An indicator of freeze-kill damages to fruit trees during flowering.

This paper demonstrates the use of climatological data and published information to develop a thaw-freeze/freeze-kill indicator for fruit trees during flowering. In fruit-producing regions, when budding and flowering occur before the last spring freeze, a freeze-kill event can cause substantial losses. As spring onset is occurring earlier with climate change, thaw-freeze events have the potential to become more of a hazard both in terms of current production and in terms of potential adaptation strategies. To model the spring thaw-freeze and its magnitude or intensity, we proposed an indicator based on the accumulation of daily minimum temperature between successive freezing dates and its maximum value over the spring. This indicator was tested on apple and peach production in southern Ontario, Canada, using data from eight climate stations in southern Ontario. The indicator showed promise in its utility in that its magnitude was greater when freezing occurred after blooming and it was demonstrated to be correlated to the estimated blooming dates of apple and peach fruits grown in southern Ontario. The annual series was shown to fit the generalized extreme value distribution thereby allowing the extreme risk to be modelled and the return period to be calculated. It was also shown that the reported thaw-freeze events that caused significant apple and peach losses had a return period on the order of 10 years.

Carbon footprint of Canadian dairy products: calculations and issues.

The Canadian dairy sector is a major industry with about 1 million cows. This industry emits about 20% of the total greenhouse gas (GHG) emissions from the main livestock sectors (beef, dairy, swine, and poultry). In 2006, the Canadian dairy herd produced about 7.7 Mt of raw milk, resulting in about 4.4 Mt of dairy products (notably 64% fluid milk and 12% cheese). An integrated cradle-to-gate model (field to processing plant) has been developed to estimate the carbon footprint (CF) of 11 Canadian dairy products. The on-farm part of the model is the Unified Livestock Industry and Crop Emissions Estimation System (ULICEES). It considers all GHG emissions associated with livestock production but, for this study, it was run for the dairy sector specifically. Off-farm GHG emissions were estimated using the Canadian Food Carbon Footprint calculator, (cafoo)(2)-milk. It considers GHG emissions from the farm gate to the exit gate of the processing plants. The CF of the raw milk has been found lower in western provinces [0.93 kg of CO2 equivalents (CO2e)/L of milk] than in eastern provinces (1.12 kg of CO2e/L of milk) because of differences in climate conditions and dairy herd management. Most of the CF estimates of dairy products ranged between 1 and 3 kg of CO2e/kg of product. Three products were, however, significantly higher: cheese (5.3 kg of CO2e/kg), butter (7.3 kg of CO2e/kg), and milk powder (10.1 kg of CO2e/kg). The CF results depend on the milk volume needed, the co-product allocation process (based on milk solids content), and the amount of energy used to manufacture each product. The GHG emissions per kilogram of protein ranged from 13 to 40 kg of CO2e. Two products had higher values: cream and sour cream, at 83 and 78 kg of CO2e/kg, respectively. Finally, the highest CF value was for butter, at about 730 kg of CO2e/kg. This extremely high value is due to the fact that the intensity indicator per kilogram of product is high and that butter is almost exclusively fat. Protein content is often used to compare the CF of products; however, this study demonstrates that the use of a common food component is not suitable as a comparison unit in some cases. Functionality has to be considered too, but it might be insufficient for food product labeling because different reporting units (adapted to a specific food product) will be used, and the resulting confusion could lead consumers to lose confidence in such labeling. Therefore, simple units might not be ideal and a more comprehensive approach will likely have to be developed.

Influence of two management practices in the Canadian Prairies on radiative forcing.

Surface albedo and soil carbon sequestration are influenced by agricultural management practices which impact the Earth's radiation budget and climate change. In this study we investigate the impact of reduced summer fallowing and reduced tillage in the Canadian Prairies on climate change by estimating the change in radiative forcing due to albedo and soil carbon sequestration. Seasonal variations of albedo, which are dependent on agricultural management practices and soil colour in three soil zones, were derived from 10-day composite 250-m Moderate Resolution Imaging Spectroradiometer (MODIS) data. Using this information, we found an overall increase of surface albedo due to the conversion from summer fallowing to continuous cropping and from conventional tillage (CT) to either no-tillage (NT) or reduced tillage (RT). The increase was dependent on soil brightness, type of vegetation and snow cover. Using data from the Census of Agriculture and taking into consideration both albedo and soil carbon changes, we estimated that from 1981 to 2016, the total radiative forcing for the cropland area in the Canadian Prairies was -405 µW m-2 due to the conversion of CT to either NT or RT and about 70% was due to the change in albedo. During the same period, the total radiative forcing was -410 µW m-2 due to a reduction in the area under summer fallow and about 62% was due to the change in albedo. The equivalent atmospheric CO2 drawdown from these two management changes from albedo change was about 7.8 and 8.7 Tg CO2 yr-1, respectively. These results demonstrate that it is important to consider both the changes of soil carbon and surface albedo in evaluating climate change impacts due to agricultural management practices.

Assessing the effects of manure application rate and timing on nitrous oxide emissions from managed grasslands under contrasting climate in Canada.

It is uncertain whether process-based models are currently capable of simulating the complex soil, plant, climate, manure management interactions that influence soil nitrous oxide (N2O) emissions from perennial cropping systems. The objectives of this study were (1) to calibrate and evaluate the DeNitrification DeComposition (DNDC) model using multi-year datasets of measured nitrous oxide (N2O) fluxes, soil moisture, soil inorganic nitrogen, biomass and soil temperature from managed grasslands applied with manure slurry in contrasting climates of Canada, and (2) to simulate the impact of different manure management practices on N2O emissions including slurry application i) rates (for both single vs. split); and ii) timing (e.g., early vs. late spring). DNDC showed "fair" to "excellent" performance in simulating biomass (4.7% ≤ normalized root mean square error (NRMSE) ≤ 29.8%; -9.5% ≤ normalized average relative error (NARE) ≤ 16.1%) and "good" performance in simulating soil temperature (13.2% ≤ NRMSE ≤ 18.1%; -0.7% ≤ NARE ≤ 10.8%) across all treatments and sites. However, the model only showed "acceptable" performances in estimating soil water and inorganic N contents which was partially attributed to the limitation of a cascade water sub-model and inaccuracies in simulating root development/uptake. Although, the DNDC model only demonstrated "fair" performance in simulating daily N2O fluxes, it generally captured the impact of the timing and rate of slurry application and soil texture (loam vs. sandy loam) on total N2O emissions. The DNDC model simulated N2O emissions from spring better than split manure application (fall and spring) at the Manitoba site partially due to the overestimation of available substrates for microbial denitrification from fall application during the wet spring periods. Although DNDC performed adequately for simulating most of the manure management impacts considered in this study we recommend improvements in the simulation of soil freeze-thaw cycles, manure decomposition dynamics, soil water storage, rainfall canopy interception, and microbial denitrification and nitrification activities in grasslands.

Aircraft monitoring of surface carbon dioxide exchange.

Aircraft-mounted sensors were used to measure the exchange of carbon dioxide above a cornfield, a forest, and a lake under midday conditions. Mean absorption values of 3400, 1200, and 100 milligrams of carbon dioxide per square meter per hour, respectively, are consistent with reported ground-based observations of carbon dioxide flux. Such information, gathered by aircraft, could be used to provide a quantitative evaluation of source and sink distributions of carbon dioxide in the biosphere, to establish a correlation between satellite data and near-surface measurements, and to monitor crop performance.

Mefloquine (WR 142,490) in the treatment of human malaria.

Mefloquine hydrochloride, a new 4-quinolinemethanol, was administered as a single oral dose to 47 volunteers infected with malaria. Treatment resulted in rapid clearence of fever and parasitemia. No recrudescence of parasites was observed after treatment of chloroquine-sensitive infections of Plasmodium falciparum. More significantly, in nonimmune persons with chloroquine-resistant infections, 1 gram of mefloquine cured 10 of 12 patients and 1.5 grams cured all 8 patients who received this dose of the drug. The marked activity of a single dose of mefloquine against chloroquine-resistant strains of Plasmodium falciparum suggests that this agent may be more useful than currently available drugs are for the treatment of drug-resistant malaria.

The proprotein convertase PC1/3 regulates TLR9 trafficking and the associated signaling pathways.

Endosomal TLR9 is considered as a potent anti-tumoral therapeutic target. Therefore, it is crucial to decipher the mechanisms controlling its trafficking since it determines TLR9 activation and signalling. At present, the scarcity of molecular information regarding the control of this trafficking and signalling is noticeable. We have recently demonstrated that in macrophages, proprotein convertase 1/3 (PC1/3) is a key regulator of TLR4 Myd88-dependent signalling. In the present study, we established that PC1/3 also regulates the endosomal TLR9. Under CpG-ODN challenge, we found that PC1/3 traffics rapidly to co-localize with TLR9 in CpG-ODN-containing endosomes with acidic pH. In PC1/3 knockdown macrophages, compartmentalization of TLR9 was altered and TLR9 clustered in multivesicular bodies (MVB) as demonstrated by co-localization with Rab7. This demonstrates that PC1/3 controls TLR9 trafficking. This clustering of TLR9 in MVB dampened the anti-inflammatory STAT3 signalling pathway while it promoted the pro-inflammatory NF-kB pathway. As a result, macrophages from PC1/3 KO mice and rat PC1/3-KD NR8383 macrophages secreted more pro-inflammatory cytokines such as TNF-α, IL6, IL1α and CXCL2. This is indicative of a M1 pro-inflammatory phenotype. Therefore, PC1/3 KD macrophages represent a relevant mean for cell therapy as "Trojan" macrophages.

Influence of chronic obstructive lung disease on the disposition of an acidic drug (sulfamethazine).

The influence of chronic respiratory failure (CRF) on the pharmacokinetics of an acidic drug has been studied in 11 patients and in eight normal volunteers who received 10 mg/kg of oral sulfamethazine. Blood and urine samples were collected for 24 and 48 hours, respectively. No differences were observed in the rate of sulfamethazine absorption, but bioavailability was decreased when compared with control subjects. Sulfamethazine volume of distribution (Vd) was larger in patients than in control subjects. These differences in Vd may be secondary to an increase in sulfamethazine unbound fraction. No differences were observed in sulfamethazine elimination. It is concluded that in patients with CRF sulfamethazine bioavailability decreases, and Vd increases secondary to a decrease in binding. Despite the fact that plasma concentrations of the test drug will be decreased, the administration of higher doses may not be advisable.

Metabolic clearance and production rates of 3,3',5-triiodothyronine in hyperthyroid, euthyroid, and hypothyroid subjects.

To further elucidate the peripheral metabolism of rT3 and to determine if rT3 production rates vary directly with thyroid function, we measured the disappearance of [125I]rT3 in thyrotoxic and hypothyroid subjects as well as in athyreotic patients maintained eumetabolic on exogenous T4. Kinetic parameters were determined by noncompartmental analysis, and serum concentrations of rT3 and T4 were determined by specific RIAs. In six hyperthyroid, seven euthyroid, and six hypothyroid subjects, the MCRs were 190.7 +/- 15.7, 111.7 +/- 13.2, and 71.8 +/- 7.0 liters/day kg, respectively (mean +/- SE). Production rates (PR) for these same groups were 271.3 +/- 40.5, 51.7 +/- 9.1, and 4.3 +/- 0.6 micrograms/day/70 kg. The observed differences in MCR and PR among the three study groups were highly significant (P less than 0.002). These data indicate that in comparison to euthyroid subjects, rT3 PR and MCR are increased in thyrotoxic and decreased in hypothyroid individuals.

The method of separate exponentials: a simple aid to devising intravenous drug-loading regimens.

Stimulation of complex dosage regimens for drugs with multicompartmental kinetics is described using the method of separate exponentials. This approach requires that alpha- and beta-phases are treated separately throughout and summed only at the end of the stimulation. The method was used to devise a loading regimen for pirmenol, comprising a priming injection, and a rapid loading infusion, followed by a maintenance infusion. The regimen was tested in a patient with excellent agreement. The method of separate exponentials is mathematically simple and of informational value in that it demonstrates when the early distribution phase is important. Its use can avoid the potentially dangerous assumption of one-compartmental kinetics in the design of intravenous loading regimens.

Pharmacokinetics and metabolism of allopurinol riboside.

There are no safe and effective oral drugs to treat leishmaniasis and Chagas' disease. The safety, pharmacokinetics, and metabolism of single and multiple oral doses of allopurinol riboside, an investigational antiparasitic agent, were evaluated in a randomized, double-blinded, placebo-controlled study in 32 healthy male volunteers, at levels up to 25 mg/kg q.i.d. for 13 doses. No significant toxicity was detected. Allopurinol riboside peaks in plasma 1.6 hours after administration, has an elimination half-life of 3 hours, and steady-state concentrations in the therapeutic range. However, in contrast to preclinical studies in dogs (plasma levels proportional to oral doses up to 200 mg/kg), we found that plasma levels were unexpectedly low and did not rise with increasing dose. Furthermore, allopurinol and oxypurinol (unanticipated metabolites) were detected at levels proportional to the dose of allopurinol riboside. We present a model that includes incomplete absorption, metabolism of residual drug by enteric flora, and absorption of bacterial metabolites to explain these findings in humans.

Acute epiglottitis in children-treatment with nasotracheal intubation: report of 14 consecutive cases.

Fourteen consecutive cases of acute epiglottitis were treated by nasotracheal intubation during a ten-month period. The duration of intubation averaged 47.2 hours. No mortality or morbidity occurred. Mean hospitalization was 4.6 days. This study demonstrates the ease of maintaining an assured airway by nasotracheal intubation in cases of acute epiglottitis.

Dental implants: tissue-integrated prosthesis utilizing the osseointegration concept.

As an alternative to conventional removable dentures, osseointegrated dental implants can now be used in carefully selected edentulous or partially edentulous patients. The implant consists of a dental prosthesis and an anchorage unit made up of screw-connected components. The implantation procedure is performed in two phases: fixture installation and fixture uncovering and abutment connection. After completion of these surgical procedures, the dental prosthesis is fabricated and inserted. Follow-up examinations are scheduled at 1, 3, and 6 months and then annually thereafter. During a 2-year period at the Mayo Clinic, 358 osseointegrated dental fixtures were implanted in 70 patients. The overall success rate in this consecutive series of patients was 98%, and the associated complications were minimal and easily resolved.

Safety profile of cefixime.

The clinical and laboratory safety of cefixime based on analysis of data from 1575 adults (1118 treated daily and 457 treated twice a day) and 615 children (299 treated daily and 316 treated twice a day) in studies of urinary tract and lower and upper respiratory tract infections (including otitis media) is reviewed. The incidence of adverse clinical experiences and occurrence of laboratory abnormalities were similar to those seen with other beta-lactam antimicrobial agents. Gastrointestinal side effects were the predominant adverse experiences seen in both daily and twice daily programs in adults and children. The incidence of gastrointestinal intolerance was not dependent upon the frequency of the dosage. Symptoms of drug hypersensitivity were infrequently reported. No serious chemical, hematologic or urologic abnormalities were noted. The data confirm the safety of cefiximine in both adults and children, whether it is administered once or twice a day.

Measuring temporal resolution in infants using mismatch negativity.

We show that the mismatch negativity (MMN) component of the event-related potential can be used to measure auditory temporal resolution in human infants. Infrequent stimuli with silent gaps of 4, 8, or 12 ms modulated the P2 component, generated MMN, and produced a P3a-like positivity. The data indicate that within-channel gap detection thresholds at 6 months are essentially at adult levels under conditions of little adaptation. Since MMN is elicited without attention and does not require a behavioural response, it can be measured similarly across the lifespan. We are now in a position to study the development of cross-channel temporal resolution and adaptation effects in infancy, and to examine how these abilities in infancy relate to later language acquisition.

Using mismatch negativity to measure auditory temporal resolution thresholds.

It has been hypothesized that poor auditory temporal resolution is related to language-learning problems in children as well as problems with speech perception in noise in the elderly. We show that the presence of occasional silent gaps between short tone pips elicits mismatch negativity (MMN) in young adults. We also measured gap-detection thresholds with MMN that agree well with behavioural thresholds. Near threshold, the MMN increases as the gap size increases millisecond by millisecond. The MMN methodology for measuring temporal resolution is not only robust, but can be applied identically across the life span as it does not require the attention of participants or a behavioural response. We are now in a position to examine temporal resolution in infancy.

Use of non-human plasma for in vitro cultivation and antimalarial drug susceptibility testing of Plasmodium falciparum.

Viability, growth rate, and chemotherapeutic susceptibility of the CDC/Indochina III, CDC/Sierra Leone I, and FCR-3 (Subline F-86) isolates of Plasmodium falciparum grown continuously in RPMI 1640 medium supplemented with goat, horse, porcine, bovine, or ovine plasma were evaluated. Results were compared to those obtained from parallel cultures maintained in medium supplemented with non-immune human plasma. Only media supplemented with goat or horse plasma supported significant continuous multiplication of the isolates. Medium supplemented with either ovine or porcine plasma supported continuous multiplication of the CDC/Indochina III isolate, but not the FCR-3 isolate. Medium supplemented with bovine plasma did not support continuous growth of any of the isolates tested. The light microscopic appearance of the isolates during and after continuous culture in medium supplemented with either goat or horse plasma was identical to that of the control parasites maintained in medium supplemented with human plasma. There were no statistically significant differences in the susceptibility to antimalarial drugs of the culture lines maintained in medium supplemented with either human or goat plasma.

Evaluation of the antimalarial activity of the phenanthrenemethanol halofantrine (WR 171,669).

Halofantrine (WR 171,669) was administered to 27 nonimmune subjects infected with the multi-drug resistant Vietnam Smith strain of Plasmodium falciparum. It was also administered to three other subjects, one infected with the Cambodian Buchanan strain of P. falciparum, and two with blood-induced infection with the Chesson strain of P. vivax. It cured infections with all three parasites. Against the highly chloroquine-resistant Smith strain, it was curative in single day treatment regimens. The drug was well tolerated and produced rapid clearance of parasitemia in every case.

Dose proportionality of bisoprolol enantiomers in humans after oral administration of the racemate.

Dose proportionality of racemic bisoprolol and the stereoselectivity of its enantiomers were studied after single oral dosing of 5 to 40 mg of bisoprolol hemifumarate in eight healthy male volunteers in an open-label, randomized, four-way cross-over trial. There were dose-proportional increases in mean peak plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) values for the racemate and the individual enantiomers. No statistically significant differences were detected between the mean half life (t 1/2), Cmax, and time to reach Cmax (tmax) of the R- and S-isomers at each of the four dose levels studied. These findings support dose proportionality and absence of stereoselective pharmacokinetics for bisoprolol in the dose range studied.

Importance of oral dosing rate on the hemodynamic and pharmacokinetic profile on nilvadipine.

Nilvadipine was administered as an oral solution formulation to 12 normotensive subjects in a three-way randomized crossover study at a dose of 16 mg as three different dosing regimens: 1) as a single 16 mg dose, 2) as a 1.6 mg dose given hourly for 10 doses, and 3) as an initial dose of 4.8 mg, followed by 1.6 mg doses given every hour for seven additional doses. After each dose, clinical effects, hemodynamic changes and the pharmacokinetic profile of the drug were determined. The mean maximum changes in diastolic (DBP) and systolic (SBP) blood pressure and heart rate (HR) after dosing regimens 1, 2, and 3 were: -33, -13 and +46%; -17, -14 and +38%; and -24, -14 and +36%, respectively. There was a relationship between the changes in DBP and HR and plasma concentrations of nilvadipine only after dosing regimen 1. The effect-concentration relationships were fit to a modified Emax model. There was no relationship between the change in SBP and plasma concentration after any of the dosing regimens. While there were no significant differences in the mean area under the plasma concentration-time curve (AUC0----infinity) between dosing regimens 2 (38.7 ng.hr/mL) and 3 (42.1 ng.hr/mL) (P greater than 0.05), the mean AUC0----infinity after regimen 1 (76.3 ng.hr/mL) was significantly greater than after dosing regimens 2 or 3 (P less than 0.05). The mean maximal plasma concentrations (Cmax) were 31.6, 1.3 and 6.3 ng/mL after dosing regimens 1, 2 and 3, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)