLB, and compare these to those in Alzheimer's disease (AD) and the general population.
A large database of mental health and dementia care in South London was used to assemble a cohort of patients diagnosed with DLB. These were 1:4 matched with patients diagnosed with AD on age, gender, and cognitive status.
Rates of hospital admissions in the year after dementia diagnosis were significantly higher in 194 patients with DLB than in 776 patients with AD (crude incidence rate ratio 1.50; 95% confidence interval: 1.28–1.75) or the catchment population (indirectly standardized hospitalization rate 1.22; 95% confidence interval: 1.06–1.39). Patients with DLB had on average almost four additional hospital days per person-year than patients with AD. Multivariate Poisson regression models indicated poorer physical health early in the disease course as the main driver of this increased rate of hospitalization, whereby neuropsychiatric symptoms additionally explained the higher number of hospital days.
Patients with DLB are more frequently admitted to general hospitals and utilize inpatient care to a substantially higher degree than patients with AD or the general elderly population. These data highlight an opportunity to reduce hospital days by identifying DLB earlier and providing more targeted care focused on the specific triggers for hospitalization and associations of prolonged stay.
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