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Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascularization. Mechanistically, TAp73 interacts with the regulatory subunit (α) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1α polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen-independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer. published

Platelets play an important role in cardiovascular thrombosis as well as in many other pathological conditions such as inflammation, atherosclerosis and cancer. While multi-target strategies to treat complex diseases are gaining considerable attention, current development of antiplatelet therapies is mostly oriented towards several single targets, arising from our present understanding of the regulation of platelet activation. Limited efforts to develop multi-target agents or multidrug therapies are mostly due to a lack of a systematic basis to define target combinations with synergistic effects. Here we discuss the perspective to use high content phenotypic screening of in vitro models as a potential source for inference of synergetic multi-target strategies to control platelet activation.

Background. Preemptive transplantation results in excellent patient and graft survival yet most transplant candidates are referred for transplantation after initiation of dialysis. The goal of this study was to determine barriers to preemptive renal transplantation. Methods. A nonvalidated questionnaire was administered to prospective kidney transplant recipients to determine factors that hindered or favored referral for transplantation before the initiation of dialysis. Results. One hundred ninety-seven subjects referred for a primary renal transplant completed the questionnaire. Ninety-one subjects (46%) had been informed of preemptive transplantation before referral, and 80 (41%) were predialysis at the time of evaluation. The median time from diagnosis of renal disease to referral was 60 months (range, 2Y444 months). In bivariate analysis, among other factors, knowledge of preemptive transplantation was highly associated (odds ratio=94.69) with referral before initiation of dialysis. Given the strong association between knowledge of preemptive transplantation and predialysis referral, this variable was not included in the multivariate analysis. Using multivariate logistic regression analysis, white recipient race, referral by a transplant nephrologist, recipient employment, and the diagnosis of polycystic kidney disease were significantly associated with presentation to the pretransplant clinic before initiation of dialysis. Conclusion. The principle barrier to renal transplantation referral before dialysis was patient education regarding the option of preemptive transplantation. Factors significantly associated with referral before dialysis were the diagnosis of polycystic kidney disease, white recipient race, referral by a transplant nephrologist, and employed status. Greater effort should be applied to patient education regarding preemptive transplantation early after the diagnosis of end-stage renal disease.

Classical scholar, art collector and connoisseur Richard Payne Knight (1751–1824) took a keen interest in aesthetics and was a key figure in the debate on the picturesque. Of independent means, he journeyed across Europe, often in the company of artists. His home, Downton Castle in Herefordshire, set the fashion for crenellations. He sat in Parliament from 1780 to 1806, but beauty interested him more than politics. Following important works on aesthetics by such writers as Edmund Burke and Uvedale Price, Knight published his most successful work in 1805, cementing his reputation as an authority on matters of taste. Here he moves away from the ideas of Price and Burke, instead exploring the role of associations in the expression of aesthetic judgement. Knight's Analytical Essay on the Greek Alphabet (1791) and Inquiry into the Symbolical Language of Ancient Art and Mythology (1818) are also reissued in this series.

Originally published in 1791, this work by classical scholar and connoisseur Richard Payne Knight (1751–1824) attempts to reconstruct the original pronunciation of ancient Greek. Emphasising the importance of knowing what the various ancient dialects sounded like in order to better appreciate surviving works of ancient literature, Knight engages in textual criticism of certain notable writings, including the poetry of Homer and Hesiod and the plays of Sophocles. Representing a learned contribution to classical philology, the essay also goes some way towards analysing the ways in which Greek sounds were distorted by their inclusion in other languages. Several plates at the end of the text reproduce a selection of ancient inscriptions on stone, coins and ceramics. Knight's Analytical Inquiry into the Principles of Taste (1805) and Inquiry into the Symbolical Language of Ancient Art and Mythology (1818) are also reissued in this series.

Background In renal transplantation, BK virus infection can result in significant graft nephropathy and loss. While reduction in immunosuppression (IS) is considered standard therapy, adjunct agents may be warranted. Data are suggestive of a possible role of cidofovir for the management of BK. This study aims to describe the course of BK viremia (BKV) in a large cohort of renal transplant patients receiving adjunct cidofovir. Methods We evaluated kidney and kidney-pancreas recipients who received cidofovir combined with reduced IS for management of high-level BKV or BK virus nephropathy (BKVN). We examined the rate and timing of BKV clearance, and performed a multivariate analysis to identify risk factors associated with long-term (>6 months) viremia. Results In total, 75 patients received a median of 13 doses of cidofovir in conjunction with reduced IS; 32 patients (43%) had short-term BKV (≤6 months), and 43 (57%) had long-term BKV. Overall, 53 of 75 patients (71%) eventually cleared BKV at a median of 4.2 months (interquartile range 2.1–9.3 months). Independent factors associated with long-term BKV included older age (odds ratio [OR] 1.1, P = 0.02), delayed graft function (OR 31.4, P = 0.01), and higher peak BKV (OR 12.8, P = 0.02), while BKV reduction by at least 1 log10copies/mL at 1 month of treatment was associated with clearance within 6 months (OR 49.3, P

Multiple clinical studies have correlated gene expression with survival outcome in cancer on a genome-wide scale. However, in many cases, no obvious correlation between expression of well-known tumour-related genes (that is, p53, p73 and p21) and survival rates of patients has been observed. This can be mainly explained by the complex molecular mechanisms involved in cancer, which mask the clinical relevance of a gene with multiple functions if only gene expression status is considered. As we demonstrate here, in many such cases, the expression of the gene interaction partners (gene 'interactome') correlates significantly with cancer survival and is indicative of the role of that gene in cancer. On the basis of this principle, we have implemented a free online datamining tool (http://www.bioprofiling.de/PPISURV). PPISURV automatically correlates expression of an input gene interactome with survival rates on >40 publicly available clinical expression data sets covering various tumours involving about 8000 patients in total. To derive the query gene interactome, PPISURV employs several public databases including protein-protein interactions, regulatory and signalling pathways and protein post-translational modifications.

Background. Renal transplant recipients with de novo DSA (dDSA) experience higher rates of rejection and worse graft survival than dDSA-free recipients. This study presents a single-center review of dDSA monitoring in a large, multi-ethnic cohort of renal transplant recipients. Methods. The authors performed a nested case-control study of adult kidney and kidney-pancreas recipients from July 2007 through July 2011. Cases were defined as dDSA-positive whereas controls were all DSA-negative transplant recipients. DSA were determined at 1, 3, 6, 9, and 12 months posttransplant, and every 6 months thereafter. Results. Of 503 recipients in the analysis, 24% developed a dDSA, of whom 73% had dDSA against DQ antigen. Median time to dDSA was 6.1 months (range 0.2Y44.6 months). After multivariate analysis, African American race, kidney-pancreas recipient, and increasing numbers of human leukocyte antigen mismatches were independent risk factors for dDSA. Recipients with dDSA were more likely to suffer an acute rejection (AR) (35% vs. 10%, PG0.001), an antibody-mediated AR (16% vs. 0.3%, PG0.001), an AR ascribed to noncompliance (8% vs. 2%, P=0.001), and a recurrent AR (6% vs. 1%, P=0.002) than dDSA-negative recipients. At a median follow-up of 31 months, the deathcensored actuarial graft survival of dDSA recipients was worse than the DSA-free cohort (P=0.002). Yet, for AR-free recipients, there was no difference in graft survival between cohorts (P=0.66). Conclusions. Development of dDSA was associated with an increased incidence of graft loss, yet the detrimental effect of dDSA was limited in the intermediate term to recipients with AR.

Background. Cytotoxic T-lymphocyte antigen 4 (CTLA4) has been shown to play a critical role in the down-regulation of the immune response. We retrospectively examined the association between acute rejection and two polymorphisms in the CTLA4 gene, the dinucleotide (AT) n repeat polymorphism in exon 3 and the single nucleotide polymorphism A/G at position 49 in exon 1, in a cohort of liver and kidney transplant recipients. Methods and Results. A total of 207 liver and 167 renal transplant recipients were analyzed. In the case of the (AT) n repeat polymorphism we found an increased incidence of acute rejection in association with allele 3 and 4 in both liver and kidney (P=0.002 and 0.05, respectively). In addition, in liver transplant recipients, allele 7 was associated with acute rejection independent of ethnicity (P

Residential development is occurring at unprecedented rates in the Rocky Mountain region of the United States, with unknown ecological consequences. We conducted our research in exurban development in Pitkin County, Colorado, between May and June in 1998 and 1999. Unlike suburban development, exur- ban development occurs beyond incorporated city limits, and the surrounding matrix remains the original ecosystem type. We surveyed songbirds and medium-sized mammals at 30, 180, and 330 m away from 40 homes into undeveloped land to examine the effect of houses along a distance gradient, and in developments of two different housing densities as well as undeveloped sites to examine the effect of housing density. We placed bird species into one of two groups for the house-distance effect: (1) human-adapted species, birds that occurred in higher densities close to developments and lower densities farther away and (2) human-sensitive species, birds that occurred in highest densities farthest from homes and in lowest densities close to develop- ment. For both groups, densities of individual species were statistically different between the 30- and 180-m sites. Six species were classified as human-adapted, and six were classified as human-sensitive for the house- distance effect. Dogs ( Canis familiaris ) and house cats ( Felis domesticus ) were detected more frequently closer to homes than farther away, and red foxes ( Vulpes vulpes ) and coyotes ( Canis latrans ) were detected more fre- quently farther away from houses. With respect to the effect of housing density, most avian densities did not differ significantly between high- and low-density development but were statistically different from undevel- oped sites. Six species were present in higher densities in developed areas, and eight species were present in higher densities in undeveloped parcels. Similar results were found for mammalian species, with dogs and cats detected more frequently in high-density developments and red foxes and coyotes detected more fre- quently in undeveloped parcels of land. From an ecological standpoint, it is preferable to cluster houses and leave the undeveloped areas in open space, as opposed to dispersing houses across the entire landscape.

Background Apoptosis contributes to cell loss after ischemia/reperfusion injury in the heart. This study describes the time course and level of apoptosis in different cell types in the intact heart during ischemia/reperfusion injury. Methods and Results Isolated Langendorff-perfused rat hearts were subjected to perfusion alone (control) or to 35 minutes of regional ischemia, either alone or followed by 5, 60, or 120 minutes of reperfusion. Sections were stained by terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) and propidium iodide and with anti-von Willebrand factor, anti-desmin, or anti-active caspase 3 antibodies; they were then visualized by confocal microscopy. Sections were also examined by electron microscopy. No TUNEL-positive cells were seen in control hearts or hearts exposed to ischemia alone. Early in reperfusion, TUNEL staining was colocalized with endothelial cells from small coronary vessels. Endothelial apoptosis peaked at 1 hour of reperfusion and, at this time, there was clear perivascular localization of apoptotic cardiac myocytes, whose number was inversely proportional to their distance from a positive vessel. After 2 hours of reperfusion, apoptotic cardiac myocytes assumed a more homogeneous distribution. Active caspase 3 labeling was seen independent of DNA fragmentation during ischemia alone, but it colocalized with TUNEL staining over the 3 time points of reperfusion. Immunocytochemical findings were confirmed by electron microscopy and Western blotting. Conclusions In the very early stages of reperfusion, apoptosis is first seen in the endothelial cells from small coronary vessels. The radial spread of apoptosis to surrounding cardiac myocytes suggests that reperfusion induces the release of soluble pro-apoptotic mediators from endothelial cells that promote myocyte apoptosis.

Conservationists have an admirable history of documenting the impacts of human land uses on biodiversity to better inform resource-management decisions. Considering all that, the state of our current knowledge about land-use changes in the Mountain West of the United States is less than satisfactory. Across the region, we work to diminish extractive and commodity-based industries, such as water development, logging, mining, and livestock grazing, but have largely failed to recognize the ecological consequences of our own actions, especially where we choose to live and play. While we devote much of our attention to the traditional consumptive land uses that characterized the "Old West," other threats to biodiversity become more pervasive each year with the emergence of a "New West." Urban sprawl and outdoor recreation, for example, are the second and fourth leading causes of the decline in federally listed threatened and endangered species (Czech, Krausman, and Devers 2000). The character of the New West is being shaped by a flood of immigrants seeking to enjoy the natural amenities and recreational opportunities of a region rich in public lands (Power 1996; Masnick 2001). Importantly, however, only half of the West is public lands; the most productive lands in the region are in private ownership (Scott and others 2001). This is critical, because the most profound land-use change in the New West is the conversion of private lands presently in ranching and farming to rural residential, or exurban, developments (Knight 2002). Unfortunately, conservationists have given scant attention to studying the ecological implications of this western land-use conversion. Addressed here are some of the ecological issues associated with land-use change in the Mountain West. For readers who are unfamiliar with the region's current status, we provide a brief review of the changes that are occurring with human population, dominant land uses, and growth patterns. We then examine an emerging strategy that is being implemented to protect biodiversity from these growth pressures. Testing the unstated assumptions of this new conservation strategy, we present the results of a comparison of bio diversity on the three principal land uses beyond incorporated city limits in the Mountain West: protected areas (areas protected from residential development),livestock ranches, and exurban developments. We conclude by considering the implications of our findings for conservation. EXURBANIZATION OF THE MOUNTAIN WEST The Mountain West of the United States is experiencing a human population boom that rivals any in its history. Of the eight states that make up this region--Arizona, Colorado, Idaho, Montana, Nevada, New Mexico, Utah, and Wyoming--five are the fastest growing in the country (Figure 1). Metropolitan areas and their suburbs have accommodated much of this in-migration, but rural areas are growing at a faster rate (Heimlich and Anderson 2001). Driven by a mixture of economic and quality-of-life features, people are increasingly drawn to the rural Mountain West (Power 1996). Unlike previous booms driven by resource extraction and commodity production, the present period of growth is fueled by the expansion of service, recreation, and information industries and is marked by the conversion of private land use from agriculture to exurban development (Riebsame, Gosnell, and Theobald 1996; Sullins and others 2002). As a result, three of the principal land uses in the rural Mountain West today are protection, livestock ranching, and exurban development. Exurban development refers to low-density residential development that occurs beyond incorporated city limits (Nelson and Dueker 1990; Knight 1999). The main human use in protected areas is outdoor recreation and the protection of perceived natural values; on ranches it is livestock production; in exurban developments it is human residence. The amount of land in protection is relatively static, with little added annually. …

Previously we reported that ischemia results in apoptosis and is accompanied by phosphorylation on Tyr-701 and increased expression and transcriptional activity of the signal transducer and activator of transcription-1 (STAT-1). In the present study, we show that exposure of cardiomyocytes to ischemia induced the phosphorylation of STAT-1 at another site, Ser-727. Moreover, STAT-1 is critical for the induction of Fas receptor and Fas ligand expression by ischemia/reperfusion (I/R). Transcriptional activation of Fas and FasL was dependent on Ser-727 of STAT-1 but was independent of Tyr-701. Similarly, Ser-727 but not Tyr-701 was required for enhancement of cardiomyocyte cell death by STAT-1 during I/R. In addition, inhibition of the p38 pathway prevented the induction and transcriptional activation of Fas and FasL in cardiac cells exposed to I/R, whereas inhibition of p42/p44 MAPK had no effect. Finally, I/R also induced phosphorylation of STAT-1 on Ser-727 and expression of Fas/FasL in ventricular myocytes in the intact heart ex vivo. These results indicate that Fas/FasL genes and apoptosis are activated by STAT-1 in cardiac myocytes exposed to I/R and these effects are dependent on the Ser-727 but not the Tyr-701 phosphorylation sites of STAT-1.

Background. We investigated whether recipients of living donor grafts who suffer an acute rejection progress to graft loss because of chronic rejection at a slower rate than recipients of cadaveric grafts. Methods. A retrospective review was made of 296 renal transplantations performed at Mount Sinai Hospital. Only grafts functioning for at least 3 months were included in this analysis. Demographic variables of donor and recipient age, race, sex, and serum creatinine at 3 months after transplantation were compared between groups. Results. Among the acute rejection-free cohort, the estimated 5-year graft survival was 90% for those receiving transplants from living relatives and 88% for those receiving cadaveric transplants (P=0.76). However, in grafts with early acute rejection, the 5-year survival was 40% for cadaveric recipients compared with 73% for living related graft recipients (P

Human intermodulation distortion product otoacoustic emissions (DPOAE) can be a mixture of low and high latency components. They have different level, phase, and suppression characteristics, which indicate that emissions arise both from the frequency region of the primary tones directly and indirectly via the DP frequency place. Which component dominates the measured DPOAE in the ear canal depends on the stimulus parameters, especially the frequency ratio, f2/f1. Interference between the two emissions adds complexity to measurements of DPOAE. The behavior and even existence of whichever emission route is lower in level often cannot directly be deduced from the raw DPOAE data because the other emission covers it. It is therefore not known whether both emissions are present for all stimulus parameters or whether the trends seen in each emission when they are the dominant emission route continue under stimulus conditions when they are not dominant. In this study, the two DPOAE components are separated by a post-processing method. Previously, maps of raw DPOAE data against f2/f1 and DP frequency have been obtained. To separate the components, sets of data consisting of f2/f1 sweeps were transformed by an inverse Fourier transform into the time domain. The low and high latency components appeared as two distinct peaks because of their different phase gradients. These peaks were separated by windowing in the time domain and two frequency domain maps were reconstructed, representing the low and high latency DPOAEs. It was found that the low latency component of the 2 f1-f2 DP was only emitted strongly with f2/f1 between approximately 1.1 and 1.3. The removal of the high latency component revealed the low ratio edge of this region, at which the level falls sharply. However, the low latency emission has been traced at reduced amplitude over a wide range of stimulus parameters. Although previously only observed at small frequency ratios, the high latency component was found to be present widely in the lower sideband, its level reducing slowly at larger f2/f1. Its phase behavior changes in the lower sideband, being approximately constant with DP frequency at small ratios of f2/f1, but deviating from this at wider ratios. These results support the hypothesis that a DPOAE component which propagates to and is re-emitted from the DP frequency place (place fixed emission) is present across a wide parameter range. However, for all but the close primary condition the lower sideband DPOAE is dominated by direct emission from the region of f2 and f1 wave interaction (wave fixed emission). A simple transmission line model is presented to illustrate how the observed DPOAE maps can arise on the basis of this hypothesis.

Changes in several components of the hydrological cycle over the contiguous United States have been documented during the twentieth century: an increase of precipitation, especially heavy and very heavy precipitation, and a significant retreat in spring snow cover extent over western regions during the last few decades. These changes have affected streamflow, including the probability of high flow. In the eastern half of the United States a significant relationship is found between the frequency of heavy precipitation and high streamflow events both annually and during the months of maximum streamflow. Two factors contributed to finding such a relation: 1) the relatively small contribution of snowmelt to heavy runoff in the eastern United States (compared to the west), and 2) the presence of a sufficiently dense network of streamflow and precipitation gauges available for analysis. An increase of spring heavy precipitation events over the eastern United States indicates with high probability that...

Study Objective: Although the addition of H 2 blockers to H 1 antagonists has been promoted for use in anaphylaxis, there have been no large studies establishing the advantage of this approach in treating acute allergic syndromes. In this study we tested the hypothesis that combined H 1 and H 2 blockage results in improved outcomes in patients treated for acute allergic syndromes compared with treatment with H 1 blockade alone. Methods: In a randomized, double-blind, placebo-controlled trial, 91 adult patients with acute allergic syndromes were treated with either 50 mg of diphenhydramine and saline solution (control group) or with 50 mg of diphenhydramine and 50 mg of ranitidine (active group). These patients were treated with parenteral administration. Patients were recruited from an emergency department at an urban academic medical center. The primary endpoints were resolution of urticaria, angioedema, or erythema at 2 hours after protocol treatment. Areas of cutaneous involvement, heart rates, blood pressures, respiratory findings, and symptom scores were also assessed at baseline, 1 hour, and 2 hours. Results: There were significantly more patients without urticaria at 2 hours among the patients in the active group compared with those in the control group. Both groups had similar proportions of urticaria at baseline. Logistic regression models to predict resolution of urticaria, which accounted for baseline urticarial involvement, showed odds ratios in favor of the active group treatment. Similar findings were observed when the absence of both urticaria and angioedema was considered as the dependent variable. There was not a significant difference between the 2 groups with regard to the absence of erythema or angioedema (irrespective of the presence of urticaria) at 2 hours. Blood pressure and symptoms did not show differences between the 2 groups over time. Lower heart rates were observed 1 hour after treatment in the active treatment group (mean reduction 10 beats/min) compared with those found in the placebo group (mean reduction 6 beats/min). Conclusion: These data show that adding H 2 blockers to H 1 antagonists results in additional improvement of certain cutaneous outcomes for patients presenting with acute allergic syndromes. These findings favor the recommendation for using combined H 1 and H 2 antihistamines in acute allergic syndromes. [Lin RY, Curry A, Pesola GR, Knight RJ, Lee H-S, Bakalchuk L, Tenenbaum C, Westfal RE. Improved outcomes in patients with acute allergic syndromes who are treated with combined H 1 and H 2 antagonists. Ann Emerg Med. November 2000;36:462-468.]

Background: Emergency department visits for acute allergic reactions are common. Although the diagnosis and classification of these allergic reactions is primarily empiric, it is not always clear whether certain signs and symptoms constitute systemic mediator release syndromes, such as anaphylaxis, and thus may warrant more aggressive therapy or follow-up. Objective: We sought to determine associations between various clinical signs and symptoms with both plasma histamine levels and serum tryptase levels in adult patients presenting to an emergency department with acute allergic syndromes. The clinical correlates of raised β-tryptase levels were also investigated. Methods: Ninety-seven adult emergency department patients were prospectively studied by using a questionnaire, physical examination, and serum-plasma sampling. Plasma histamine and serum total and β-tryptase levels were determined. Clinical groupings were compared for mediator levels by using simple and multivariate analysis. Results: Elevated levels of plasma histamine (>10 nmol/L) and serum total tryptase (>15 ng/mL) were observed in 42 and 20 patients, respectively. Detectable β-tryptase (≥1 ng/mL) was observed in 23 patients, including 15 of the patients with elevated total tryptase levels. Suspected food allergy incidences and the duration of reaction were similar in patients with increased histamine levels and in patients with increased tryptase levels. Increased total tryptase levels, histamine levels, or both were observed in some patients who did not have airway, cardiovascular, or abdominal signs. Histamine levels correlated better with clinical signs than tryptase levels. Histamine elevations (>10 nmol/L) were observed more frequently in patients characterized by the following clinical signs in univariate analysis: the presence of urticaria, more extensive erythema, abnormal abdominal findings, and wheezing. Total tryptase increases were observed more frequently only in patients with urticaria. Histamine levels correlated with initial heart rates. In multivariate analysis the extent of urticaria was the best single predictor of plasma histamine levels and of either an elevated histamine or tryptase level. Detectable β-tryptase levels were observed in some patients who had neither elevated total tryptase nor elevated histamine levels. Unlike patients without detectable β-tryptase levels, patients who had detectable β-tryptase levels had a significant correlation between total tryptase and histamine levels ( P Conclusions: Raised histamine and, less commonly, raised tryptase levels are observed in almost 50% of patients presenting to emergency departments with acute allergic reactions. Some cases associated with systemic mediator release do not have classical features of severe anaphylaxis, such as hypotension or tachycardia. The lack of total tryptase elevations in many patients with elevated plasma histamine levels suggests basophil involvement. The clinical utility of β-tryptase determinations in the evaluation of acute allergic reactions needs further study. (J Allergy Clin Immunol 2000;106:65-71.)

We investigated the functions of perch relocations within a communal night roost of wintering bald eagles (Haliaeetus leucocephalus) along the Nooksack River, Washington, during two winters. We tested seven predictions of two nonexclusive hypotheses: (1) bald eagles relocate within roosts to assess foraging success of conspecifics and (2) bald eagles relocate to obtain thermoregulatory benefits from an improved microclimate. Additionally, we gathered descriptive information to allow refinement of further alternative hypotheses. We rejected the hypothesis that relocations are a means of assessing foraging success. Contrary to our expectations, immature eagles did not relocate to be closer to adults, and relocations were less frequent when food was less abundant. Our data support the hypothesis that eagles relocate within night roosts to obtain a favorable microclimate during winters when they are subjected to cold stress and food stress. In both winters, relocations were more frequent in the evening than in the morning. In both winters, most evening relocations were to the center of the roost rather than to its edge, and the frequency of relocation to the center was greater when temperatures were low. The microclimate hypothesis, however, explains only a limited number of relocations. Based on our findings, it is likely that relocation has multiple functions, including establishing and (or) maintaining foraging associations, establishing and (or) maintaining social-dominance hierarchies when food is less abundant, and nonsocial activities.

During the time between May of 1997 and September of 1998, for sixteen consecutive months, each month broke the previous monthly all-time record high temperature. Using autoregressive intervention moving average (ARMA) models in a series of Monte Carlo experiments the probability of such an event was analyzed for various rates of temperature change. The string of record-breaking global temperatures could not be readily explained by the best fit linear increase of temperature since the late 1970's (2°C/Century), although the event was not implausible (probabilities slightly less than 5%). The 1997–98 event could signal yet another change point in the rate of global temperature increase, but the warming rate over the past few decades is already comparable to that projected during the 21st Century based on IPCC business as usual scenarios of anthropogenic climate change (Kattenberg et al., 1996).

Objective: [2-18F] 2-fluorodeoxyglucose (FDG) is widely used to trace glucose metabolism for cardiac imaging with positron emission tomography. Because the transport and phosphorylation rates differ for glucose and FDG, a lumped constant (LC) is used to correct for these differences. The effects of ischemia and reperfusion on the LC in vivo are unknown. To determine the validity of FDG as a tracer of glucose metabolism in post-ischemic myocardium in vivo, the relationship between glucose uptake (GU) and FDG metabolic rate (FDG-MR) was assessed early post-reperfusion following a transient ischemic event. Methods: FDG metabolic rate, measured with FDG and PET, was compared to invasive measurements of substrate metabolism in reperfused and global myocardium of dogs subjected to 25 min ischemia and 2 h reperfusion. Results: The FDG metabolic rate was decreased 20±4% in reperfused relative to remote myocardium. Glucose oxidation and lactate uptake were also decreased in reperfused relative to global myocardium, by 26±6% and 60±8% respectively. Glucose uptake did not differ significantly between reperfused and global myocardium. A linear correlation between FDG metabolic rate and glucose uptake was found in both reperfused and remote myocardium. Estimates of the LC from the slopes of the regression lines were similar in reperfused and remote myocardium, 1.25 and 1.44 respectively, and did not differ significantly from the LC determined in control dogs, 1.1. Conclusions: We conclude that the FDG metabolic rate continues to correlate well with glucose metabolism in reperfused myocardium. While FDG metabolic rate was modestly decreased in the absence of a significant change in glucose uptake, large alterations in the LC are not found 2 h post-reperfusion in vivo.

The Institute of Gas Technology samples high-pressure fuel gas from its RENUGAS® gasifiers by withdrawing the sample isokinetically at process conditions, removing particulates in a hot filter, and cooling the gas stream to condense unreacted steam and oils, which are then collected in a series of cooled traps at system pressure. Gas flow rate is controlled and measured to quantify the oil content in the bulk fuel gas, and fuel gas composition is continuously measured with an on-line GC. The sampling system vessels are later rinsed with dichloromethane to obtain quantitative oil samples. Analyses of oils are performed off-line using capillary GC–FID and GC–MS. Using this methodology, IGT has obtained extensive data from a 10-tonne/day PDU in Chicago and a 90-tonne/day demonstration plant in Hawaii. The distribution of four oil fractions as a function of feedstock type, gasifier temperature, gasifier pressure, and steam:feed ratio were determined for wood chips, whole tree chips, and bagasse.

Most published data comparing the amplitudes of transient evoked otoacoustic emissions (TEOAEs) and bi-tonally evoked otoacoustic emissions (DPOAEs) indicate a low level of correlation, raising the question to what extent do the two responses share the same relationship with hearing function. However, DPOAE intensities are sensitive to stimulus parameters and comparisons with TEOAE have mostly been made with the specific range of DPOAE parameters found to optimize DP output level. To determine if other DPOAE stimulus parameter domains give closer correspondence between TEOAE and DPOAE characteristics, 2 f1−f2 and 2 f2−f1 DPOAE intensity and phase measurements were made across a sample 1/2-octave frequency range centered on 2 kHz in nine normally hearing subjects using a wide range of stimulus parameter configurations. The DP fine structure was resolved by detailed measurements and the mean DP levels were compared to those in the corresponding frequency range from TEOAE measurements obtained with the same ...

Apoptosis is a distinct form of cell death, induced, for example, by ischaemia/reperfusion injury, that results in characteristic alterations in cell morphology and fate. In tissue sections, the most commonly used technique to detect apoptosis is terminal deoxynucleotidyl transferase mediated nick end labelling (TUNEL) staining which labels the ends of DNA strand breaks characteristic of the apoptotic process. However, without the employment of additional staining, TUNEL is only a qualitative procedure that gives no information about the proportion of negative cells nor the cell type undergoing apoptosis. We have utilised propidium iodide (PI) as a counterstain to visualise TUNEL negative nuclei together with anti-desmin antibody in order to assess quantitatively apoptosis in specific cell types. The procedure has been evaluated in tissue sections from isolated perfused rat hearts subjected to ischaemia and reperfusion. Hearts were cross-sectioned into four 2.5 mm thick slices which were fixed in 4% formaldehyde and embedded in paraffin. Serial sections (5 microns) were cut, dewaxed and pretreated by incubation with trypsin at 37 degrees C for 30 min. After the employment of the TUNEL assay, sections were labelled with anti-desmin antibody, counterstained with PI and finally examined by confocal fluorescent microscopy. Apoptosis was not seen in sections from hearts subjected to ischaemia alone nor in control hearts. After 35 min of ischaemia the percentages of TUNEL positive cells were very low both in myocytes (0.1%) and in non-myocytes (0.3%). In ischaemic-reperfused hearts, the number of TUNEL positive cells was only significantly higher in vascular cells (44+/-5%) and cardiac myocytes (6+/-2%). This simple method therefore allows quantification of apoptosis in myocytic and non-myocytic cells in tissue sections. Use of alternative immunohistochemical markers would permit adaptation of the method to the quantitative assessment of apoptosis in other tissues.

Background: Acute rejection (AR) is an important risk factor for long-term renal graft loss. Furthermore, donor age is also associated with graft outcome. We analyzed the combined effects of cadaver donor age and AR on long-term graft survival. Methods: A retrospective review was made of 112 cadaver renal transplants at a single center. Only grafts functioning at least 3 months were included in this analysis. Results: The 3-year survival of AR-free grafts was superior to that of grafts with AR (98% vs 67%, P 50 years (P < .05) had an additional negative impact on graft survival. The 3-year survival of an older donor graft with AR was 33% versus 82% for a younger donor graft with AR. Conclusions: AR was a significant predictor of long-term graft loss. Older donor kidneys with AR had poorer graft survival than did younger donor kidneys with AR. (Surgery 1999;125:318-24.)

Itch is a HECT-containing E3 ligase that induces proteasomal degradation of many proteins. Two targets of Itch, JunB and Notch, have been found involved in the activation of T-helper cells. It has been proposed that alterations in pathways leading to Th1 and Th2 differentiations could be involved in inflammatory diseases and in autoimmune disorders respectively. Moreover knockout mice for Itch gene displayed inflammatory immune responses and constant itching of the skin. The aim of this work was to screen the putative functional regions of Itch in order to investigate if gene polymorphisms are present in healthy population and if they are differently represented in patients affected by rheumatoid arthritis or atopic dermatitis. Genomic DNA purified from blood samples of 100 healthy volunteers, 25 atopic dermatitis, and 45 rheumatoid arthritis patients were analysed by sequencing. We found 8 substitutions in the functional regions of Itch, but we could not find significant differences between patients and ...

We compared the plant communities on cliffs used for rock climbing with cliffs not used for climbing. Eighteen cliffs in Joshua Tree National Park, California (six each with no climbing, moderate climbing, and intensive climbing) were sampled for plant diversity and community structure. Plants were sampled on cliff faces and at the base of cliffs. The dominant taxa were Quercus cornelius-mulleri, Ericameria cuneata var. cuneata, and Bromus madritensis ssp. rubens. Plant species richness on cliff faces and at the base of cliffs was greater for cliffs with no evidence of climbing and lowest for cliffs with intensive use. Numbers of individual plants decreased with increased climbing use. Trees, shrubs, forbs, and cacti had greater relative abundances on cliffs without climbing than on cliffs with climbing. Plant cover on cliff faces decreased with increased climbing use. Adaptive management will be necessary to minimize the deleterious effects of rock climbing on plant communities associated with cliffs. Efectos de Alpinismo sobre las Comunidades de Plantas en Acantilados en el Parque Nacional Joshua Tree, California Comparamos las comunidades de plantas en acantilados usados para alpinismo contra acantilados no usados para esta actividad. Dieciocho acantilados del Parque Nacional Joshua Tree, California (seis con alpinismo, seis con alpinismo moderado y seis sin alpinismo) fueron muestreados para determinar la diversidad de plantas y la estructura de la comunidad. Las plantas fueron muestreadas en las caras y bases de los acantilados. Los taxones dominantes fueron Quercus cornelius-mulleri, Ericameria cuneata var. cuneata y Bromus madritensis ssp. rubens. La riqueza de especies en las caras y bases de los acantilados fue mayor en aquellos sin evidencia de alpinismo y menor para aquellos acantilados con uso intensivo. Los numeros individuales de plantas disminuyeron con un incremento en el uso para alpinismo. Arboles, arbustos, pastos y cactus tuvieron una abundancia relativa mayor en acantilados sin alpinismo que en aquellos con alpinismo. La cobertura de las plantas en las caras de los acantilados disminuyo con un incremento en el alpinismo. Sera necesario emplear un manejo adaptable para minimizar los efectos daninos del alpinismo en roca sobre comunidades de plantas asociadas con acantilados.

The calculation of global land surface air temperature trends using the instrumental record has been based primarily upon two methods of maximizing the availability of station records. Hansen and Lebedeff[1987] developed a technique that is still used today, known as the reference station method; Jones et al. [1986a] popularized the climate anomaly method in their calculations of global temperature trends. In this paper we introduce yet another approach designed to maximize station records, referred to as the first difference method. To test the sensitivity of global temperature trend analysis to the method used, we calculate worldwide-averaged land surface mean temperature using each of these methods with an identical data base, the Global Historical Climatology Network. For further comparisons, a global climate model (GCM) transient model simulation is interpolated to the Global Historical Climatology Network station locations and the three techniques are then applied to data interpolated to the station locations from the model. The Intergovernmental Panel on Climate Change (IPCC); [Nicholls et al., 1996] estimated a global land and ocean temperature change of 0.45°C ± 0.15°C since the 19th century. Their assessment of the uncertainty associated with this temperature trend did not specifically address the differences that the method of calculating a global temperature time series might produce. Our results indicate that the differences in 1880-1990 trends produced by these three different methods are only a few hundredths of a degree centigrade per 100 years on trends of approximately 0.5°C/100 years. This is quite small compared to the 0.15°C/100 years uncertainty associated with the IPCC global land and ocean assessment which included factors such as data homogeneity which are not addressed here. Indeed, our results indicate that the source of differences in trends is more likely to be the method used to calculate a linear trend from a global temperature time series than the method used to create the global temperature time series. The modeled results confirm this finding but highlight other important characteristics: the reference station method has uncharacteristically low interannual variance, more similar to time series from the entire globe (land and ocean) than the global land area from which the data were observed. This lower variance can impact the statistical significance associated with linear trends.

Pulmonary sarcoidosis involves development of parenchymal granulomata that usually resolve spontaneously; however, it remains unclear what pathogenic mechanisms are responsible for the progression to local or diffuse fibrosis with irreversible lung remodeling that occurs in 20% of patients. Alveolar macrophages have a pivotal role in sarcoidosis, releasing mediators including insulin-like growth factor (IGF)-1, a potent profibrogenic molecule. IGF-1 bioavailability in the lung is dependent on at least six high-affinity IGF-binding proteins (IGFBP), which mainly inhibit IGF-1 action. We have investigated their presence in patients with established stage III sarcoidosis to determine whether IGF-1 and IGFBP contribute to the fibrogenic process in these patients and as such contribute to the (clinical) progression of the disease. The fibroblast mitogenic potential of bronchoalveolar lavage fluid (BALF) was more than 3-fold higher (P < 0.005) in sarcoid patients. Sarcoid BALF-induced activity could be inhibited (P < 0.0005) by neutralizing antibodies to IGF-1. We established the IGFBP profile of BALF with Western ligand analysis and quantified expression of IGFBP-3 by immunoblotting. IGFBP-2 and IGFBP-4 predominate in normal and sarcoid BALF, but IGFBP-3 occurs only as a modified, smaller, 29-kD form, expression of which was raised (P < 0.003) in sarcoid patients. Gene expression of IGF-1 and IGFBP-3 was demonstrated by reverse transcription-polymerase chain reaction in BAL cells. Thus, local production of pro-fibrogenic IGF-1 may be subject to substantial post-translational regulation by associated IGFBP and IGFBP proteases that may contribute to enhanced fibrogenesis in sarcoidosis patients with evidence of progression or (development) of fibrosis.

Ecosystem management argues for the maintenance of native biological diversity, in addition to commodity and amenity uses, on our public lands. Heretofore, natural resource management agencies have focused on managing for single species, usually those that are commercially valuable, threatened or endangered, or over-abundant. For a variety of reasons, the future of public-land management will place increasing importance on managing for species communities. Three approaches which can be used to manage for communities include: (1) a species approach, (2) an ecological processes approach, and (3) a landscape approach. Each method is briefly discussed.

Pyruvate dehydrogenase (PDH) is regulated both by covalent modification and through modulation of the active enzyme by metabolites. In the isolated heart, post-ischaemic inhibition of PDH, leading to uncoupling of glycolysis and glucose oxidation and a decrease in cardiac efficiency, has been described. In vivo, post-ischaemic reperfusion leads to metabolic abnormalities consistent with PDH inhibition, but the effects of ischaemia/reperfusion on PDH are not well characterized. We therefore investigated PDH regulation following transient ischaemia in vivo. In 33 open-chest dogs, the left anterior descending (LAD) was occluded for 20 min followed by 4 h reperfusion. In 17 dogs, dichloroacetate (DCA) was injected prior to reperfusion, while 16 dogs served as controls. In dogs without DCA, glucose oxidation and lactate uptake were lower in reperfused than in remote tissue, suggesting reduced flux through PDH. However, percent active and total PDH measured in myocardial biopsies were similar in both territories, excluding covalent enzyme modification or loss of functional enzyme. DCA activated PDH activity similarly in both regions and abolished differences in glucose oxidation and lactate uptake. Thus, decreased PDH flux in reperfused myocardium does not result from covalent modification or loss of total enzyme activity, but more likely from metabolite inhibition of the active enzyme. DCA leads to essentially complete activation of PDH, increases overall glucose utilization and abolishes post-ischaemic inhibition of glucose oxidation.

We investigated the influence of recreational trails on breeding bird communities in forest and mixed-grass prairie ecosystems in Boulder County, Colorado, United States, during 1994 and 1995. Species composition, nest predation, and brood parasitism by Brown-headed Cowbirds (Molothrus ater) were examined near and away from existing recreational trails. Bird species composition was altered adjacent to trails in both ecosystems. Generalist species were more abundant near trails, whereas specialist species were less common. Within the grassland ecosystem, birds were less likely to nest near trails. Within both ecosystems, nest predation was greater near trails. In forests, the rate of brood parasitism was not influenced by trails. No brood parasitism was found in the grassland ecosystem. Our results may be useful to natural-lands managers who must implement management policies regarding the spatial arrangement of trails and trail-use restrictions.

Twentieth century trends of precipitation are examined by a variety of methods to more fully describe how precipitation has changed or varied. Since 1910, precipitation has increased by about 10% across the contiguous United States. The increase in precipitation is reflected primarily in the heavy and extreme daily precipitation events. For example, over half (53%) of the total increase of precipitation is due to positive trends in the upper 10 percentiles of the precipitation distribution. These trends are highly significant, both practically and statistically. The increase has arisen for two reasons. First, an increase in the frequency of days with precipitation ]6 days (100 yr)−1[ has occurred for all categories of precipitation amount. Second, for the extremely heavy precipitation events, an increase in the intensity of the events is also significantly contributing (about half) to the precipitation increase. As a result, there is a significant trend in much of the United States of the highest...

The use of existing drugs for new therapeutic applications, commonly referred to as drug repositioning, is a way for fast and cost-efficient drug discovery. Drug repositioning in oncology is commonly initiated by in vitro experimental evidence that a drug exhibits anticancer cytotoxicity. Any independent verification that the observed effects in vitro may be valid in a clinical setting, and that the drug could potentially affect patient survival in vivo is of paramount importance. Despite considerable recent efforts in computational drug repositioning, none of the studies have considered patient survival information in modelling the potential of existing/new drugs in the management of cancer. Therefore, we have developed DRUGSURV; this is the first computational tool to estimate the potential effects of a drug using patient survival information derived from clinical cancer expression data sets. DRUGSURV provides statistical evidence that a drug can affect survival outcome in particular clinical conditions to justify further investigation of the drug anticancer potential and to guide clinical trial design. DRUGSURV covers both approved drugs (∼1700) as well as experimental drugs (∼5000) and is freely available at http://www.bioprofiling.de/drugsurv. published

To determine the impact of Safety, Minimization and Awareness Radiation Training (SMART) on fluoroscopy time during unilateral uncomplicated ureteroscopy for urolithiasis performed by urology residents.All consecutive ureteroscopy cases for urolithiasis meeting inclusion criteria and performed by first-year urology residents over a 2-year period were reviewed. Fluoroscopy times during SMART and without SMART were compared.A total of 202 ureteroscopy cases were reviewed. The mean patient age was 48.7 years. The mean stone diameter was 7.6 ± 3.3 mm. The mean operating time was 79.8 ± 34.3 minutes. The mean cumulative fluoroscopy time was 85.6 ± 36.9 seconds per case. A Spearman rank correlation identified 8 variables significantly correlated with fluoroscopy time, with the most significant correlation between shorter fluoroscopy time and SMART exposure (rho = 0.532; P.001). Multivariate regression analysis (r = 0.701) revealed that fluoroscopy time was significantly shorter with SMART (P.001). Post hoc comparisons revealed the fluoroscopy time of the cases performed during SMART (mean, 45 seconds) to be significantly shorter than the fluoroscopy time of cases performed by the same residents before SMART (mean, 102 seconds; P = .005), and the fluoroscopy time of cases performed by residents the previous year with similar ureteroscopic experience but without SMART (mean, 78 seconds; P.001).SMART reduces fluoroscopy time during unilateral uncomplicated ureteroscopy for urolithiasis performed by urology residents by 56%.

To determine predictors of fluoroscopy time during uncomplicated, unilateral ureteroscopy for urolithiasis performed by urology residents during the first 2 years of residency. The patient charts and computed tomography scans of consecutive, unilateral, uncomplicated ureteroscopy cases for urolithiasis were retrospectively reviewed. The cases were performed by beginning urology residents over the course of their first 2 years of urology residency training. A total of 200 ureteroscopy cases were reviewed. The mean stone diameter was 7.1 (±3.2) mm. Forty-three percent of cases were performed for renal stones and 58 % for ureteral stones. The mean operative time was 80.2 (±36.9) min. The mean fluoroscopy time was 69.1 (±38.2) s. No significant differences existed between cases performed by each of the two residents, and no statistical differences in case difficulty were observed throughout the study period. Linear regression analysis revealed the strongest association with lower fluoroscopy time to be increasing resident experience (p

Inhibition of distinct ubiquitin E3 ligases might represent a powerful therapeutic tool. ITCH is a HECT domain-containing E3 ligase that promotes the ubiquitylation and degradation of several proteins, including p73, p63, c-Jun, JunB, Notch and c-FLIP, thus affecting cell fate. Accordingly, ITCH depletion potentiates the effect of chemotherapeutic drugs, revealing ITCH as a potential pharmacological target in cancer therapy. Using high throughput screening of ITCH auto-ubiquitylation, we identified several putative ITCH inhibitors, one of which is clomipramine--a clinically useful antidepressant drug. Previously, we have shown that clomipramine inhibits autophagy by blocking autophagolysosomal fluxes and thus could potentiate chemotherapy in vitro. Here, we found that clomipramine specifically blocks ITCH auto-ubiquitylation, as well as p73 ubiquitylation. By screening structural homologs of clomipramine, we identified several ITCH inhibitors and putative molecular moieties that are essential for ITCH inhibition. Treating a panel of breast, prostate and bladder cancer cell lines with clomipramine, or its homologs, we found that they reduce cancer cell growth, and synergize with gemcitabine or mitomycin in killing cancer cells by blocking autophagy. We also discuss a potential mechanism of inhibition. Together, our study (i) demonstrates the feasibility of using high throughput screening to identify E3 ligase inhibitors and (ii) provides insight into how clomipramine and its structural homologs might interfere with ITCH and other HECT E3 ligase catalytic activity in (iii) potentiating chemotherapy by regulating autophagic fluxes. These results may have direct clinical applications. Fil: Rossi, Mario. University of Leicester; Reino Unido. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Rotblat, B.. University of Leicester; Reino Unido Fil: Ansell, K.. Medical Research Council; Reino Unido Fil: Amelio, I.. University of Leicester; Reino Unido Fil: Caraglia, M.. Seconda Universita Degli Studi Di Napoli; Italia Fil: Misso, G.. Seconda Universita Degli Studi Di Napoli; Italia Fil: Bernassola, F.. Universita Tor Vergata; Italia Fil: Cavasotto, Claudio Norberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Knight, R.. University of Leicester; Reino Unido Fil: Ciechanover, A.. Technion-Israel Institute of Technology; Israel Fil: Melino, G.. University of Leicester; Reino Unido

The mir-34 family was originally cloned and characterized in 2007 as a p53 target gene. Almost immediately it became clear that its major role is as a master regulator of tumor suppression. Indeed, when overexpressed, it directly and indirectly represses several oncogenes, resulting in an increase of cancer cell death (including cancer stem cells), and in an inhibition of metastasis. Moreover, its expression is deregulated in several human cancers. In 2013, a miR-34 mimic has become the first microRNA to reach phase 1 clinical trials. Here we review the miR-34 family and their role in tumor biology, and discuss the potential therapeutic applications of miR-34a mimic.

Objective: To assess the effects of pregnancy on cyclosporine levels in six renal allograft patients. Methods: Maternal demographic, laboratory, clinical, and perinatal outcome data were recorded in six pregnant women with previous renal allografts receiving cyclosporine immunosuppression. The cyclosporine and serum creatinine levels were measured before pregnancy, during each trimester, and postpartum. Results: The mean (standard deviation [SD]) maternal age was 29.1 (3.8) years. Parity ranged from 0 to 3. Mean serum creatinine levels tended to be lower during pregnancy than before or after, as did the mean cyclosporine levels. After adjusting for dose, five of six patients had declines in cyclosporine level during pregnancy. The mean (SD) gestational age at delivery was 37.5 (2.8) weeks with a mean (SD) birth weight of 2837 (538) g. Conclusion: Pregnancy in patients with renal allografts can lead to a substantial decline in cyclosporine levels.

SUMMARY Human rhinoviruses (HRV) are a major cause of upper respiratory tract infections in man, and can exacerbate existing pulmonary disease. The major group of HRV attach to ICAM-1, which is expressed on nasal and bronchial epithelial cells. To study the influence of biological mediators on ICAM-1 expression, and consequently HRV attachment and infection, we compared the effects of various cytokines, alone and in combination, on ICAM-1 expression by an uninfected and HRV-infected bronchial epithelial cell line H292. Cytokines known to be released soon after viral infection, such as tumour necrosis factor-alpha (TNF-α), IL-1β and the chemokine IL-8 increase ICAM-1 expression on uninfected cells. Epithelial cells infected with live HRV-14 displayed marked up-regulation of ICAM-1 compared with baseline. TNF-α further enhanced the HRV-induced increase in ICAM-1 expression on epithelial cells, peaking at day 4 after infection, whilst IL-8 exhibited a steady increase in ICAM-1 expression over 14 days. In contrast, IFN-γ, a known Th1 antiviral lymphokine, whilst increasing the level of ICAM-1 on uninfected cells, induced a significant persistent down-regulation of ICAM-1 expression on HRV-infected epithelial cells. With combinations of TNF-α and IFN-γ, ICAM-1 expression on HRV-infected cells was reduced to basal levels. The effects of IFN-γ were paralleled by a reduction in viral titres. Our in vitro model has provided useful insights into the early pathogenic events of HRV infection at the level of the host cell–virus interaction. Our data confirm that biological mediators play a crucial role in the pathogenesis as well as the course of HRV infection which is modulated by the types, and time kinetics of inflammatory cytokines in the immediate microenvironment.

Background. The pathogenesis of chronic rejection likely involves an interplay between immunogenic and nonimmunogenic factors. The objective of this study was to determine the influence of cold ischemic preservation injury on the rate of progression to chronic rejection in the Lewis to F344 cardiac allograft model. Methods. To induce an ischemic injury, donor hearts were stored for 3 hr at 4°C in University of Wisconsin solution before transplantation. Allografts were excised at 1, 7, and 90 days after transplantation or at rejection. Vasculopathy was graded for degree of inti-mal thickening based on the involvement of vascular perimeter and luminal compromise. Results. The degree of vessel injury in ischemic injured allografts at 90 days was significantly greater than in nonischemic injured allografts (2.8±0.4 vs. 1.6±0.5, P