Infrared spectroscopy and anharmonic theory of H3 +Ar2,3 complexes: The role of symmetry in solvation.

The vibrational spectra of H3 +Ar2,3 and D3 +Ar2,3 are investigated in the 2000 cm-1 to 4500 cm-1 region through a combination of mass-selected infrared laser photodissociation spectroscopy and computational work including the effects of anharmonicity. In the reduced symmetry of the di-argon complex, vibrational activity is detected in the regions of both the symmetric and antisymmetric hydrogen stretching modes of H3 +. The tri-argon complex restores the D3h symmetry of the H3 + ion, with a concomitant reduction in the vibrational activity that is limited to the region of the antisymmetric stretch. Throughout these spectra, additional bands are detected beyond those predicted with harmonic vibrational theory. Anharmonic theory is able to reproduce some of the additional bands, with varying degrees of success.

National survey of occupational advice for lower limb arthroplasty patients.

BACKGROUND: Little is known what advice or support patients are given about return to work (RTW) after hip or knee replacement surgery. AIMS: This study aims to understand the delivery, timing and content of 'RTW' advice currently delivered by surgical teams offering hip and knee replacements across the UK. METHODS: National online survey exploring five specific areas relating to 'RTW' advice: (i) timings of interactions between hospital orthopaedic teams and patients prior to surgery, (ii) routine delivery of 'RTW' advice, (iii) methods used to deliver 'RTW' advice, (iv) confidence delivering advice and (v) need for an occupational 'RTW' advice intervention. RESULTS: A total of 152 participants including surgeons, physiotherapists, occupational therapists and nurses from 59 different public and private health providers responded. Only 20% (n = 30) of respondents reported that working patients were identified as a specific subgroup in need of additional support. Overall, 62% (n = 92) stated that they did not routinely offer 'RTW' advice. When given, 'RTW' advice was almost always verbal, generic advice using blanket timescales and based on the respondent's anecdotal experience rather than the patients individualized needs. Overall, 116 (78%) felt an occupational advice intervention was needed. CONCLUSIONS: This national survey demonstrated wide variation in the timing, content and delivery of information and advice for patients in work and intending to RTW after hip and knee replacement surgery. Current RTW advice provided to hip and knee replacement patients is inadequate.

Level of adherence to prescribed exercise in spondyloarthritis and factors affecting this adherence: a systematic review.

Adherence is a primary determinant of the effectiveness of any intervention. Exercise is considered essential in the management of spondyloarthritis (SpA); however, the overall adherence to exercise programmes and factors affecting adherence are unknown. The aim of this systematic review was to examine measures of, and factors influencing adherence to, prescribed exercise programmes in people with SpA. A search was performed in August 2018 using five data bases; the Cochrane library, CINAHL, EMBASE, MEDLINE, and Web of Science Collections. Inclusion criteria were: studies with adults (> 18 years) with SpA, with a prescribed exercise intervention or educational programme with the aim of increasing exercise participation. Article quality was independently assessed by two assessors. Extracted descriptive data included: populations, interventions, measures of adherence and factors affecting adherence. Percentage adherence rates to prescribed exercises were calculated if not reported. Nine studies were included with a total of 658 participants, 95% of participants had a diagnosis of ankylosing spondylitis. Interventions and measurement of adherence varied, making comparisons difficult. Rates of adherence ranged from 51.4 to 95%. Single studies identified; adherence improved following educational programmes, and higher disease severity and longer diagnostic delays were associated with higher adherence. Conflicting evidence was found as to whether supervision of exercise improved adherence. Three consecutive studies demonstrated adherence reduced over time. Adherence to prescribed exercise in SpA was poorly reported and predominately for people with AS. The levels of adherence and factors affecting prescribed exercise in SpA remain unclear. Future research should measure adherence across a longer time period and investigate possible factors which may influence adherence.

Trauma to the Superior Mesenteric Artery and Superior Mesenteric Vein: A Narrative Review of Rare but Lethal Injuries.

Mesenteric vessels, including the superior mesenteric artery (SMA) and vein (SMV), provide and drain the rich blood supply of the midgut and hindgut. SMA and SMV injuries are rare and often lethal. Clinical management of these injuries is not well established, but treatment options include operative, non-operative, and endovascular strategies. A narrative review of the literature was conducted using MEDLINE Complete-EBSCO. Relevant studies, specifically those focusing on diagnosis and management of SMA and SMV injuries, were selected. Only original reports and collected series were selected to prevent duplication of cases. A search of the literature for mesenteric arterial injuries yielded 87 studies. Vessel-specific breakdown of the studies yielded 40 with SMA injuries and 41 with SMV injuries. These searches were winnowed to 26 individual studies, which were included in this collective review. Limitations of this study are similar to all narrative literature reviews: the dependence on previously published research and availability of references as outlined in our methodology. Although historically rare, mesenteric vessel injuries are seen with increasing incidence and continue to present a challenge to trauma surgeons due to their daunting mortality rates. Currently, universal treatment guidelines do not exist, but the various options for their management have been extensively reviewed in the literature.

Communication: Trapping a proton in argon: Spectroscopy and theory of the proton-bound argon dimer and its solvation.

Ion-molecule complexes of the form H+Arn are produced in pulsed-discharge supersonic expansions containing hydrogen and argon. These ions are analyzed and mass-selected in a reflectron spectrometer and studied with infrared laser photodissociation spectroscopy. Infrared spectra for the n = 3-7 complexes are characterized by a series of strong bands in the 900-2200 cm-1 region. Computational studies at the MP2/aug-cc-pVTZ level examine the structures, binding energies, and infrared spectra for these systems. The core ion responsible for the infrared bands is the proton-bound argon dimer, Ar-H+-Ar, which is progressively solvated by the excess argon. Anharmonic vibrational theory is able to reproduce the vibrational structure, identifying it as arising from the asymmetric proton stretch in combination with multiple quanta of the symmetric argon stretch. Successive addition of argon shifts the proton vibration to lower frequencies, as the charge is delocalized over more ligands. The Ar-H+-Ar core ion has a first solvation sphere of five argons.

Ropivacaine plasma levels following high-dose local infiltration analgesia for total knee arthroplasty.

We measured total and free plasma concentrations of ropivacaine following high-volume, high-dose local infiltration analgesia in 28 patients aged 65 years or over undergoing unilateral total knee arthroplasty. Patients received infiltration of ropivacaine 400 mg followed by infusion at 20 mg.h(-1) through an intra-articular catheter. Total and free plasma levels of ropivacaine were measured at specified time intervals during a 24-h period after tourniquet release. Patients were monitored for symptoms and signs of local anaesthetic toxicity. Total levels of plasma ropivacaine varied from 0.147 to 3.093 µg.ml(-1) (mean (SD) 1.105 (0.518) µg.ml(-1) ). Free levels of plasma ropivaca-ine varied from 0.001 to 0.104 µg.ml(-1) (mean (SD) 0.037 (0.020) µg.ml(-1) ). Six samples had total plasma ropivacaine levels greater the toxic threshold of 2.2 µg.ml(-1) . No samples reached the toxic threshold for free venous ropivacaine concentration. We conclude that the use of high-dose ropivacaine infiltration and catheter infusion for total knee arthroplasty in an elderly population does not result in free plasma ropivacaine levels previously associated with toxicity but that raised total plasma levels may be observed.

Osteopathology in the Equine Distal Phalanx Associated With the Development and Progression of Laminitis.

Although the equine distal phalanx and hoof lamellae are biomechanically and physiologically integrated, bony changes in the distal phalanx are poorly described in laminitis. The aims of this study were (1) to establish a laminitis grading scheme that can be applied to the wide spectrum of lesions seen in naturally occurring cases and (2) to measure and describe changes in the distal phalanx associated with laminitis using micro-computed tomography (micro-CT) and histology. Thirty-six laminitic and normal feet from 15 performance and nonperformance horses were evaluated. A laminitis grading scheme based on radiographic, gross, histopathologic, and temporal parameters was developed. Laminitis severity grades generated by this scheme correlated well with clinical severity and coincided with decreased distal phalanx bone volume and density as measured by micro-CT. Laminitic hoof wall changes included progressive ventral rotation and distal displacement of the distal phalanx with increased thickness of the stratum internum-corium tissues with lamellar wedge formation. Histologically, there was epidermal lamellar necrosis with basement membrane separation and dysplastic regeneration, including acanthosis and hyperkeratosis, corresponding to the lamellar wedge. The changes detected by micro-CT corresponded to microscopic findings in the bone, including osteoclastic osteolysis of trabecular and osteonal bone with medullary inflammation and fibrosis. Bone changes were identified in horses with mild/early stages of laminitis as well as severe/chronic stages. The authors conclude that distal phalangeal pathology is a quantifiable and significant component of laminitis pathology and may have important implications for early detection or therapeutic intervention of equine laminitis.

Ropivacaine plasma levels following local infiltration analgesia for primary total hip arthroplasty.

We measured total and free plasma concentrations of ropivacaine following high-volume, high-dose local infiltration analgesia in 19 patients aged 65 years or over undergoing unilateral total hip arthroplasty. The patients received 180 ml ropivacaine 0.2% (360 mg), which was injected into the deep and peri-capsular tissues, the gluteal muscles and fascia lata, and the subcutaneous tissues and skin. Patients were monitored for clinical symptoms and signs of systemic local anaesthetic toxicity. Total levels of plasma ropivacaine varied from 0.081 to 1.707 µg.ml(-1) (mean (SD) 0.953 (0.323) µg.ml(-1) ). Free levels of plasma ropivacaine varied from 0.000 to 0.053 µg.ml(-1) (mean (SD) 0.024 (0.011) µg.ml(-1) ). No samples reached the toxic threshold for venous ropivacaine concentration, although four patients exhibited mild symptoms consistent with local anaesthetic toxicity. One patient had episodes of complete heart block on ECG monitoring, but plasma ropivacaine levels were below toxic levels. We conclude that plasma levels for ropivacaine associated with toxicity in a volunteer population (total 2.2 µg.ml(-1) , free 0.15 µg.ml(-1) ) are not reached during local infiltration analgesia for hip arthroplasty in elderly patients.

Associative white matter tracts selectively predict sensorimotor learning.

Human learning varies greatly among individuals and is related to the microstructure of major white matter tracts in several learning domains, yet the impact of the existing microstructure of white matter tracts on future learning outcomes remains unclear. We employed a machine-learning model selection framework to evaluate whether existing microstructure might predict individual differences in learning a sensorimotor task, and further, if the mapping between tract microstructure and learning was selective for learning outcomes. We used diffusion tractography to measure the mean fractional anisotropy (FA) of white matter tracts in 60 adult participants who then practiced drawing a set of 40 unfamiliar symbols repeatedly using a digital writing tablet. We measured drawing learning as the slope of draw duration over the practice session and measured visual recognition learning for the symbols using an old/new 2-AFC task. Results demonstrated that tract microstructure selectively predicted learning outcomes, with left hemisphere pArc and SLF3 tracts predicting drawing learning and the left hemisphere MDLFspl predicting visual recognition learning. These results were replicated using repeat, held-out data and supported with complementary analyses. Results suggest that individual differences in the microstructure of human white matter tracts may be selectively related to future learning outcomes.

The genomic consequences of adaptive divergence and reproductive isolation between species of manakins.

The processes of adaptation and speciation are expected to shape genomic variation within and between diverging species. Here we analyze genomic heterogeneity of genetic differentiation and introgression in a hybrid zone between two bird species (Manacus candei and M. vitellinus) using 59 100 SNPs, a whole genome assembly, and Bayesian models. Measures of genetic differentiation (FST) and introgression (genomic cline center [α] and rate [ß]) were highly heterogeneous among loci. We identified thousands of loci with elevated parameter estimates, some of which are likely to be associated with variation in fitness in Manacus populations. To analyze the genomic organization of differentiation and introgression, we mapped SNPs onto a draft assembly of the M. vitellinus genome. Estimates of FST, α, and ß were autocorrelated at very short physical distances (< 100 bp), but much less so beyond this. In addition, average statistical associations (linkage disequilibrium) between SNPs were generally low and were not higher in admixed populations than in populations of the parental species. Although they did not occur with a constant probability across the genome, loci with elevated FST, α, and ß were not strongly co-localized in the genome. Contrary to verbal models that predict clustering of loci involved in adaptation and isolation in discrete genomic regions, these results are consistent with the hypothesis that genetic regions involved in adaptive divergence and reproductive isolation are scattered throughout the genome. We also found that many loci were characterized by both exceptional genetic differentiation and introgression, consistent with the hypothesis that loci involved in isolation are also often characterized by a history of divergent selection. However, the concordance between isolation and differentiation was only partial, indicating a complex architecture and history of loci involved in isolation.

Associative white matter tracts selectively predict sensorimotor learning.

Human learning is a complex phenomenon that varies greatly among individuals and is related to the microstructure of major white matter tracts in several learning domains, yet the impact of the existing myelination of white matter tracts on future learning outcomes remains unclear. We employed a machine-learning model selection framework to evaluate whether existing microstructure might predict individual differences in the potential for learning a sensorimotor task, and further, if the mapping between the microstructure of major white matter tracts and learning was selective for learning outcomes. We used diffusion tractography to measure the mean fractional anisotropy (FA) of white matter tracts in 60 adult participants who then underwent training and subsequent testing to evaluate learning. During training, participants practiced drawing a set of 40 novel symbols repeatedly using a digital writing tablet. We measured drawing learning as the slope of draw duration over the practice session and visual recognition learning as the performance accuracy in an old/new 2-AFC recognition task. Results demonstrated that the microstructure of major white matter tracts selectively predicted learning outcomes, with left hemisphere pArc and SLF 3 tracts predicting drawing learning and the left hemisphere MDLFspl predicting visual recognition learning. These results were replicated in a repeat, held-out data set and supported with complementary analyses. Overall, results suggest that individual differences in the microstructure of human white matter tracts may be selectively related to future learning outcomes and open avenues of inquiry concerning the impact of existing tract myelination in the potential for learning. Significance statement: A selective mapping between tract microstructure and future learning has been demonstrated in the murine model and, to our knowledge, has not yet been demonstrated in humans. We employed a data-driven approach that identified only two tracts, the two most posterior segments of the arcuate fasciculus in the left hemisphere, to predict learning a sensorimotor task (drawing symbols) and this prediction model did not transfer to other learning outcomes (visual symbol recognition). Results suggest that individual differences in learning may be selectively related to the tissue properties of major white matter tracts in the human brain.

Historical stocking data and 19th century DNA reveal human-induced changes to native diversity and distribution of cutthroat trout.

Many species are threatened with extinction and efforts are underway worldwide to restore imperilled species to their native ranges. Restoration requires knowledge of species' historical diversity and distribution. For some species, many populations were extirpated or individuals moved beyond their native range before native diversity and distribution were documented, resulting in a lack of accurate information for establishing restoration goals. Moreover, traditional taxonomic assessments often failed to accurately capture phylogenetic diversity. We illustrate a general approach for estimating regional native diversity and distribution for cutthroat trout in the Southern Rocky Mountains. We assembled a large archive of historical records documenting human-mediated change in the distribution of cutthroat trout (Oncorhynchus clarkii) and combined these data with phylogenetic analysis of 19th century samples from museums collected prior to trout stocking activities and contemporary DNA samples. Our study of the trout in the Southern Rocky Mountains uncovered six divergent lineages, two of which went extinct, probably in the early 20th century. A third lineage, previously declared extinct, was discovered surviving in a single stream outside of its native range. Comparison of the historical and modern distributions with stocking records revealed that the current distribution of trout largely reflects intensive stocking early in the late 19th and early 20th century from two phylogenetically and geographically distinct sources. Our documentation of recent extinctions, undescribed lineages, errors in taxonomy and dramatic range changes induced by human movement of fish underscores the importance of the historical record when developing and implementing conservation plans for threatened and endangered species.

Phylogeography of the Cape velvet worm (Onychophora: Peripatopsis capensis) reveals the impact of Pliocene/Pleistocene climatic oscillations on Afromontane forest in the Western Cape, South Africa.

Habitat specialists such as soft-bodied invertebrates characterized by low dispersal capability and sensitivity to dehydration can be employed to examine biome histories. In this study, the Cape velvet worm (Peripatopsis capensis) was used to examine the impacts of climatic oscillations on historical Afromontane forest in the Western Cape, South Africa. Divergence time estimates suggest that the P. capensis species complex diverged during the Pliocene epoch. This period was characterized by dramatic climatic and topographical change. Subsequently, forest expansion and contraction cycles led to diversification within P. capensis. Increased levels of genetic differentiation were observed along a west-to-south-easterly trajectory because the south-eastern parts of the Cape Fold Mountain chain harbour larger, more stable fragments of forest patches, have more pronounced habitat heterogeneity and have historically received higher levels of rainfall. These results suggest the presence of three putative species within P. capensis, which are geographically discreet and genetically distinct.

Angiopoietin-1 protects the adult vasculature against plasma leakage.

Pathological increases in vascular leakage lead to edema and swelling, causing serious problems in brain tumors, in diabetic retinopathy, after strokes, during sepsis and also in inflammatory conditions such as rheumatoid arthritis and asthma. Although many agents and disease processes increase vascular leakage, no known agent specifically makes vessels resistant to leaking. Vascular endothelial growth factor (VEGF) and the angiopoietins function together during vascular development, with VEGF acting early during vessel formation, and angiopoietin-1 acting later during vessel remodeling, maturation and stabilization. Although VEGF was initially called vascular permeability factor, there has been less focus on its permeability actions and more effort devoted to its involvement in vessel growth and applications in ischemia and cancer. Recent transgenic approaches have confirmed the profound permeability effects of VEGF (refs. 12-14), and have shown that transgenic angiopoietin-1 acts reciprocally as an anti-permeability factor when provided chronically during vessel formation, although it also profoundly affects vascular morphology when thus delivered. To be useful clinically, angiopoietin-1 would have to inhibit leakage when acutely administered to adult vessels, and this action would have to be uncoupled from its profound angiogenic capabilities. Here we show that acute administration of angiopoietin-1 does indeed protect adult vasculature from leaking, countering the potentially lethal actions of VEGF and inflammatory agents.

Oral immune dysfunction is associated with the expansion of FOXP3+PD-1+Amphiregulin+ T cells during HIV infection.

Residual systemic inflammation and mucosal immune dysfunction persist in people living with HIV, despite treatment with combined anti-retroviral therapy, but the underlying immune mechanisms are poorly understood. Here we report that the altered immune landscape of the oral mucosa of HIV-positive patients on therapy involves increased TLR and inflammasome signaling, localized CD4+ T cell hyperactivation, and, counterintuitively, enrichment of FOXP3+ T cells. HIV infection of oral tonsil cultures in vitro causes an increase in FOXP3+ T cells expressing PD-1, IFN-γ, Amphiregulin and IL-10. These cells persist even in the presence of anti-retroviral drugs, and further expand when stimulated by TLR2 ligands and IL-1ß. Mechanistically, IL-1ß upregulates PD-1 expression via AKT signaling, and PD-1 stabilizes FOXP3 and Amphiregulin through a mechanism involving asparaginyl endopeptidase, resulting in FOXP3+ cells that are incapable of suppressing CD4+ T cells in vitro. The FOXP3+ T cells that are abundant in HIV-positive patients are phenotypically similar to the in vitro cultured, HIV-responsive FOXP3+ T cells, and their presence strongly correlates with CD4+ T cell hyper-activation. This suggests that FOXP3+ T cell dysregulation might play a role in the mucosal immune dysfunction of HIV patients on therapy.

Molecular modeling studies of peptide inhibitors highlight the importance of conformational prearrangement for inhibition of calpain.

The overexpression of the cysteine protease calpain is associated with many diseases, including brain trauma, spinal cord injury, Alzheimer's disease, Parkinson's disease, muscular dystrophy, arthritis, and cataract. Calpastatin is the naturally occurring specific regulator of calpain activity. It has previously been reported that a 20-mer peptide truncated from region B of calpastatin inhibitory domain 1 (named CP1B) retains both the affinity and selectivity of calpastatin toward calpain, exhibiting a K(i) of 26 nM against mu-calpain, and is 1000-fold more selective for mu-calpain than cathepsin L. Both the wild-type and beta-Ala mutant CP1B peptides exhibit a propensity to adopt a looplike conformation between Glu10 and Lys13. A computational study of human wild-type CP1B and the beta-Ala mutants of this peptide was conducted. The resulting structural predictions were compared with the crystal structure of the calpain-calpastatin complex and were correlated with experimental IC(50) values. These findings suggest that the conformational preference of the loop region between Glu10 and Lys13 of CP1B in the absence of calpain may contribute to the inhibitory activity of this series of peptides against calpain.

Evaluating anti-tumor activity of palbociclib plus radiation in anaplastic and radiation-induced meningiomas: pre-clinical investigations.

PURPOSE: Meningiomas are common brain tumors, the majority of which are considered benign. Despite surgery and/or radiation therapy, recurrence rates are approximately 8-10%. One likely cause is the dysregulation of cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway, which controls the cell cycle restriction point. This pathway is commonly dysregulated in anaplastic meningioma cell lines (AM) and radiation-induced meningioma cells (RIM), making it a rational target for anti-meningioma therapy. In this study, we investigate the effect of a CDK4/6 inhibitor, palbociclib, with radiation in relevant pre-clinical models. METHODS: In vitro cell culture, ex vivo slice culture and in vivo cell line-derived orthotopic xenograft animal models of AM/RIM were utilized to assess treatment efficacy with palbociclib plus radiation. Treatment effects were examined by immunoblot, cell viability, apoptosis, and cell cycle progression. RESULTS: The in vitro and ex vivo studies demonstrate that palbociclib plus radiation treatment reduced proliferation and has additional effects on cell cycling, including induction of an RB-associated G (1) arrest in Rb+ AM and RIM cells, but not in Rb- cells. Our results also demonstrated reduced CDK4 and CDK6 expression as well as reduced E2F target gene expression (CCNA2 and CCNE2) with the combination therapy. MRI results in vivo demonstrated reduced tumor size at 5 weeks when treated with 14 days palbociclib (10 mg/kg) plus 6 Gy radiation compared to saline-treated tumors. Finally, no hepatic toxicity was found after treatments. CONCLUSION: A pre-clinical murine model provides preclinical evidence for use of palbociclib plus radiation as a therapeutic agent for Rb+ meningiomas.

Localization of axonally transported 125I-wheat germ agglutinin beneath the plasma membrane of chick retinal ganglion cells.

The distribution of 125I-wheat germ agglutinin (WGA) transported by axons of chick retinal ganglion cells to layer d of the optic tectum was studied by electron microscopic autoradiography. We found that 52% of the radioactivity was located in axons and axon terminals in the contralateral optic tectum 22 h after intravitreal injection of affinity-purified 125I-WGA. Axons comprised 43% of the volume of layer d. Dendrites, glial cells, and neuron cell bodies contained 20%, 17%, and 3% of the label, whereas these structures comprised 24%, 21%, and 2% of the tissue volume, respectively. We also measured the distances between the autoradiographic silver grains and the plasma membranes of these profiles, and compared observed distributions of grains to theoretical distributions computed for band-shaped sources at various distances from the plasma membranes. This analysis revealed that the radioactive source within axons was distributed in a band of cytoplasm extending in from the plasma membrane a distance of 63 nm. Because WGA is known to bind to specific membrane glycoconjugates, we infer that at least some glycoconjugates may be concentrated within an annular region of cytoplasm just beneath the axonal plasma membrane after axoplasmic transport from the neuron cell body.

Bird orientation: a method of study.

A psychophysical technique has been applied to the study of bird orientation. The technique enables precise determinations of the accuracy with which a bird can orient itself. Data indicate that a pigeon can detect angular displacement as little as 3.4 degrees.

Superconductivity and the quantization of energy.

Ideas about quantized energy levels originated in atomic physics, but research in superconductivity has led to unparalleled precision in the measurement of energy levels. A comparison of levels produced by two Josephson junctions shows that they differ by no more than 3 parts in 10(19) at an energy of 0.0003 electron volt. The fact that the myriad of interactions of 10(12) particles in a macroscopic body, a Josephson junction, can produce sharply defined energy levels suggests a dynamical state effectively divorced from the complexities of its environment. The existence of this state, the macroscopic quantum state of superconductors, is well established, but its isolation from intrinsic perturbations has recently been shown to be extraordinary. These new results, with an improved precision of about ten orders of magnitude, are discussed in the context of highly accurate results from quantum electrodynamics, atomic spectroscopy, and the standards of metrology. Further refinements in precision may be achievable at higher energy levels, about 12 electron volts, as they become available from a new series array of 18,992 Josephson junctions.