HLA and cross-reactive antigen group matching for cadaver kidney allocation

Background. Allocation of cadaver kidneys by graded human leukocyte antigen (HLA) compatibility scoring arguably has had little effect on overall survival while prejudicing the transplant candidacy of African-American and other hard to match populations. Consequently, matching has been proposed of deduced amino acid residues of the individual HLA molecules shared by cross- reactive antigen groups (CREGs). We have examined the circumstances under which compatibility with either method impacted graft survival. Methods. Using Cox proportional hazards regression modeling, we studied the relationship between levels of conventional HLA mismatch and other donor and recipient factors on primary cadaver kidney survival between 1981 and 1995 at the University of Pittsburgh (n=1,780) and in the United Network for Organ Sharing (UNOS) Scientific Registry during 1991-1995 (n=31,291). The results were compared with those obtained by the matching of amino acid residues that identified CREG-compatible cases with as many as four (but not five and six) HLA mismatches. Results. With more than one HLA mismatch (>85% of patients in both series), most of the survival advantage of a zero mismatch was lost. None of the HLA loci were 'weak.' In the UNOS (but not Pittsburgh) category of one-HLA mismatch (n=1334), a subgroup of CREG-matched recipients (35.3%) had better graft survival than the remaining 64.7%, who were CREG-mismatched. There was no advantage of a CREG match in the two- to four-HLA incompatibility tiers. Better graft survival with tacrolimus was observed in both the Pittsburgh and UNOS series. Conclusions. Obligatory national sharing of cadaver kidneys is justifiable only for zero-HLA-mismatched kidneys. The potential value of CREG matching observed in the one-HLA-mismatched recipients of the UNOS (but not the Pittsburgh) experience deserves further study

Enzymatic Characterization of ER Stress-Dependent Kinase, PERK, and Development of a High-Throughput Assay for Identification of PERK Inhibitors

PERK is serine/threonine kinase localized to the endoplasmic reticulum (ER) membrane. PERK is activated and contributes to cell survival in response to a variety of physiological stresses that affect protein quality control in the ER, such as hypoxia, glucose depravation, increased lipid biosynthesis, and increased protein translation. Pro-survival functions of PERK are triggered by such stresses, suggesting that development of small-molecule inhibitors of PERK may be efficacious in a variety of disease scenarios. Hence, we have conducted a detailed enzymatic characterization of the PERK kinase to develop a high-throughput-screening assay (HTS) that will permit the identification of small-molecule PERK inhibitors. In addition to establishing the Km of PERK for both its primary substrate, eIF2?, and for adenosine triphosphate, further mechanistic studies revealed that PERK targets its substrate via either a random/steady-state ordered mechanism. For HTS, we developed a time-resolved fluorescence resonance energy transfer–based assay that yielded a robust Z? factor and percent coefficient of variation value, enabling the successful screening of 79,552 compounds. This approach yielded one compound that exhibited good in vitro and cellular activity. These results demonstrate the validity of this screen and represent starting points for drug discovery efforts

Lowering of amyloid beta peptide production with a small molecule inhibitor of amyloid-? precursor protein dimerization

The amyloid ? precursor protein (APP) is a single-pass transmembrane glycoprotein that is ubiquitously expressed in many cell types, including neurons. Amyloidogenic processing of APP by ?- and ?-secretases leads to the production of amyloid-? (A?) peptides that can oligomerize and aggregate into amyloid plaques, a characteristic hallmark of Alzheimer’s disease (AD) brains. Multiple reports suggest that dimerization of APP may play a role in A? production; however, it is not yet clear whether APP dimers increase or decrease A? and the mechanism is not fully understood. To better understand the relationship between APP dimerization and production of A?, a high throughput screen for small molecule modulators of APP dimerization was conducted using APP-Firefly luciferase enzyme complementation to detect APP dimerization. Selected modulators identified from a compound library of 77,440 compounds were tested for their effects on A? generation. Two molecules that inhibited APP dimerization produced a reduction in A? levels as measured by ELISA. The inhibitors did not change sAPP? or ?-CTF levels, but lowered sAPP? levels, suggesting that blocking the dimerization is preventing the cleavage by ?-secretase in the amyloidogenic processing of APP. To our knowledge, this is the first High Throughput Screen (HTS) effort to identify small molecule modulators of APP dimerization. Inhibition of APP dimerization has previously been suggested as a therapeutic target in AD. The findings reported here further support that modulation of APP dimerization may be a viable means of reducing the production of A?

Turbulence in the Solar Atmosphere: Manifestations and Diagnostics via Solar Image Processing

Intermittent magnetohydrodynamical turbulence is most likely at work in the magnetized solar atmosphere. As a result, an array of scaling and multi-scaling image-processing techniques can be used to measure the expected self-organization of solar magnetic fields. While these techniques advance our understanding of the physical system at work, it is unclear whether they can be used to predict solar eruptions, thus obtaining a practical significance for space weather. We address part of this problem by focusing on solar active regions and by investigating the usefulness of scaling and multi-scaling image-processing techniques in solar flare prediction. Since solar flares exhibit spatial and temporal intermittency, we suggest that they are the products of instabilities subject to a critical threshold in a turbulent magnetic configuration. The identification of this threshold in scaling and multi-scaling spectra would then contribute meaningfully to the prediction of solar flares. We find that the fractal dimension of solar magnetic fields and their multi-fractal spectrum of generalized correlation dimensions do not have significant predictive ability. The respective multi-fractal structure functions and their inertial-range scaling exponents, however, probably provide some statistical distinguishing features between flaring and non-flaring active regions. More importantly, the temporal evolution of the above scaling exponents in flaring active regions probably shows a distinct behavior starting a few hours prior to a flare and therefore this temporal behavior may be practically useful in flare prediction. The results of this study need to be validated by more comprehensive works over a large number of solar active regions.Comment: 26 pages, 7 figure

Purposeful selection of variables in logistic regression

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Evidence-Based Priority Setting for Health Care and Research: Tools to Support Policy in Maternal, Neonatal, and Child Health in Africa

As part of a series on maternal, neonatal, and child health in sub-Saharan Africa, Igor Rudan and colleagues discuss various priority-setting tools for health care and research that can help develop evidence-based policy

Measurement of Mutual Coulomb Dissociation in sNN=130\sqrt{s_{NN}}=130 GeV Au+Au collisions at RHIC

We report on the first measurement of Mutual Coulomb Dissociation in heavy ion collisions. We employ forward calorimeters to measure neutron multiplicity at beam rapidity in peripheral collisions. The cross-section for simultaneous electromagnetic breakup of Au nuclei at $\sqrt{s_{NN}}=130$ GeV is $\sigma_{MCD}=3.67\pm 0.25$ barns in good agreement with calculations.Comment: This paper has been submitted for publication in Phys. Rev. Let

Setting Research Priorities to Reduce Global Mortality from Childhood Pneumonia by 2015

Igor Rudan and colleagues report the results of their consensus building exercise that identified health research priorities to help reduce child mortality from pneumonia

Cyclophosphamide and human organ transplantation.

Cyclophosphamide, a drug that has not previously had an important role in whole-organ transplantation, was given as a primary immunosuppressant to one liver and eleven kidney recipients, in combination with prednisone and horse antilymphocyte globulin. One of the patients died despite good renal-graft function. Two kidneys from a common cadaveric donor failed. The other nine patients have excellent function of their homografts after 2-3 months. Cyclophosphamide was substituted for azathioprine in one hepatic and five renal recipients who were suspected of having liver toxicity from azathioprine 3 months to almost 8 years post-transplantation. Graft function was maintained after this change, and the evidence of liver injury subsided. © 1971

Carbogen breathing increases prostate cancer oxygenation: a translational MRI study in murine xenografts and humans

Hypoxia has been associated with poor local tumour control and relapse in many cancer sites, including carcinoma of the prostate. This translational study tests whether breathing carbogen gas improves the oxygenation of human prostate carcinoma xenografts in mice and in human patients with prostate cancer. A total of 23 DU145 tumour-bearing mice, 17 PC3 tumour-bearing mice and 17 human patients with prostate cancer were investigated. Intrinsic susceptibility-weighted MRI was performed before and during a period of carbogen gas breathing. Quantitative R2* pixel maps were produced for each tumour and at each time point and changes in R2* induced by carbogen were determined. There was a mean reduction in R2* of 6.4% (P=0.003) for DU145 xenografts and 5.8% (P=0.007) for PC3 xenografts. In all, 14 human subjects were evaluable; 64% had reductions in tumour R2* during carbogen inhalation with a mean reduction of 21.6% (P=0.0005). Decreases in prostate tumour R2* in both animal models and human patients as a result of carbogen inhalation suggests the presence of significant hypoxia. The finding that carbogen gas breathing improves prostate tumour oxygenation provides a rationale for testing the radiosensitising effects of combining carbogen gas breathing with radiotherapy in prostate cancer patients