A decade (1982 to 1992) of pediatric cardiac transplantation and the impact of FK 506 immunosuppression

The decade from 1982 through 1992 witnessed tremendous growth in pediatric cardiac transplantation. At Children's Hospital of Pittsburgh 66 cardiac transplants were performed during this period (age range 7 hours to 18 years). The cause of cardiomyopathy was congenital (n = 30), cardiomyopathy (n = 29), myocarditis (n = 2), doxorubicin toxicity (n = 2), ischemic (n = 1), valvular (n = 1), and cardiac angiosarcoma (n = 1). Nine children (14 %) required mechanical circulatory support before transplantation: extracorporeal membrane oxygenation (n = 8) and Novacor left ventricular assist system (n = 1) (Baxter Healthcare Corp., Novacor Div., Oakland, Calif.). The mean follow-up time was 2 years (range 4 months to 8 years). The overall survival in the group was 67 %. In children with congenital heart disease (>6 months of age) the perioperative (30 day) mortality was 66 % before mid-1988 (n = 10) and 0 % since mid-1988 (n = 11). The late mortality (>30 days) in children with cardiomyopathy transplanted prior to mid-1988 was 66 % (n = 14) and 7 % since mid-1988 (n = 15). Since mid-1988 1- and 3-year survival was 82 % in children with congenital heart disease and 90 % in children with cardiomyopathy. Twenty-six children have had FK 506 as their primary immunosuppressive therapy since November 1989. Survival in this group was 82 % at 1 and 3 years. The actuarial freedom from grade 3A rejection in the FK group was 60 % at 3 and 6 months after transplantation versus 20 % and 12 %, respectively, in the 15 children operated on before the advent of FK 506, who were treated with cyclosporine-based triple-drug therapy (p < 0.001, Mantel-Cox and Breslow). Twenty of 24 children (83 %) in the FK 506 group are receiving no steroids. The prevalence of posttransplantation hypertension was 4 % in the FK 506 group versus 70 % in the cyclosporine group (p < 0.001, Fisher). Renal toxicity in children treated with FK 506 has been mild. Additionally, eight children have been switched to FK 506 because of refractory rejection and drug toxicity. FK 506 has not produced hirsutism, gingival hyperplasia, or abnormal facial bone growth. The absence of these debilitating side effects, together with the observed immune advantage and steroid-sparing effects of FK 506, hold tremendous promise for the young patient facing cardiac transplantation and a future wedded to immunosuppression

Assessment of vitamin D status - a changing landscape.

peer reviewedIn recent years it has been shown that vitamin D deficiency is associated with an increased incidence as well as the progression of a broad range of diseases including osteoporosis, rickets, cardiovascular disease, autoimmune disease, multiple sclerosis and cancer. Consequently, requests for the assessment of vitamin D status have increased dramatically. Despite significant progress in the analysis of vitamin D metabolites and an expansion of our pathophysiological knowledge of vitamin D, the assessment of vitamin D status remains a challenging and partially unresolved issue. Current guidelines from scientific bodies recommend the measurement of 25-hydroxy vitamin D (25-OHD) in blood as the preferred test. However, growing evidence indicates significant limitations of this test, including analytical aspects and interpretation of results. In addition, the relationships between 25-OHD and various clinical indices, such as bone mineral density and fracture risk, are rather weak and not consistent across races. Recent studies have systematically investigated new markers of vitamin D status including the vitamin D metabolite ratio (VMR) (ratio between 25-OHD and 24,25-dihydroxy vitamin D), bioavailable 25-OHD [25-OHD not bound to vitamin D binding protein (DBP)], and free 25-OHD [circulating 25-OHD bound to neither DBP nor albumin (ALB)]. These parameters may potentially change how we will assess vitamin D status in the future. Although these new biomarkers have expanded our knowledge about vitamin D metabolism, a range of unresolved issues regarding their measurement and the interpretation of results prevent their use in daily practice. It can be expected that some of these issues will be overcome in the near future so that they may be considered for routine use (at least in specialized centers). In addition, genetic studies have revealed several polymorphisms in key proteins of vitamin D metabolism that affect the circulating concentrations of vitamin D metabolites. The affected proteins include DBP, 7-dehydrocholesterol synthase and the vitamin D receptor (VDR). Here we aim to review existing knowledge regarding the biochemistry, physiology and measurement of vitamin D. We will also provide an overview of current and emerging biomarkers for the assessment of vitamin D status, with particular attention methodological aspects and their usefulness in clinical practice

Narrative-based computational modelling of the Gp130/JAK/STAT signalling pathway.

BACKGROUND: Appropriately formulated quantitative computational models can support researchers in understanding the dynamic behaviour of biological pathways and support hypothesis formulation and selection by "in silico" experimentation. An obstacle to widespread adoption of this approach is the requirement to formulate a biological pathway as machine executable computer code. We have recently proposed a novel, biologically intuitive, narrative-style modelling language for biologists to formulate the pathway which is then automatically translated into an executable format and is, thus, usable for analysis via existing simulation techniques. RESULTS: Here we use a high-level narrative language in designing a computational model of the gp130/JAK/STAT signalling pathway and show that the model reproduces the dynamic behaviour of the pathway derived by biological observation. We then "experiment" on the model by simulation and sensitivity analysis to define those parameters which dominate the dynamic behaviour of the pathway. The model predicts that nuclear compartmentalisation and phosphorylation status of STAT are key determinants of the pathway and that alternative mechanisms of signal attenuation exert their influence on different timescales. CONCLUSION: The described narrative model of the gp130/JAK/STAT pathway represents an interesting case study showing how, by using this approach, researchers can model biological systems without explicitly dealing with formal notations and mathematical expressions (typically used for biochemical modelling), nevertheless being able to obtain simulation and analysis results. We present the model and the sensitivity analysis results we have obtained, that allow us to identify the parameters which are most sensitive to perturbations. The results, which are shown to be in agreement with existing mathematical models of the gp130/JAK/STAT pathway, serve us as a form of validation of the model and of the approach itself

The Samurai Project: verifying the consistency of black-hole-binary waveforms for gravitational-wave detection

We quantify the consistency of numerical-relativity black-hole-binary waveforms for use in gravitational-wave (GW) searches with current and planned ground-based detectors. We compare previously published results for the $(\ell=2,| m | =2)$ mode of the gravitational waves from an equal-mass nonspinning binary, calculated by five numerical codes. We focus on the 1000M (about six orbits, or 12 GW cycles) before the peak of the GW amplitude and the subsequent ringdown. We find that the phase and amplitude agree within each code's uncertainty estimates. The mismatch between the $(\ell=2,| m| =2)$ modes is better than $10^{-3}$ for binary masses above $60 M_{\odot}$ with respect to the Enhanced LIGO detector noise curve, and for masses above $180 M_{\odot}$ with respect to Advanced LIGO, Virgo and Advanced Virgo. Between the waveforms with the best agreement, the mismatch is below $2 \times 10^{-4}$. We find that the waveforms would be indistinguishable in all ground-based detectors (and for the masses we consider) if detected with a signal-to-noise ratio of less than $\approx14$, or less than $\approx25$ in the best cases.Comment: 17 pages, 9 figures. Version accepted by PR

Older Adult Compendium of Physical Activities: Energy Costs of Human Activities in Adults Aged 60 and Older

Purpose: To describe the development of a Compendium for estimating the energy costs of activities in adults ≥60 years (OA Compendium). Methods: Physical activities (PAs) and their metabolic equivalent of task (MET) values were obtained from a systematic search of studies published in 4 sport and exercise databases (PubMed, Embase, SPORTDiscus (EBSCOhost), and Scopus) and a review of articles included in the 2011 Adult Compendium that measured PA in older adults. MET values were computed as the oxygen cost (VO2, mL/kg/min) during PA divided by 2.7 mL/kg/min (MET60+) to account for the lower resting metabolic rate in older adults. Results: We identified 68 articles and extracted energy expenditure data on 427 PAs. From these, we derived 99 unique Specific Activity codes with corresponding MET60+ values for older adults. We developed a website to present the OA Compendium MET60+ values: https://pacompendium.com. Conclusion: The OA Compendium uses data collected from adults ≥60 years for more accurate estimation of the energy cost of PAs in older adults. It is an accessible resource that will allow researchers, educators, and practitioners to find MET60+ values for older adults for use in PA research and practice

Interactions between Plasmodium falciparum skeleton-binding protein 1 and the membrane skeleton of malaria-infected red blood cells

During development inside red blood cells (RBCs), Plasmodium falciparum malaria parasites export proteins that associate with the RBC membrane skeleton. These interactions cause profound changes to the biophysical properties of RBCs that underpin the often severe and fatal clinical manifestations of falciparum malaria. P. falciparum erythrocyte membrane protein 1 (PfEMP1) is one such exported parasite protein that plays a major role in malaria pathogenesis since its exposure on the parasitised RBC surface mediates their adhesion to vascular endothelium and placental syncytioblasts. En route to the RBC membrane skeleton, PfEMP1 transiently associates with Maurer\u27s clefts (MCs), parasite-derived membranous structures in the RBC cytoplasm. We have previously shown that a resident MC protein, skeleton-binding protein 1 (SBP1), is essential for the placement of PfEMP1 onto the RBC surface and hypothesised that the function of SBP1 may be to target MCs to the RBC membrane. Since this would require additional protein interactions, we set out to identify binding partners for SBP1. Using a combination of approaches, we have defined the region of SBP1 that binds specifically to defined sub-domains of two major components of the RBC membrane skeleton, protein 4.1R and spectrin. We show that these interactions serve as one mechanism to anchor MCs to the RBC membrane skeleton, however, while they appear to be necessary, they are not sufficient for the translocation of PfEMP1 onto the RBC surface. The N-terminal domain of SBP1 that resides within the lumen of MCs clearly plays an essential, but presently unknown role in this process

Immunoglobulin M Antibody Test To Detect Genogroup II Norwalk-Like Virus Infection

Sera obtained from adult volunteers inoculated with genogroup II Norwalk-like viruses (NLVs), Hawaii virus, and Snow Mountain virus and from patients involved in outbreaks of gastroenteritis were tested for genogroup II NLV Mexico virus-specific immunoglobulin M (IgM) by use of a monoclonal antibody, recombinant Mexico virus antigen (rMXV)-based IgM capture enzyme-linked immunosorbent assay (ELISA). Sera from genogroup I Norwalk virus (NV)-inoculated volunteers and from patients involved in a genogroup I NLV outbreak were also tested. In sera from those infected with genogroup I NV or NLVs in volunteer and outbreak studies, only 3 of 25 were rMXV IgM positive; in contrast, 24 of 25 were IgM positive for recombinant NV (rNV). In sera from those infected with genogroup II NLVs in volunteer and outbreak studies, 28 of 47 were rMXV IgM positive and none were IgM positive for rNV, showing the specificity of each IgM test for its respective genogroup. In an outbreak of gastroenteritis not characterized as being of viral etiology but suspected to be due to NV, 7 of 13 persons had IgM responses to rMXV, whereas none had IgM responses to rNV, thus establishing the diagnosis as genogroup II NLV infection. The rMXV-based IgM capture ELISA developed is specific for the diagnosis of genogroup II NLV infections

Herschel observations of interstellar chloronium

Using the Herschel Space Observatory's Heterodyne Instrument for the Far-Infrared (HIFI), we have observed para-chloronium (H2Cl+) toward six sources in the Galaxy. We detected interstellar chloronium absorption in foreground molecular clouds along the sight-lines to the bright submillimeter continuum sources Sgr A (+50 km/s cloud) and W31C. Both the para-H2-35Cl+ and para-H2-37Cl+ isotopologues were detected, through observations of their 1(11)-0(00) transitions at rest frequencies of 485.42 and 484.23 GHz, respectively. For an assumed ortho-to-para ratio of 3, the observed optical depths imply that chloronium accounts for ~ 4 - 12% of chlorine nuclei in the gas phase. We detected interstellar chloronium emission from two sources in the Orion Molecular Cloud 1: the Orion Bar photodissociation region and the Orion South condensation. For an assumed ortho-to-para ratio of 3 for chloronium, the observed emission line fluxes imply total beam-averaged column densities of ~ 2.0E+13 cm-2 and ~ 1.2E+13 cm-2, respectively, for chloronium in these two sources. We obtained upper limits on the para-H2-35Cl+ line strengths toward H2 Peak 1 in the Orion Molecular cloud and toward the massive young star AFGL 2591. The chloronium abundances inferred in this study are typically at least a factor ~10 larger than the predictions of steady-state theoretical models for the chemistry of interstellar molecules containing chlorine. Several explanations for this discrepancy were investigated, but none has proven satisfactory, and thus the large observed abundances of chloronium remain puzzling.Comment: Accepted for publication in the Astrophysical Journa