Quantifying the influence of short-term emission reductions on climate.

The COVID-19 (coronavirus disease 2019) pandemic has resulted in a marked slowdown in greenhouse gas and aerosol emissions. Although the resulting emission reductions will continue to evolve, this will presumably be temporary. Here, we provide estimates of the potential effect of such short-term emission reductions on global and regional temperature and precipitation by analyzing the response of an Earth System Model to a range of idealized near-term emission pathways not considered in available model intercomparison projects. These estimates reveal the modest impact that temporary emission reductions associated with the COVID-19 pandemic will have on global and regional climate. Our simulations suggest that the impact of carbon dioxide and aerosol emission reductions is actually a temporary enhancement in warming rate. However, our results demonstrate that even large emission reductions applied for a short duration have only a small and likely undetectable impact.

Attribution of the Influence of Human-Induced Climate Change on an Extreme Fire Season.

A record 1.2 million ha burned in British Columbia, Canada's extreme wildfire season of 2017. Key factors in this unprecedented event were the extreme warm and dry conditions that prevailed at the time, which are also reflected in extreme fire weather and behavior metrics. Using an event attribution method and a large ensemble of regional climate model simulations, we show that the risk factors affecting the event, and the area burned itself, were made substantially greater by anthropogenic climate change. We show over 95% of the probability for the observed maximum temperature anomalies is due to anthropogenic factors, that the event's high fire weather/behavior metrics were made 2-4 times more likely, and that anthropogenic climate change increased the area burned by a factor of 7-11. This profound influence of climate change on forest fire extremes in British Columbia, which is likely reflected in other regions and expected to intensify in the future, will require increasing attention in forest management, public health, and infrastructure.

Incorporating model quality information in climate change detection and attribution studies.

In a recent multimodel detection and attribution (D&A) study using the pooled results from 22 different climate models, the simulated "fingerprint" pattern of anthropogenically caused changes in water vapor was identifiable with high statistical confidence in satellite data. Each model received equal weight in the D&A analysis, despite large differences in the skill with which they simulate key aspects of observed climate. Here, we examine whether water vapor D&A results are sensitive to model quality. The "top 10" and "bottom 10" models are selected with three different sets of skill measures and two different ranking approaches. The entire D&A analysis is then repeated with each of these different sets of more or less skillful models. Our performance metrics include the ability to simulate the mean state, the annual cycle, and the variability associated with El Niño. We find that estimates of an anthropogenic water vapor fingerprint are insensitive to current model uncertainties, and are governed by basic physical processes that are well-represented in climate models. Because the fingerprint is both robust to current model uncertainties and dissimilar to the dominant noise patterns, our ability to identify an anthropogenic influence on observed multidecadal changes in water vapor is not affected by "screening" based on model quality.

Identification of human-induced changes in atmospheric moisture content.

Data from the satellite-based Special Sensor Microwave Imager (SSM/I) show that the total atmospheric moisture content over oceans has increased by 0.41 kg/m(2) per decade since 1988. Results from current climate models indicate that water vapor increases of this magnitude cannot be explained by climate noise alone. In a formal detection and attribution analysis using the pooled results from 22 different climate models, the simulated "fingerprint" pattern of anthropogenically caused changes in water vapor is identifiable with high statistical confidence in the SSM/I data. Experiments in which forcing factors are varied individually suggest that this fingerprint "match" is primarily due to human-caused increases in greenhouse gases and not to solar forcing or recovery from the eruption of Mount Pinatubo. Our findings provide preliminary evidence of an emerging anthropogenic signal in the moisture content of earth's atmosphere.

Forced and unforced ocean temperature changes in Atlantic and Pacific tropical cyclogenesis regions.

Previous research has identified links between changes in sea surface temperature (SST) and hurricane intensity. We use climate models to study the possible causes of SST changes in Atlantic and Pacific tropical cyclogenesis regions. The observed SST increases in these regions range from 0.32 degrees C to 0.67 degrees C over the 20th century. The 22 climate models examined here suggest that century-timescale SST changes of this magnitude cannot be explained solely by unforced variability of the climate system. We employ model simulations of natural internal variability to make probabilistic estimates of the contribution of external forcing to observed SST changes. For the period 1906-2005, we find an 84% chance that external forcing explains at least 67% of observed SST increases in the two tropical cyclogenesis regions. Model "20th-century" simulations, with external forcing by combined anthropogenic and natural factors, are generally capable of replicating observed SST increases. In experiments in which forcing factors are varied individually rather than jointly, human-caused changes in greenhouse gases are the main driver of the 20th-century SST increases in both tropical cyclogenesis regions.

Applications of immunohistochemistry in the evaluation of immunosuppressive agents.

Immunohistochemistry (IHC) can be a valuable endpoint to evaluate lymphocyte subpopulations in tissues following exposure to presumptive immunosuppressive agents. IHC is more sensitive than conventional histology in detecting subtle differences in lymphocyte numbers and distribution in tissue. In combination with flow cytometric analysis of peripheral lymphocyte subpopulations, IHC can determine if alterations detected in the peripheral blood are a result of trafficking or reflective of changes in tissue distribution. These techniques can be used to evaluate adult animals as well as to evaluate the effects of immunosuppressive agents on fetal tissues in reproductive toxicology studies. While IHC can enhance the detection of subtle changes in lymphocyte subpopulations in tissue, the evaluation of additional endpoints of immune function must be done to further assess the biological or clinical significance of these changes.

Evaluation of the renal effects of an antisense phosphorothioate oligodeoxynucleotide in monkeys.

Antisense phosphorothioate oligodeoxynucleotides are therapeutic agents that provide target specificity resulting from Watson-Crick base pairing. However, there are nonspecific effects that in some instances result in toxicity. These compounds accumulate in the kidney and induce renal proximal tubular degeneration at high doses. The relationship between accumulation of phosphorothioate oligodeoxynucleotides in the kidney, indicators of renal toxicity, and histomorphology were investigated in rhesus monkeys. Monkeys received vehicle or an escalating dose regimen of 3, 10, 40, and 80 mg/kg of ISIS 2105 and were then evaluated for changes in clinical pathology indices, urinalysis parameters, and renal histopathology. Urinalysis revealed an increase in protein levels and a slight increase in blood content following the third 40 mg/kg dose and continuing through the 80 mg/kg doses, whereas other urinary markers of renal toxicity were unchanged. Creatinine clearance was slightly decreased in monkeys during the 80 mg/kg dose cycle. Granulation in the cytoplasm of proximal tubular epithelial cells was evident by microscopic examination of kidney and was present at all doses examined and increased with dose. Immunohistochemical staining localized the oligodeoxynucleotide within these granules. Histopathologic changes consisting of minimal to moderate tubular degeneration were present only at the higher doses of 40 and 80 mg/kg and at high tissue concentrations, and these changes occurred concurrent with functional alterations, whereas lower doses (< or = 10 mg/kg) did not affect a pathologic or functional change.

Molecular pathology in the preclinical development of biopharmaceuticals.

Advances in cell and molecular biology have engendered a wide range of techniques that can be used to study the molecular events that underlie the cause of disease, thus producing a new field of study called "molecular pathology." These techniques can be either slide-based or non-slide-based (solution-based). The slide-based techniques include immunohistochemistry, in situ hybridization, and in situ polymerase chain reaction; pathologists play a unique role in the administration of these techniques because of their ability to interpret the end product (i.e., the slide). In this manuscript, we briefly discussed the use and impact of these slide-based techniques within all phases of drug development in the pharmaceutical industry.

Correlation of toxicity and pharmacokinetic properties of a phosphorothioate oligonucleotide designed to inhibit ICAM-1.

ISIS 2302 is a phosphorothioate oligodeoxynucleotide with a sequence complementary to the mRNA of human intercellular adhesion molecule 1 (ICAM-1). Hybridization of ISIS 2302 to the mRNA inhibits expression of the ICAM-1 protein in response to inflammatory stimuli. A murine active antisense oligonucleotide, ISIS 3082, has been used for in vivo pharmacology studies and has anti-inflammatory activity in models of organ transplant rejection, ulcerative colitis, and collagen-induced arthritis at doses ranging from 0.03 to 5 mg/kg. The safety assessment for ISIS 2302 includes general toxicity studies up to 6 mo in duration in mice and monkeys, genetic toxicity studies, and reproductive/fertility studies. ISIS 3082 was examined in parallel with ISIS 2302 in mouse toxicity and reproductive studies. The toxicities observed following systemic administration of ISIS 2302 and ISIS 3082 were similar and consistent with those observed for other compounds in this chemical class and, therefore, are independent of the suppression of ICAM-1 expression. Toxicokinetic evaluation demonstrated that toxicities occurred in organs containing the highest concentrations of ISIS 2302. Evidence of immune stimulation. including dose-dependent splenomegaly, lymphoid hyperplasia, and multiorgan mixed mononuclear cell infiltrates, was the most common finding in rodent studies. Monkeys were much less sensitive than mice to immune stimulation. Kidney contained the highest concentrations of ISIS 2302. Morphologic changes observed in kidney included atrophic and regenerative changes in proximal tubular epithelium; however, there was no evidence of functional abnormalities. Additional histologic changes noted in proximal tubular epithelium included basophilic granules, which were reflective of oligonucleotide distribution and uptake in these cells. Liver also contained high concentrations of oligonucleotide, which were associated with Kupffer cell hypertrophy in mice. Changes in serum transaminases, cholesterol, and triglycerides were reflective of hepatic alterations. In monkeys, high concentrations of oligonucleotide caused a transient increase in clotting times and activation of the alternative complement pathway. All toxicities associated with ISIS 2302 were reversible and occurred at doses well above those required for pharmacologic activity or currently used in clinical trials. In addition, there has been no evidence of genetic toxicity associated with ISIS 2302, and no changes in reproductive performance, fertility, or fetal development have been noted in animals treated with ISIS 2302 or ISIS 3082.

Dose responses from inhaled monodisperse aerosols of 244Cm2O3 in the lung, liver and skeleton of F344 rats and comparison with 239PuO2.

The purpose of this study was to obtain information on the alpha-particle dose-response relationship of 244Cm in rats. Rats were exposed briefly by inhalation to graded levels of monodisperse aerosols of 244Cm2O3 heat-treated at 1150 degrees C. The initial lung burden (ILB) of each animal was determined by the use of the gamma-ray-emitting radionuclide 243Cm in the aerosols. Seven groups of 84-day-old F344/Crl rats (a total of 637 males and 645 females) were exposed once to 244Cm2O3 or sham-exposed to filtered ambient air. Mean ILBs of all rats per group ranged from 0.51 +/- 0.17 (+/-SD) to 240 +/- 82 kBq kg-1 body weight. Mean lifetime alpha-particle doses to the lungs per group ranged from 0.20 +/- 0.069 (+/-SD) to 36 +/- 6.5 Gy. After death, each rat was radiographed and necropsied. Dose-related increases occurred in incidences of benign and malignant lung neoplasms, except for the groups of rats with higher mean ILBs that were examined histologically (98 +/- 18 and 240 +/- 77 kBq kg-1 body weight) in which survival was markedly decreased. Also, average alpha-particle doses of 0.0014 +/- 0.00058 (+/-SD) to 0.17 +/- 0.091 Gy and 0.18 +/- 0.007 to 1.6 +/- 1.1 Gy were also absorbed by the liver and skeleton, respectively, in the rats in the different exposure groups. Primary liver neoplasms occurred in several rats. However, the incidence of these lesions was not related to dose. Increased incidences of bone neoplasms occurred only in rats receiving higher doses to the skeleton. Excess numbers of rats with lung neoplasms per 10(4) Gy to the lung per group ranged from 760 +/- 430 (+/- SE) at a mean dose of 0.48 Gy to 84 +/- 16 at a mean dose of 37 Gy. Risk factors for the lowest and highest ILB kg-1 body weight groups were not considered reliable because of large errors associated with these calculations and the life-span shortening in the highest ILB kg-1 group. Inhaled 244Cm2O3 appeared to be about 50% less effective as a lung carcinogen in rats compared to 239PuO2 at similar doses.

Porcine and bovine cartilage transplants in cynomolgus monkey: I. A model for chronic xenograft rejection.

Transplantation of discordant xenograft tissues usually results in antibody-mediated hyperacute rejection response. It has been speculated that because cartilage has a limited vascular, neural, and lymphatic supply, it might be immunologically privileged and may not undergo hyperacute or chronic rejection. Moreover, porcine and bovine cartilage were found to express very low amounts of alpha-galactosyl epitopes (Gal alpha1-3Gal beta1-4GlcNAc-R). To evaluate animal cartilage for possible human transplantation, xenograft meniscal cartilage was transplanted from pigs and cows into the suprapatellar pouches of six cynomolgus monkeys (group 1). In a second group of six monkeys (group 2), porcine meniscal cartilage and porcine articular cartilage plugs were evaluated. During the 2-month evaluation period in group 1, all monkeys displayed an extensive humoral response to the xenograft, as indicated by the increase in production of antibodies against bovine and porcine cartilage. Upon explant, all meniscal cartilage samples in this group demonstrated histological evidence of chronic rejection, including fibroplasia, encapsulation, mononuclear infiltrates, foreign body giant cells, and eosinophilic infiltrates. There was no difference between the response seen in untreated tissues and that seen in tissues treated with UV irradiation or ozone oxidation. In group 2, the menisci explanted after 1 month displayed extensive infiltration of eosinophils alone or eosinophils mixed with mononuclear cells. The mononuclear infiltrates consisted primarily of CD4+ and CD8+ T cells and of macrophages. The articular cartilage plugs demonstrated only a small area of fibrous encapsulation and leukocyte infiltration at the periphery. This study suggests that xenograft cartilage tissue does not appear to be immunoprivileged and is unsuitable for human implantation due to a chronic rejection mechanism, which is evident already within 1 month after transplantation. In addition, this study may serve as a general model for the primate immune response against xenografts in the absence of hyperacute rejection.

An experimental model of intracranial hemorrhage during thrombolytic therapy with t-PA.

Multiple clinical trials have proven that thrombolytic therapy is an effective treatment for acute myocardial infarction. Spontaneous intracranial hemorrhage (ICH) occurs in a small percentage of patients as a result of the treatment. The etiology of the ICH is unknown and there is currently no established experimental model for this side effect. A model of ICH during thrombolytic therapy has been developed using spontaneously hypertensive rats (SHR). The SHR were made susceptible to ICH during thrombolytic therapy by bilateral ligation of the external jugular veins. This procedure produced asymptomatic hemorrhagic lesions in the brains of the animals in the hours preceding the administration of t-PA/heparin. The incidence of ICH following the administration of test substances was assessed by histological examination and by measuring the red blood cell count in a sample of cerebrospinal fluid taken from the atlanto-occipital space. t-PA administration produced a low frequency of ICH in this model. The incidence and severity of ICH were dramatically increased, and significant mortality at 24h was observed, by combining heparin were administered sequentially rather than simultaneously. Furthermore, ICHs were observed whether the t-PA dose was administered over 4 h, 1 h, or as a double bolus 30 min apart. The potentiation of ICH by heparin was dose dependent and proportional to the prolongation of the aPTT. Although the precise mechanism of ICH during thrombolytic therapy is unknown, many similarities exist between the observations made in this model and in the human clinical experience.

Toxicity of inhaled plutonium dioxide in beagle dogs.

This study was conducted to determine the biological effects of inhaled 238PuO2 over the life spans of 144 beagle dogs. The dogs inhaled one of two sizes of monodisperse aerosols of 238PuO2 to achieve graded levels of initial lung burden (ILB). The aerosols also contained 169Yb to provide a gamma-ray-emitting label for the 238Pu inhaled by each dog. Excreta were collected periodically over each dog's life span to estimate plutonium excretion; at death, the tissues were analyzed radiochemically for plutonium activity. The tissue content and the amount of plutonium excreted were used to estimate the ILB. These data for each dog were used in a dosimetry model to estimate tissue doses. The lung, skeleton and liver received the highest alpha-particle doses, ranging from 0.16-68 Gy for the lung, 0.08-8.7 Gy for the skeleton and 0.18-19 for the liver. At death all dogs were necropsied, and all organs and lesions were sampled and examined by histopathology. Findings of non-neoplastic changes included neutropenia and lymphopenia that developed in a dose-related fashion soon after inhalation exposure. These effects persisted for up to 5 years in some animals, but no other health effects could be related to the blood changes observed. Radiation pneumonitis was observed among the dogs with the highest ILBs. Deaths from radiation pneumonitis occurred from 1.5 to 5.4 years after exposure. Tumors of the lung, skeleton and liver occurred beginning at about 3 years after exposure. Bone tumors found in 93 dogs were the most common cause of death. Lung tumors found in 46 dogs were the second most common cause of death. Liver tumors, which were found in 20 dogs but were the cause of death in only two dogs, occurred later than the tumors in bone and lung. Tumors in these three organs often occurred in the same animal and were competing causes of death. These findings in dogs suggest that similar dose-related biological effects could be expected in humans accidentally exposed to 238PuO2.

Expression of the genes encoding the rat renal insulin-like growth factor-I system.

Insulin-like growth factor-I (IGF-I) modulates renal function, growth, and repair. IGF-I produced in the kidney is one component of the intrarenal IGF-I system comprising the IGF-I receptor (IGF-IR) and six IGF-binding proteins (IGFBP). Because of the physiologic importance of IGF-I and its potential therapeutic properties, the renal sites of mRNA synthesis for IGF-I, IGF-IR, and IGFBP-I through IGFBP-5 were characterized in rat kidney by in situ hybridization. Anatomical heterogeneity was prominent. IGF-I mRNA was present in the thick ascending limb of Henle in the outer medulla, whereas IGF-IR mRNA was diffusely present at low levels throughout the kidney. IGFBP-I mRNA was localized to cells within the distal convoluted tubules as well as the thick ascending limb of Henle. IGFBP-2 mRNA was expressed in glomeruli, medullary ray collecting ducts, pelvic smooth muscle and uroepithelium, and the papilla tip; IGFBP-3 mRNA was localized to the cortical interstitium, whereas IGFBP-4 mRNA was expressed in proximal tubules, medullary ray collecting ducts, and glomeruli. IGFBP-5 was strongly positive throughout the medulla with lesser expression in the distal convoluted tubules and glomeruli. This study highlights the complexity of the intrarenal IGF-I system. The striking heterogeneity of IGFBP gene expression suggests that the various IGFBP may have diverse modulatory effects on the action of IGF-I or discrete effects of their own.

Chemokine expression in rheumatoid arthritis (RA): evidence of RANTES and macrophage inflammatory protein (MIP)-1 beta production by synovial T cells.

Earlier studies from this laboratory provided evidence for restricted cytokine expression in the T cell population in RA tissues. Specifically, IL-2, IL-4, IL-6 and interferon-gamma (IFN-gamma) gene expression levels were low. The selective chemoattractant and activation effects of chemokines on leucocytes identify them as potentially ideal candidates in mediating selective inflammatory processes in RA. Accordingly, we undertook studies to examine constitutive chemokine gene expression in RA tissues. RANTES, monocyte chemotactic protein-1 (MCP-1) and MIP-1 beta gene expression was examined in both the T and non-T cell populations in RA peripheral blood (PB), synovial fluid (SF) and synovial tissues (ST). Our results identified elevated levels of both RANTES and MIP-1 beta gene expression in circulating RA PB and SF T cells. By contrast, MCP-1 expression was virtually absent in RA PB, yet elevated MCP-1 mRNA levels were detected primarily in the non-T cell populations of the SF and ST samples. Histological examination of affected rheumatoid joints revealed extensive RANTES and MIP-1 beta expression in sites of lymphocyte infiltration and cell proliferation, namely the synovial lining and sublining layers. Fractionation or RA ST patient samples revealed that RANTES expression was restricted to the T cells, whereas MIP-1 beta expression was detected in both T and non-T fractions. These data suggest that MCP-1, MIP-1 beta and RANTES may have a central role in the trafficking of reactive molecules involved in immunoregulation and in the inflammatory processes in RA.

Beneficial effects of growth hormone and insulin-like growth factor-1 in experimental heart failure in rats treated with chronic ACE inhibition.

The effects of growth hormone (GH) plus insulin-like growth factor-1 (IGF-1) were tested in an experimental model of cardiac failure treated with chronic angiotensin-converting enzyme (ACE) inhibition. Myocardial infarction was induced in rats by left coronary artery ligation. Two weeks after ligation, the animals received either captopril (2 g/L in drinking water) or water for 3 months. The rats were then given either GH (2 mg/kg/day) plus IGF-1 (2 mg/kg/day) or vehicle for 14 days. Captopril treatment decreased mean arterial pressure (MAP), left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance (SVR) (p < 0.05), and increased cardiac index (CI) and stroke volume index (SVI) (p < 0.05). GH/IGF-1 or captopril+GH/IGF-1 treatment decreased MAP, LVEDP, and SVR (p < 0.05), and increased left ventricular maximum dP/dt, CI, and SVI (p < 0.05). The increases in CI and SVI were significantly greater in the captopril+GH/IGF-1-treated animals than in those treated with captopril alone (p < 0.05). The beneficial effect of captopril in reducing cardiac hypertrophy was preserved in the captopril+GH/IGF-1 group. The results indicate that GH/IGF-1 and captopril can improve cardiac performance in congestive heart failure by independent and complementary mechanisms.

Growth hormone improves cardiac performance in experimental heart failure.

BACKGROUND: Growth hormone has been shown to increase maximum isometric active force of the left ventricular papillary muscle of rats in vitro. Administration of growth hormone causes an increase in myocardial contractility in normal humans. Our preliminary study suggests that treatment with growth hormone results in increased ventricular contractility in rats with left ventricular dysfunction. In the present study, the effects of growth hormone on cardiac function, including cardiac output, stroke volume, and peripheral vascular resistance, were determined in a rat model of heart failure. METHODS AND RESULTS: Ligation of the left coronary artery or sham operation was performed; 4 weeks after surgery, recombinant human growth hormone (2 mg/kg per day SC) or vehicle then was administered for 15 days. The animals were catheterized after 13 days of the treatment. Cardiac output, measured by a thermodilution method, and other hemodynamic parameters were measured in the conscious animals 2 days after catheterization. The infarct sizes induced by left coronary ligation were comparable between growth hormone-treated and vehicle-treated rats. Six weeks after ligation, rats treated with vehicle exhibited significant decreases in cardiac index, stroke volume index, and left ventricular maximum dP/dt and increases in left ventricular end-diastolic pressure compared with sham rats. In the ligated rats, treatment with growth hormone increased cardiac index, stroke volume index, and left ventricular maximum dP/dt (P < .05) and reduced left ventricular end-diastolic pressure and systemic vascular resistance (P < .05). In sham rats, growth hormone slightly reduced arterial pressure but did not significantly alter cardiac performance. There was no significant difference in heart rate between the experimental groups. CONCLUSIONS: These results suggest that growth hormone treatment may improve cardiac function by both increased myocardial contractility and decreased peripheral vascular resistance in heart failure.

Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis.

To investigate the relationship between angiogenesis and hepatic tumorigenesis, we examined the expression of vascular endothelial growth factor (VEGF) in 8 human colon carcinoma cell lines and in 30 human colorectal cancer liver metastases. Abundant message for VEGF was found in all tumors, localized to the malignant cells within each neoplasm. Two receptors for VEGF, KDR and flt1, were also demonstrated in most of the tumors examined. KDR and flt1 mRNA were limited to tumor endothelial cells and were more strongly expressed in the hepatic metastases than in the sinusoidal endothelium of the surrounding liver parenchyma. VEGF monoclonal antibody administration in tumor-bearing athymic mice led to a dose- and time-dependent inhibition of growth of subcutaneous xenografts and to a marked reduction in the number and size of experimental liver metastases. In hepatic metastases of VEGF antibody-treated mice, neither blood vessels nor expression of the mouse KDR homologue flk-1 could be demonstrated. These data indicate that VEGF is a commonly expressed angiogenic factor in human colorectal cancer metastases, that VEGF receptors are up-regulated as a concomitant of hepatic tumorigenesis, and that modulation of VEGF gene expression or activity may represent a potentially effective antineoplastic therapy in colorectal cancer.