Multicenter Analysis of Immune Biomarkers and Heart Transplant Outcomes: Results of the Clinical Trials in Organ Transplantation-05 Study.

Identification of biomarkers that assess posttransplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti-HLA- and auto-antibodies, angiogenic proteins, peripheral blood allo-reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti-HLA antibody (p < 0.04). Recipient CMV-negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor-C (OR 20; 95%CI:1.9-218) combined with decreases in endothelin-1 (OR 0.14; 95%CI:0.02-0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation.

Finite Nuclei in the Quark-Meson Coupling Model.

We report the first use of the effective quark-meson coupling (QMC) energy density functional (EDF), derived from a quark model of hadron structure, to study a broad range of ground state properties of even-even nuclei across the periodic table in the nonrelativistic Hartree-Fock+BCS framework. The novelty of the QMC model is that the nuclear medium effects are treated through modification of the internal structure of the nucleon. The density dependence is microscopically derived and the spin-orbit term arises naturally. The QMC EDF depends on a single set of four adjustable parameters having a clear physics basis. When applied to diverse ground state data the QMC EDF already produces, in its present simple form, overall agreement with experiment of a quality comparable to a representative Skyrme EDF. There exist, however, multiple Skyrme parameter sets, frequently tailored to describe selected nuclear phenomena. The QMC EDF set of fewer parameters, derived in this work, is not open to such variation, chosen set being applied, without adjustment, to both the properties of finite nuclei and nuclear matter.

Magnetic dipole moment of the doubly-closed-shell plus one proton nucleus 49Sc.

The nucleus 49Sc, having a single f(7/2) proton outside doubly magic 48Ca (Z=20, N=28), is one of the very few isotopes which makes possible testing of the fundamental theory of nuclear magnetism. The magnetic moment has been measured by online ß NMR of nuclei oriented at milli-Kelvin temperatures to be (+)5.616(25) µ(N). The result is discussed in terms of a detailed theory of the structure of the magnetic moment operator, showing excellent agreement with calculated departure from the f(7/2) Schmidt limit extreme single-particle value. The measurement completes the sequence of moments of Sc isotopes with even numbers of f(7/2) neutrons: the first such isotopic chain between two major shells for which a full set of moment measurements exists. The result further completes the isotonic sequence of ground-state moments of nuclei with an odd number of f(7/2) protons coupled to a closed subshell of f(7/2) neutrons. Comparison with a recent shell-model calculation of the latter sequence is made.

Solar irradiance and ENSO affect food security in Lake Tanganyika, a major African inland fishery.

Food security in a warming world is a grave concern for rapidly growing impoverished populations. Low-latitude inland fisheries provide protein for millions of rural poor, yet the impacts of high-frequency climate oscillations on these aquatic ecosystems are unknown. Here, we present a sub-annual-to-annual resolution paleolimnological reconstruction of upwelling, productivity, and algal composition at Lake Tanganyika, one of Africa's largest landlocked fisheries. The data reveal increases in diatom production at centennial-scale solar irradiance maxima, and interannual variability in upwelling linked to La Niña. Our study shows that interactions between global climatic controls and El Niño-Southern Oscillation teleconnections exert profound influences on the foundation of Lake Tanganyika's food web. Adapting long-term management practices to account for high-frequency changes in algal production will help safeguard inland fish resources.

Nuclear spins and magnetic moments of 71,73,75Cu: inversion of pi2p3/2 and pi1f5/2 levels in 75Cu.

We report the first confirmation of the predicted inversion between the pi2p3/2 and pi1f5/2 nuclear states in the nu(g)9/2 midshell. This was achieved at the ISOLDE facility, by using a combination of in-source laser spectroscopy and collinear laser spectroscopy on the ground states of 71,73,75Cu, which measured the nuclear spin and magnetic moments. The obtained values are mu(71Cu)=+2.2747(8)mu(N), mu(73Cu)=+1.7426(8)mu(N), and mu(75Cu)=+1.0062(13)mu(N) corresponding to spins I=3/2 for 71,73Cu and I=5/2 for 75Cu. The results are in fair agreement with large-scale shell-model calculations.

Training Community Health Ambassadors to Administer SOPARC.

Preparing lay Community Health Ambassadors (CHA) to assess, document and monitor physical activity using standardized instruments can be daunting. Administering some instruments needs specialized training. System for Observing Play and Recreation in Communities (SOPARC) is a standardized instrument requiring extensive training. The question guiding this project was: Can lay Community Health Ambassadors (CHA) be trained to administer SOPARC at Racial and Ethnic Approaches to Community Health (REACH) physical activity fitness sites? This manuscript presents the process undertaken to train Community Health Ambassadors (CHAs) and some preliminary results. Preliminary results are that fifty-six (56) Community Health Ambassadors (CHAs) representing four (4) community partner groups were certified in the SOPARC training. These CHAs successfully documented pre/post data for 20 different physical activity sites. Additionally, the results support the premise that Community Health Ambassadors are a viable liaison in community health delivery.

Cerebral [18 F]T807/AV1451 retention pattern in clinically probable CTE resembles pathognomonic distribution of CTE tauopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder most commonly associated with repetitive traumatic brain injury (TBI) and characterized by the presence of neurofibrillary tangles of tau protein, known as a tauopathy. Currently, the diagnosis of CTE can only be definitively established postmortem. However, a new positron emission tomography (PET) ligand, [18F]T807/AV1451, may provide the antemortem detection of tau aggregates, and thus various tauopathies, including CTE. Our goal was to examine [18F]T807/AV1451 retention in athletes with neuropsychiatric symptoms associated with a history of multiple concussions. Here we report a 39-year-old retired National Football League player who suffered 22 concussions and manifested progressive neuropsychiatric symptoms. Emotional lability and irritability were the chief complaints. Serial neuropsychological exams revealed a decline in executive functioning, processing speed and fine motor skills. Naming was below average but other cognitive functions were preserved. Structural analysis of longitudinally acquired magenetic resonance imaging scans revealed cortical thinning in the left frontal and lateral temporal areas, as well as volume loss in the basal ganglia. PET with [18F]florbetapir was negative for amyloidosis. The [18F]T807/AV1451 PET showed multifocal areas of retention at the cortical gray matter-white matter junction, a distribution considered pathognomonic for CTE. [18F]T807/AV1451 standard uptake value (SUV) analysis showed increased uptake (SUVr⩾1.1) in bilateral cingulate, occipital, and orbitofrontal cortices, and several temporal areas. Although definitive identification of the neuropathological underpinnings basis for [18F]T807/AV1451 retention requires postmortem correlation, our data suggest that [18F]T807/AV1451 tauopathy imaging may be a promising tool to detect and diagnose CTE-related tauopathy in living subjects.

Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves.

BACKGROUND: The mechanisms of extracellular matrix changes accompanying myxomatous valvular degeneration are uncertain. METHODS AND RESULTS: To test the hypothesis that valvular interstitial cells mediate extracellular matrix degradation in myxomatous degeneration by excessive secretion of catabolic enzymes, we examined the functional characteristics of valvular interstitial cells in 14 mitral valves removed for myxomatous degeneration from patients with mitral regurgitation and in 11 normal mitral valves obtained at autopsy. Immunohistochemical staining assessed (1) cell phenotype using antibodies to alpha-actin (microfilaments), vimentin and desmin (intermediate filaments), smooth muscle myosin (SM1), and SMemb (a nonmuscle myosin produced by activated mesenchymal cells) and (2) the expression of proteolytic activity using antibodies to collagenases (matrix metalloproteinase [MMP]-1, MMP-13), gelatinases (MMP-2, MMP-9), cysteine endoproteases (cathepsin S and K), and interleukin-1beta, a cytokine that can induce secretion of proteolytic enzymes. Although interstitial cells in normal valves stained positively for vimentin, but not alpha-actin or desmin, cells in myxomatous valves contained both vimentin and alpha-actin or desmin (characteristics of myofibroblasts). Moreover, cells in myxomatous valves strongly expressed SMemb, MMPs, cathepsins, and interleukin-1beta, which were weakly stained in controls. Nevertheless, interstitial cells in both groups strongly expressed procollagen-I mRNA (in situ hybridization), suggesting preserved ability to synthesize collagen in myxomatous valves. CONCLUSIONS: Interstitial cells in myxomatous valves have features of activated myofibroblasts and express excessive levels of catabolic enzymes, without altered levels of interstitial collagen mRNA. We conclude that valvular interstitial cells regulate matrix degradation and remodeling in myxomatous mitral valve degeneration.

Synergistic activation of soluble guanylate cyclase by YC-1 and carbon monoxide: implications for the role of cleavage of the iron-histidine bond during activation by nitric oxide.

BACKGROUND: Nitric oxide (.NO) is used in biology as both an intercellular signaling agent and a cytotoxic agent. In signaling, submicromolar quantities of .NO stimulate the soluble isoform of guanylate cyclase (sGC) in the receptor cell. .NO increases the Vmax of this heterodimeric hemoprotein up to 400-fold by interacting with the heme moiety of sGC to form a 5-coordinate complex. Carbon monoxide (CO) binds to the heme to form a 6-coordinate complex, but only activates the enzyme 5-fold, YC-1 is a recently discovered compound that relaxes vascular smooth muscle by stimulating sGC. RESULTS: In the presence of YC-1, CO activates sGC to the same specific activity as attained with .NO. YC-1 did not affect the NO-stimulated activity. The on-rate (kon) and off-rate (koff) of CO for binding to sGC in the presence of YC-1 were determined by stopped-flow spectrophotometry. Neither the kon nor the koff varied from values previously obtained in the absence of YC-1, indicating that YC-1 has no effect on the affinity of CO for the heme. In the presence of YC-1, the visible spectrum of the sGC-CO complex has a Soret peak at 423 nm, indicating the complex is 6-coordinate. CONCLUSIONS: YC-1 has no effect on the affinity of CO for the heme of sGC. In the presence of YC-1, maximal activation of sGC by CO is achieved by formation of a 6-coordinate complex between CO and the heme indicating that cleavage of the Fe-His bond is not required for maximal activation of sGC.

Traumatic brain injury imaging research roadmap.

The past decade has seen impressive advances in the types of neuroimaging information that can be acquired in patients with traumatic brain injury. However, despite this increase in information, understanding of the contribution of this information to prognostic accuracy and treatment pathways for patients is limited. Available techniques often allow us to infer the presence of microscopic changes indicative of alterations in physiology and function in brain tissue. However, because histologic confirmation is typically lacking, conclusions reached by using these techniques remain solely inferential in almost all cases. Hence, a need exists for validation of these techniques by using data from large population samples that are obtained in a uniform manner, analyzed according to well-accepted procedures, and correlated with closely monitored clinical outcomes. At present, many of these approaches remain confined to population-based research rather than diagnosis at an individual level, particularly with regard to traumatic brain injury that is mild or moderate in degree. A need and a priority exist for patient-centered tools that will allow advanced neuroimaging tools to be brought into clinical settings. One barrier to developing these tools is a lack of an age-, sex-, and comorbidities-stratified, sequence-specific, reference imaging data base that could provide a clear understanding of normal variations across populations. Such a data base would provide researchers and clinicians with the information necessary to develop computational tools for the patient-based interpretation of advanced neuroimaging studies in the clinical setting. The recent "Joint ASNR-ACR HII-ASFNR TBI Workshop: Bringing Advanced Neuroimaging for Traumatic Brain Injury into the Clinic" on May 23, 2014, in Montreal, Quebec, Canada, brought together neuroradiologists, neurologists, psychiatrists, neuropsychologists, neuroimaging scientists, members of the National Institute of Neurologic Disorders and Stroke, industry representatives, and other traumatic brain injury stakeholders to attempt to reach consensus on issues related to and develop consensus recommendations in terms of creating both a well-characterized normative data base of comprehensive imaging and ancillary data to serve as a reference for tools that will allow interpretation of advanced neuroimaging tests at an individual level of a patient with traumatic brain injury. The workshop involved discussions concerning the following: 1) designation of the policies and infrastructure needed for a normative data base, 2) principles for characterizing normal control subjects, and 3) standardizing research neuroimaging protocols for traumatic brain injury. The present article summarizes these recommendations and examines practical steps to achieve them.

Major glutamatergic projection from subplate into visual cortex during development.

Subplate neurons, the first neurons of the cerebral cortex to differentiate and mature, are thought to be essential for the formation of connections between thalamus and cortex, such as the system of ocular dominance columns within layer 4 of visual cortex. To learn more about the requirement for subplate neurons in the formation of thalamocortical connections, we have sought to identify the neurotransmitters and peptides expressed by the specific class of subplate neurons that sends axonal projections into the overlying visual cortex. To label retrogradely subplate neurons, fluorescent latex microspheres were injected into primary visual cortex of postnatal day 28 ferrets, just prior to the onset of ocular dominance column formation. Subsequently, neurons were immunostained with antibodies against glutamate, glutamic acid decarboxylase (GAD-67), parvalbumin, neuropeptide Y (NPY), somatostatin (SRIF), or nitric oxide synthase (NOS). Retrograde labeling results indicate that the majority of subplate neurons projecting into the cortical plate reside in the upper half of the subplate. Combined immunostaining and microsphere labeling reveal that about half of cortically projecting subplate neurons are glutamatergic; most microsphere-labeled subplate neurons do not stain for GAD-67, parvalbumin, NPY, SRIF, or NOS. These observations suggest that subplate neurons can provide a significant glutamatergic synaptic input to the cortical plate, including the neurons of layer 4. If so, excitation from the axons of subplate neurons may be required in addition to that from lateral geniculate nucleus neurons for the activity-dependent synaptic interactions that lead to the formation of ocular dominance columns during development.

Novel application of tyramide signal amplification (TSA): ultrastructural visualization of double-labeled immunofluorescent axonal profiles.

Fluorescent immunocytochemistry (FICC) allows multiple labeling approaches when enzyme-based techniques are difficult to combine, such as in double-labeling experiments targeting small-caliber axonal segments. Nevertheless, the conversion of FICC to a product visible at the electron microscopic (EM) level requires labor-intensive procedures, thus justifying the development of more user-friendly conversion methods. This study was initiated to simplify the conversion of FICC to EM by employing the unique properties of tyramide signal amplification (TSA), which allowed the simultaneous targeting of a fluorescent tag and biotin label to the same antigenic site. Briefly, one of two antigenic sites typically co-localized in damaged axonal segments was visualized by the application of a fluorescent secondary antibody, with the other tagged via a biotinylated antibody. Next, an ABC kit was used, followed by the simultaneous application of fluorophore-tyramide and biotin-tyramide. After temporary mounting for fluorescent digital photomicroscopy, sections were incubated in ABC and reacted with diaminobenzidine before EM analysis. Double-labeling fluorescent immunocytochemistry with TSA clearly delineated damaged axonal segments. In addition, these same axonal segments yielded high-quality EM images with discrete electron-dense reaction products, thereby providing a simple and reproducible means for following fluorescent analysis with EM.

The immunophilin ligand FK506 attenuates axonal injury in an impact-acceleration model of traumatic brain injury.

The immunophilin ligand, cyclosporin A (CsA), is effective in reducing the axonal damage associated with traumatic brain injury (TBI). Based upon extensive ultrastructural and immunohistochemical studies, the neuroprotection afforded by CsA appeared to be mediated via mitochondrial protection, specifically, the prevention of mitochondrial swelling and inhibition of mitochondrial permeability transition (MPT). However, the potential that CsA could also be neuroprotective via the immunophilin-mediated inhibition of the protein phosphatase, calcineurin (CN) has not been directly assessed. To address this issue, the current study assessed the ability of FK506, another immunophilin ligand that inhibits CN with no effect on MPT, to attenuate axonal damage in a rat impact-acceleration model of TBI. Traumatic axonal injury (TAI), detected via an antibody against beta-amyloid precursor protein (APP), a specific marker of axonal injury, was significantly reduced at 24 hr postinjury in Sprague-Dawley rats receiving intravenous FK506 (2 mg/kg; n = 5) 30 min prior to injury compared to vehicle controls (n = 3). While not rejecting the established efficacy of CsA in providing neuroprotection via its targeting of MPT, this study does underscore the potential importance of CN in the progressive pathobiology of TAI, suggesting that CN may constitute another important therapeutic target.

Antibodies to the C-terminus of the beta-amyloid precursor protein (APP): a site specific marker for the detection of traumatic axonal injury.

Antibodies to the amyloid precursor protein (APP) are commonly used to detect traumatic axonal injury (TAI). Carried by fast anterograde axoplasmic transport, APP will pool at regions of impaired transport associated with TAI. Based primarily upon commercial antibody availability, previous studies have targeted the N-terminus of APP, which, with respect to antigen detection, is suboptimally located within anterogradely transported vesicles. Recently, antibodies to the APP C-terminus, located on the external surface of anterogradely transported vesicles, have become available, allowing for the exploration of their utility in detecting TAI. To this end, rats were subjected to an impact acceleration injury, surviving 30 min to 24 h post-injury. They were then perfused, their brains sectioned and prepared for dual label immunofluorescent microscopy, single label bright field microscopy, and electron microscopy (EM). Antibodies to the APP C-terminus yielded the ready detection of intensely labeled TAI with significantly reduced diffuse background staining in comparison to antibodies to the APP N-terminus in both dual label immunofluorescent and single label bright-field approaches. EM examination of antibodies to the APP C-terminus in TAI revealed intense labeling of pooled intra-axonal vesicular profiles, confirming the anterogradely transported vesicular source of the APP seen in TAI. Interestingly, in addition to providing a technically superior approach and new detailed information on the subcellular localization of APP, antibodies to the APP C-terminus also proved more cost effective. Immunofluorescent studies of APP C-terminus immunoreactivity involved 1/3 the cost of targeting the N-terminus, while bright field APP C-terminus studies were performed for 1/20 the cost.

Probabilities for completely pectinate and symmetric cladograms.

Formulas for nonalgorithmically calculating probabilities for completely pectinate and symmetric cladograms are presented.

Information obtained in cladistic analysis.

The application of elementary equations from information theory to the elements involved in cladistic analysis is formalized mathematically. An equation is derived that quantifies the amount of information obtained by constructing a cladogram from a cladistic data matrix. Given particular conditions, the amount of information obtained increases monotonically with increases of the number of taxa involved and, so, may be used directly as a comparative measure of species richness for sister groups; in general, however, the amount of information obtained is related to the distribution of character states on the cladogram(s) deduced. An example is presented in which clades representing 11 phyla in the animal kingdom are compared in terms of information yielded. The amount of information obtained is consistent for different numbers of taxa and characters used in classifications. Speculative evolutionary explanations are presented for differences of information yielded among the phyla analyzed.

The spirit of D'arcy Thompson dwells in empirical morphospace.

Applications of the concept of a morphological space to the study of biological form during the past three decades are reviewed. Common features of the various types of morphological spaces constructed by morphometricians during this period are identified and used to construct a space of morphological spaces. This semiquantitative analysis reveals that the use of empirical morphospace by contemporary researchers is similar to Thompson's classic method of coordinate grid transformations, in the description of biological form.

Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica.

OBJECTIVE: The interleukin-6 pathway is up-regulated in giant cell arteritis (GCA), Takayasu arteritis (TA), and polymyalgia rheumatica (PMR). We retrospectively assessed the outcomes of 10 patients with relapsing/refractory GCA, TA, or PMR treated with tocilizumab (TCZ). METHODS: Patients with GCA (n = 7), TA (n = 2), and PMR (n = 1) received TCZ. Seven subjects had failed at least 1 second-line agent. The outcomes evaluated were symptoms of disease activity, inflammatory markers, ability to taper glucocorticoids, and cross-sectional imaging when indicated clinically. RESULTS: The mean followup time of this cohort since diagnosis was 27 months (range 16-60 months). The patients were treated with TCZ for a mean period of 7.8 months (range 4-12 months). Before TCZ therapy, the patients experienced an average of 2.4 flares/year. All patients entered and maintained clinical remission during TCZ therapy. The mean daily prednisone dosages before and after TCZ initiation were 20.8 mg/day (range 7-34.3 mg/day) and 4.1 mg/day (range 0-10.7 mg/day), respectively (P = 0.0001). The mean erythrocyte sedimentation rate declined from 41.5 mm/hour (range 11-68 mm/hour) to 7 mm/hour (range 2.2-11.3 mm/hour; P = 0.0001). The adverse effects of TCZ included mild neutropenia (n = 4) and transaminitis (n = 4). One patient flared 2 months after TCZ discontinuation. An autopsy on 1 patient who died from a postoperative myocardial infarction following elective surgery revealed persistent vasculitis of large and medium-sized arteries. CONCLUSION: TCZ therapy led to clinical and serologic improvement in patients with refractory/relapsing GCA, TA, or PMR. The demonstration of persistent large-vessel vasculitis at autopsy of 1 patient who had shown a substantial response requires close scrutiny in larger studies.