text:
|Publication number
|Publication type
|Application number
|Publication date
|Feb 16, 1988
|Filing date
|Aug 5, 1985
|Priority date
|Nov 20, 1984
|Fee status
|Publication number
|Richard A. Callahan
|Original Assignee
|Vestar Research, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (10), Referenced by (21), Classifications (4), Legal Events (8)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a continuation of application Ser. No. 673,414, filed 11/20/84, abandoned. This is a continuation of application Ser. No. 407,922, filed Aug. 13, 1983 now abandoned.
This invention relates to apparatus and methods for determining physiological or metabolic status of an organism by measuring and comparing effects of applied metabolic stresses. More specifically, this invention includes an apparatus and a method for monitoring the adaptive control of oxygen consumption to measured changes in stress. Data presented in this invention indicate that monitoring this adaptive process is an efficient means of delimiting the metabolic capacity of the organism.
It has long been thought desirable to obtain a general measure of physical health by assessing the overall metabolic capability of an organism. Metabolic tests, for example, have been a part of standard physical examinations for presumably healthy individuals for years. In contrast to attempts to diagnose specific illnesses or dysfunctions, these measurements attempt to assess the efficiency and general integrity of the physiological systems of the organism as a whole. For example, in mammalian systems, the relationship of the respiratory, cardiopulmonary, and even endocrine systems, as well as their individual capacities and status, impacts on the overall well-being of the mammal. All organisms can be assumed to be in better or poorer health depending on the individual status and integration of a number of metabolic systems.
It is, of course, desirable to have available a method for quantification of what might loosely be called good or poor health or efficiency level for the organism. There is a particular interest in assessing the effects of externally imposed environmental factors on the organism and evaluating the effects of potentially toxic substances. It is now generally thought that certain environmental factors, such as, for example, poor air quality, certain chemicals, which are found as contaminants in food, water or air, and general dietary factors, which may produce effects which are not sufficiently acute to result in measurable specific symptoms except in isolated individuals, may, in fact, cause a general diminution of well being in the population as a whole. Also, it is clear that there are potential toxic effects of medications which are associated with only vague symptoms, such as moderate discomfort or nausea, which do not uniformly impact all members of the subject population. These seem not at present to be amenable to effective pretesting, because of a lack of a quantitative system of measuring impact on the overall organism. In addition, it would be desirable to test the direct effects of drugs at as low a dosage level as is possible, and to determine the physical condition of healthy animals and human beings.
The present invention provides for quantitative assessment of these factors by using adaptive respiratory capacity as a measure of overall metabolic status. The adaptive respiratory capacity of an organism is measured by ascertaining the rate of consumption of oxygen as a function of stress in various forms.
This method employs a respirometer of a design which, itself, represents an improvement over the presently available means for assessing oxygen uptake in subject organisms, and which has also a means for applying and varying stress to the subject organism. Many devices have been designed to monitor the respiratory rate of a subject while under situations of controlled environmental situations. However, devices which measure metabolic capacity by measuring the adaptive respiratory responses of organisms to sequentially applied quantitatively measured stresses do not exist. Since most respiratory monitoring devices communicate with ambient air, they do not readily facilitate reduced oxygen pressure as one possible form of environmental stress. For example, U.S. Pat. No. 3,401,683 to Webb discloses an apparatus wherein the subject wears a helmet which causes exhaled gases to be drawn into the monitoring device. Thus, if testing at reduced pO2 is desired, the entire monitoring device must be enclosed in the test chamber. In U.S. Pat. No. 3,523,529 and U.S. Pat. No. 3,507,146, devices are disclosed which are worn by the subject and measure oxygen uptake through a breathing mask or similar apparatus attached to the nose and mouth in order to isolate the exhaled air. Resulting metabolic rate calculations must take into account effects of such cumbersome monitoring devices. Because of the above considerations, present systems severely limit the variety of organisms which may be subjected to metabolic analysis by respiratory techniques, do not measure the organisms adaptive respiratory response to stress and do not use the adaptive responses as a means for measuring metabolic disfunction. The present invention offers the capacity to measure not simply the oxygen consumption of any organism which is capable of respiration, but also provides a means to control stress levels by adjusting the oxygen concentration, increasing temperature, exercise intensity, or other physical parameters and in these fashions measure the adaptive respiratory response of the organism to these stress and use these responses to detect changes in metabolic function.
The present invention relates to a method of determining metabolic status by generating a pattern of adaptive respiratory response consisting of the rate of oxygen consumption of a subject organism at discrete and measured levels of stress. In preferred embodiments, said stress takes the form of a series of oxygen tensions and discrete levels of exercise.
In a second aspect, the invention concerns an apparatus for carrying out the method of the invention. The apparatus is characterized by the use of a feedback circuit to control the generation of oxygen by an electrolytic cell, thus enabling the measurement of oxygen uptake by measuring the oxygen generated to maintain a constant level of oxygen, which is controlled at the option of the investigator. The oxygen monitoring and generation modules are attached to a biological chamber which can be of many designs. The characteristics of the apparatus are such as to impose a measured stress on the tested animals while maintaining other environmental parameters constant.
FIG. 1 is a schematic of a preferred embodiment of the apparatus of the invention.
FIG. 1A is a schematic, and partial section view, illustrating an electrolysis cell.
FIG. 2 compares the oxygen consumption rates at two different levels of exercise in mice.
FIG. 3 is a graph showing the effect of reduced oxygen pressure on untrained mice.
FIG. 4 is a graph showing the effect of reduced oxygen pressure on conditioned mice.
FIG. 5 is a graph which compares the effects of various DNP toxin dosage levels under 21% partial oxygen pressure.
FIG. 6 is a graph which compares the effects, of various DNP toxin dosage levels under 13% partial oxygen pressure.
As used herein, "biological chamber" or "testing chamber" refers to an enclosed chamber, which is optionally capable of motion to provide physical activity demand on the subject, which will contain the organism to be tested for metabolic status. The chamber has interfaces with its surroundings which permit exchange of materials only in a limited way while the organism is being tested, i.e., oxygen is permitted to enter the chamber from the electrolysis cell used to generate oxygen in the experiment or from other oxygen generating means, and, carbon dioxide is absorbed by a carbon dioxide absorbant in conjunction with the chamber. Other chambers suitable for testing senescent biological materials such as eggs, neonates, tissue cultures, seeds, plant materials or microbes are envisioned which would substitute the exercising stress with an appropriate alternative such as heat, or radiation.
"Metabolic or physiological status" refers to the total physiological well being of the subject. It has meaning in the scope of this invention only in a comparative sense--i.e., the metabolic status of a "healthy" subject can be compared to an unhealthy one of the same species; that of a drugged subject with an undrugged one.
"pO2 " or "oxygen concentration" refers to the partial pressure of the oxygen in the testing chamber. Strictly speaking, of course, pO2 should be expressed in pressure units such as atmospheres or torr, and the invention is meant to include those situations wherein the total ambient pressure in the testing chamber is not equal to approximately one atmosphere. However, in practical usage, the total pressure inside the testing chamber will be on the order of one atmosphere or 760 torr, and the pO2 will be expressed, more conveniently, in terms of mole percentage of total gas phase, i.e., oxygen concentration as a % of total moles. This facilitates comparison with value normally found in air, which is ordinarily 21% oxygen, approximately. Under atmospheric conditions, this would correspond to a partial pressure of 160 torr.
"Failure" means a discernible change in the performance of the experimental subject such as, in the case of a mammal, a loss of motor coordination, or an inability to perform minimal exercise such as maintenance against the turning motion of the testing chamber in the preferred embodiment of the invention set forth below. Failure may be defined to be a cessation of respiration in the case of senescent subject matter, such as seeds, eggs or plant materials, when tested against a physical gradient such as heat. Therefore the term failure is simply an endpoint in the experimental protocol at which the organism can no longer accommodate the stress.
"Baseline" means that rate of oxygen consumption which is consistently maintained by a subject organism under normal oxygen pressure and consistent exercise or stress demands.
"Breakpoint" refers to the pressure of oxygen (pO2) at which the baseline rate of oxygen consumption ceases to be maintained.
"Decay line" refers to the variation of oxygen consumption with pO2 which results at the lowered pO2 levels (in non-drug conditions, always linearly decreased with decreasing pO2).
In the present invention, the function that describes the adaptation of oxygen consumption to accomodate a sequential variation in a physiological stress is used as an index of the metabolic capacity of the animal. Ordinarily, this function describes the behavior of the rate of oxygen consumption in response to stress.
The rate of oxygen consumption reflects the ability to focus metabolically limited energy supplies in order to sustain work critical for survival. Natural selection has evolved highly structured metabolic controls which optimize energy utilization under many possible stress situations. The suite of metabolic adjustments available to compensate for each increasing increment of stress should be characteristic of each species and of the overall metabolic capacity of each individual organism. The invention describes an apparatus and methodology for measuring the adaptive response of an animal to stress and relates this adaptive response to the metabolic status of the entire animal. These adaptive adjustments reflect the general metabolic status of the animal because they are integrated into the dynamic operation of the entire physiological system. Metabolic dysfunctions should therefore change the pattern of these adjustments. Adaptive respiratory functions should therefore be sensitive to dysfunctions in anaerobic as well as aerobic processes since losses in anaerobic capacity will result in changes in the adaptive hypoxic response pattern.
While the mechanisms by which the metabolic rate of specific tissues is altered in response to stress conditions is not well understood, it is clear that these mechanisms are intimately integrated into the total metabolic response of the animal. This reasoning indicates that the pattern of adaptive respiratory responses that describe physiological adjustments to stress should be responsive to dysfunctions in these integrating processes as well as dysfunctions in organs, tissues and aerobic and anaerobic metabolic pathways.
The patterns that describe these adaptive respiratory changes therefore also assess the metabolic status of animals, humans and other organisms. In the method of the present invention, metabolic status is measured by generating functions which quantitate adaptive respiratory changes as a function of changes in stress. More than one stress factor may be applied simultaneously, for example, the adaptation of oxygen consumption of mice or other mammals is measured to varying degrees of hypoxia (i.e. a decrease in the partial pressure of oxygen) at a constant level of exercise. Conversely, the method of the invention also includes measuring the adaptation of oxygen consumption of mammals to variations in exercise at a constant partial pressure of oxygen. Other forms of stress are applicable to the method of the invention as well. For example, the adaptive oxygen consumption of any respiring organism may be measured as a function of decreasing pO2 at a constant temperature; and conversely the adaptive oxygen consumption may be measured at constant pO2, but increasing or decreasing temperature. Various combinations of constant and variable stress factors, these stress factors including temperature, exercise, oxygen pressure, and administration of, for example, radiation, drugs, and chemicals are also included. Thus, the invention is directed to assessing metabolic status using as a criterion thereof a measured adaptive respiratory capacity in response to variation in combinations of stress factors.
In a specific embodiment of the method of the invention, the workload is held constant while the pO2 is sequentially lowered.
Individual organisms maintain a baseline rate of oxygen consumption under normal standardized conditions of physical activity. When subjected to stress, conveniently administered in the form of a decreased pO2 in the environment, the ability to maintain the baseline rate of oxygen consumption is at some point lost (i.e., the breakpoint), and a decrease in the rate of oxygen consumption occurs while the level of exercise (or workload) is maintained. This decrease appears to be linear with the diminution of pO2 once the ability to maintain the baseline oxygen consumption has been lost (the decay line). Both the stress level (i.e., the pO2) at which this change occurs, and the slope of the linear decrease appear to be related to the overall metabolic efficiency of the organism. In general, different organisms of the same species which have higher respiratory capacity i.e. better metabolic status, continue to maintain the baseline oxygen consumption level at lower oxygen concentrations, and the slope of the regression that describes the declining consumption of oxygen is lower. In addition, animals with higher respiratory capacity are capable of continuing to exercise at higher stress levels, typically lower partial pressures of oxygen. That is, they do not "fail" as easily.
Thus, when the respiratory capacities of organisms of a particular species are compared, the function that describes the adaptive respiratory response of the individual with the higher capacity (indicating improved metabolic status) will be characterized by three features: The animal will maintain the baseline level of oxygen consumption to a lower pO2, the consumption of oxygen will decrease at a rate slower than that for organisms with lower capacities, i.e., the slope of the decay line will be less, and the animal will fail only at higher levels of stress. Since all three of these parameters can be quantitated, the method provides a rigorous method for measuring the overall respiratory capacity of the organism.
Further, measurement of changes in the adaptive respiratory responses can be used to assess the effects of drugs, toxicants or other treatments which are administered to the experimental subject. While, many toxicants or drugs may result in what appears to be a loss of respiratory capacity or decline in the function representing the index of metabolic status, i.e., the break point is encountered sooner and the decay line has a steeper slope, it is not predictable that this will in every case be, in fact, the observed result. Some toxicants, for example, dinitrophenol (DNP) exert their toxic effects in association with increases in oxygen consumption. In such cases, therefore, the curve will be distorted by virtue of the physiological mechanism causing the metabolic dysfunction. Therefore the function that describes the adaptive respiratory response of treated animals may also contain information that reflects the mechanisms of their physiological effects. The sensitivity of the technique to discern dysfunctions as an effect of drug or toxicant dose increases with the magnitude of the stress, i.e., low oxygen concentrations. Therefore, an empirical quantitative framework must be established in each individual case, as a calibration of the technique.
In general, the apparatus employed by the method of the invention provides a means for stressing and monitoring the rate of oxygen consumption in an organism. The device ultilizes a polarographic oxygen sensing electrode and an electrolysis cell attached to a sealed chamber in which the biological material is placed. The current from the oxygen sensing electrode is proportional to the partial pressure of oxygen within the chamber and is compared to a reference voltage which may be adjusted according to the desired level of oxygen pressure within the chamber. When oxygen is consumed by the organism, the concentration of oxygen decreases within the respirometer causing the output from the electrode to decrease linearly. A comparator then perceives a difference between the oxygen sensing electrode output voltage and the preset reference voltage (which is set to maintain the oxygen concentration at a predetermined value) and closes the direct current circuit to the electrolysis cell. Oxygen then flows from the electrolysis cell to the sealed chamber while the hydrogen produced from the cell is ducted to a gas vent. As oxygen flows into the chamber, the polarographic electrode increases its current output until it equals the preset reference voltage. The comparator then terminates the current to the electrolysis cell. In addition carbon dioxide absorbant is provided to remove carbon dioxide from the chamber.
In performing the method of the invention, the testing chamber is brought to the desired oxygen concentration by introducing pure nitrogen gas while maintaining equilibration with atmospheric pressure. When the desired oxygen percentage is obtained, the testing chamber is closed off from the atmosphere and, as described above, remains capable of material exchange only with the oxygen generated from the electrolysis cell and with the carbon dioxide absorbant. At the preset pO2, the oxygen consumption is measured by calculating the moles of oxygen consumed based on a straightforward Faraday calculation based upon the coulombs of electricity consumed by the electrolysis cell. The polargraphic electrode pO2 reading and the ammeter reading, can be conveniently fed to standard data reduction systems which produce displays of oxygen consumption versus time, pO2 and/or several of the stress parameters. The pattern thus produced is diagnostic of the metabolic state of the organism.
One advantage of the above-described system is that the test organism is completely free of the monitoring apparatus. As such, test results for any applied stress are independent of interference factors or stress factors which may be caused by encumbering the organism with a breathing mask and other monitoring equipment.
A further advantage of the present system also stems from the freedom of the test organism from the monitoring device in that such a system is highly flexible and allows the metabolic analysis of a great variety of organisms ranging from humans to other animals, seeds, embryos, unicellular organisms and gametes. Biological chambers that simultaneously test more than one animal at a time produce data reflecting the sum of the responses of the animals. Such data is ideal for screening programs.
Such a wide range of organisms is also uniquely testible in this invention because the device requires no minimum threshold level of air flow in order to operate. Instead, the supply of oxygen is accurately monitored and controlled through the combination of the oxygen sensing electrode and the electrolysis cell. Such control is achieved simply by recording the flow of electrons to the electrolysis cell through its direct current supply circuit.
The sensitivity of the device is a function of the sensitivity of the oxygen probe combined with the volume of the biological chamber. Small organisms should be tested in minimally sized chambers utilizing sensitive oxygen probes. The present probe has a sensitivity of 0.1% oxygen in air and 0.1 ppm oxygen in H2 O. A further advantage of the present invention is that the oxygen sensing elecrolysis cell combination for monitoring the consumption of oxygen to the organism can also be used to stress the organism by controlling the available partial pressure of oxygen through adjustments made to the reference voltage.
Finally, since the oxygen monitoring, generation and stressing components of this invention are electronic, the device can be highly automated. Models are envisioned where stress protocols are programmed into microcomputers, which then operate the system. The data can also be collected electronically and processed or stored as appropriate. Such systems are but modular refinements of the system described herein.
FIG. 1 is a schematic of a preferred embodiment of the apparatus of the invention. In this embodiment, the oxygen consumption of an organism is measured while varying the available partial pressure of oxygen.
The essential elements of the apparatus are a testing chamber, a means to pre-set the oxygen pressure in the testing chamber, an oxygen sensor connected through a feedback circuit to an oxygen generator, and means to ascertain the amounts of oxygen generated to maintain the oxygen in the testing chamber at the pre-set level.
In the preferred embodiment, the testing chamber also contains a rotor to provide, optionally, a measured stress (exercise) on the part of an experimental subject. This feature is appropriate, of course, only for mobile subjects. Alternate measured stresses such as heat can be substituted for exercise as appropriate.
The oxygen pressure in the chamber is preset by exchanging the air in the chamber with a nitrogen stream to reduce the level of oxygen to that desired, and providing for the maintenance of this level by setting the feedback circuit to trigger at the proper level.
The oxygen sensor is a polarographic electrode which operates the feedback circuit. The oxygen generator is an electrolytic cell which decomposes water in response to the feedback circuit.
As shown in FIG. 1, the testing chamber 12 is provided with a door 13 attached by hinge 15 which permits access to experimental subjects. Gas exchange is facilitated by two manual valves, (not shown) which are opened when N2 or O2 respectively are introduced to adjust the partial pressure of oxygen, and closed to seal the chamber. Bolt 14 seals chamber door 13 to chamber 12 by compressing rubber gasket 16, which frames the door to give an air-tight seal. The chamber is also provided with a carbon dioxide absorbant (not shown).
The fan propeller 26 is driven by electric motor 25 which is magnetically coupled to the propellor to keep any heat generated by the motor outside of the chamber. The fan assures even circulation of the oxygen in the chamber.
A rotor 22 which provides mandated exercise is driven by the external motor 24.
Polarographic oxygen sensor 17 is threaded through the chamber wall. Polarographic oxygen sensors for measuring the percentage of oxygen present in a gas are well known in the art and are commercially available. U.S. Pat. No. 3,071,530 discloses one embodiment of a polarographic oxygen sensor. Since these oxygen sensors are generally temperature dependent, many commercially available units have a thermistor temperature-sensing element incorporated into the support structure of the oxygen sensing element so that temperature variations in the output current of the oxygen sensor may be compensated in the feedback control loop. Such a temperature compensation loop has been incorporated into the present system.
The space above the oxygen generating electrode of the electrolysis cell 23 is also in communication with the testing chamber. FIG. 1A shows the electrolysis cell. It contains a dilute aqueous solution suitable for electrolysis such as, for example, 4 N sulfuric acid, into which are submerged electrodes anode 21 and cathode 40. Space 21A communicates with chamber interior 35 via oxygen line 41. Space 22A vents hydrogen to the out of doors via vent 42.
As shown in FIG. 1, polarographic oxygen sensor 17 is connected in series with DC power supply 37 and comparator 18.
DC power supply 38 is in series with variable resistor 32 and comparator 18. Relay power supply 39 is in series with comparator 18 and relay 19.
Ammeter 27 is in series with electrolysis cell 23 and DC power supply 20. The readout from the ammeter 27 is displayed on a plotter 28.
The device is operated by placing an organism into the testing chamber. The chamber door 13 is then closed forming an airtight seal by tightening bolt 14 and compressing gasket 16. The desired oxygen mixture is then introduced into the chamber and the oxygen concentration is confirmed by an oxygen meter or other independent means.
The desired partial pressure of oxygen within the testing chamber is maintained by setting the variable resistor 32 such that the reference voltage within comparator 18 just equals the signal from the oxygen sensor 17.
As oxygen is consumed by the organism, the output current of polarographic oxygen sensor 17 decreases. When the output current of polarographic oxygen sensor 17 falls below the preset reference value of comparator 18, the comparator operates relay switch 19 which actuates the relay switch to the DC power supply circuit 20. The DC voltage applied by circuit 20 operates the electrolytic cell producing oxygen on the surface of anode 21 and hydrogen on the suface of cathode 40. The hydrogen gas produced by cathode 22 is disposed of through vent 42 to the atmosphere. The oxygen is released into the testing chamber interior via oxygen line 41.
As the partial pressure of oxygen rises in the testing chamber, polarographic oxygen sensor 17 again increases its output current until it equals the preset reference value of comparator 18. Comparator 18 then opens relay switch 19 thus terminating the supply of current to the electrolysis cell. Thus, through the feedback loop comprising polarographic oxygen sensor 17, comparator 18, relay switch 19, and electrolysis cell 23, any desired value of partial oxygen pressure within chamber 12 can be maintained during respiratory communication or altered by varying the preset reference voltage of comparator 18.
The amount of oxygen generated to replace that consumed by the experimental subject is calculated by measuring the current flowing through the electrolysis cell.
The electrolysis cell decomposes water into its elements and the oxygen generated in quantitavely related to the total current flow according to the laws of electrochemistry as defined by Farady, Nernst and Butler - Volmer. The accuracy and precision measurement is dependent upon the measurement of the current flowing between the electrodes and the purity of the electrolyte. Accurate and precise measurements are easily obtained.
Applying the above relationships, it can be shown that during the electrolysis of water 0.2984 grams of oxygen are liberated per amphere hour (Ah). The current supplied to the electrolysis cell of the device described herein can be varied from 0-8 AhDC. The present electronics package is capable of running four such systems simultaneously. Each respirator can therefore produce a maximum of 39.79 mg O2 per minute.
The operation of this preferred embodiment is further illustrated in the examples below, which are presented to illustrate, rather than limit the invention.
In all of the examples below, the results are plotted with time as at least an alternative abscissa on the pattern resulting. In each case, each point on the graph represents the average values of oxygen consumed over the previous 15 minutes from the time shown. That 15 mimutes is always the 15 minutes spent from the experimental subject in the testing chamber under measurement conditions. Times which are spent in adjusting oxygen concentrations, or in removing the animals for dosage or other manipulation do not appear in the abscissa line of the resulting plots. Since these removal times and adjustment times may have some impact on the response of the subject, experiments which are compared are performed to rigorously timed protocols. For example, the tests run in Examples 2 and 3 are intended to be compared to each other. Therefore, the time allotted to decrease the oxygen pressure in the testing chamber by adjusting the ratio of nitrogen to oxygen as there described is standardized as between the two Examples.
Three Balb-C mice, eight weeks old, which had not been previously conditioned were placed in the testing chamber of the apparatus shown schematically in FIG. 1. The chamber was turned at a rate of 6 rpm which was equivalent to a speed of 228 meters per hour. A total of 9 animals were used in three experimental runs conducted on the same day, three mice being used per run. This test was then repeated with animals exercising at 15 rpm (570 m/hr).
The oxygen concentrations (pO2) expressed as a percentage of oxygen in the gas mixture was maintained at ambient pressure and at 21 percent oxygen concentration throughout these first experiments. The respiration rate which is measured in mg oxygen per hour per gram is plotted on the y-axis. Each point on the curve represents the average respiration rate over the previous 15 minutes.
As seen in FIG. 2, a baseline oxygen consumption value was established at approximately 9.5 and 13.5 mg oxygen per hour per gram for animals exercising at 228 m/hr and 570 m/hr respectively. The dotted lines on the Figure represent one standard deviation from the mean value. Animals exercising at the 228 m/hr rate maintained the exercise and respiratory rate for two hours at which time the experiment was terminated. Animals exercising at 570 m/hr began lowering their respiratory rate after 90 mintes of exercise. After 105 minutes these apparently fatigued animals were rested.
Three Balb-C mice, eight weeks old, which had not been previously conditioned were placed in the testing chamber of the apparatus shown schematically in FIG. 1. The chamber was turned at a rate of 6 rpm which was equivalent to a speed of 228 meters per hour. A total of 9 animals were used in three experimental runs conducted on the same day, three mice being used per run. The results as shown in FIG. 3 are the average of the three experimental runs.
The oxygen concentrations (pO2) expressed as a percentage of oxygen in the gas mixture which is kept at ambient pressure is plotted on the x-axis of the graph shown in FIG. 3. The respiration rate which is measured in mg oxygen per hour per gram is plotted on the y-axis. Each point on the curve represents the average over the previous 15 minutes at which the pO2 was held at the value shown.
As seen in FIG. 3, a baseline oxygen consumption value was established at approximately 8.5-9.0 mg oxygen per hour per gram. (The dotted lines on the Figure represent one standard deviation from the mean value.) When the oxygen concentration was lowered to 15%, the oxygen consumption began to decline in a roughly linear fashion, within experimental error, until the animals "failed to exercise" at which time the pressure of oxygen was increased to a concentration of 21%. The oxygen consumption of these resting, fatigued mice then increased and decayed describing a curve crudely described in FIG. 3. The area under this curve is a measurement of the anaerobic respiratory capacity of the animal. Minor electrical refinements to the device described herein will allow the accurate measurement of this anaerobic capacity using this technology.
The relevant quantitation of the results is as follows: The breakpoint occurred at 15% oxygen concentration, the slope of the decay line of the respiration rate as 1.0 mg O2 hr-1 gr-1 for each percent decrease in pO2 between 15 and 11 percent O2 under the conditions of this experiment. Similar parameters can be calculated relating the decrease in respiration rate as a function of time after the breakpoint. As shown in FIG. 3, slope of the decay line for the respiratory rate is 0.066 mg hr-1 gr-1 for each minute between 60 and 105 minutes. Using the protocol described, animals became exhausted after exercising at 11% oxygen and 105 minutes.
The same mice which were used in Example 2 were tested after having been subjected to a "training program" which consisted of five days during which the animals were exposed to atmospheres of 14%, 13% and 12% oxygen for thirty minutes each while exercising at 228 m/hr. The metabolic status test was run under the same conditions as set forth in Example 2 and the results are set forth in FIG. 4. The results indicate that the same initial respiratory rate of 8.5 my oxygen per hour per gram was established. However, the consumption of oxygen did not begin to decrease until an oxygen concentration of 13% was reached. The rate of decrease in conditioned animals was slower than in the untrained mice tested in Example 2. The consumption of oxygen decreased at a rate of 0.6 mg O2 hr-1 gr-1 compared to 1.0 mg hr-1 gr-1 for each percent decrease in pO2, as reported above. Similarly, decrease in oxygen consumption as a function of time was lower in conditioned animals, 0.033 vs 0.066 mg hr-1 gr-1 for each minute between sixty minutes and failure to exercise.
The effects of dinitrophenol (DNP) a known uncoupler for oxidative phosphorylation were tested on mice both at normal oxygen concentration (21%) and at lower oxygen concentration (13%). FIGS. 5 and 6 show the results of testing this toxicant at the two levels of oxygen tension.
In the assay, 3 Balb-C mice were placed in the testing chamber of the apparatus shown in FIG. 1. The oxygen consumption was measured and DNP administered at zero time. As in the previous examples, the points shown on the curve represent the average respiration rates of the previous fifteen minute interval. Therefore, the points at -15 and 0 in FIGS. 5 and 6 represent non-dosed oxygen consumptions. As shown in FIG. 5, the effect of DNP is to increase the rate of oxygen consumption dramatically. As would be expected, the effect is greater at high dose concentrations i.e., 20 mg/kg than at lower ones i.e., 10 mg/kg. At 5 mg/kg, the effect becomes undetectable within experimental error. Only the mice given 20 mg/kg DNP failed during the 105 minutes that the experiment was conducted. The results presented in FIG. 5 are consistent with classic data concerning this well studied toxicant.
The effect of the drug becomes more pronounced if the experiment was rerun at 13% oxygen as shown in FIG. 6. The data presented in FIG. 6 were obtained by placing animals in the respirometer at 21% oxygen and exercising them as in FIG. 5 for the 15 and 0 time intervals. The animals were them removed, dosed, replaced in the respirometer and exercised at a pO2 of 13% oxygen.
As would be expected, at the lower 13% oxygen concentrations the respiration rate of control animals decreases as did that of similarly treated animals reported in FIG. 3. The animals receiving DNP at any dose level follow altered curves from that under 21% oxygen (FIG. 5) as would be expected since at an oxygen concentration of 13%, the cardiovascular system cannot supply the oxygen necessary for these high consumption rates. However, at 13% oxygen concentration all toxicant dosages including the 5.0 mg/kg dosage cause animals to fail to perform their exercise protocols. This latter dosage is indistinguishable from the control when conventional respiratory techniques are used.
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|Feb 1, 2007
|Wang Dong-Lei
|Leisure Fitness Equipment With Oxygen-Supplying Function
|Oct 30, 2007
|Feb 28, 2008
|The Government Of The United States, As Represented By The Secretary Of The Army
|Automated Inhalation Toxicology Exposure System and Method
|Mar 22, 2008
|Sep 25, 2008
|Chang Ming Yang
|Electronic Device and Method of Using the Same
|Feb 24, 2012
|Jul 18, 2012
|Device for simultaneous measurement and recording of oxygen consumption dynamic change of small animal
|Feb 24, 2012
|Jul 10, 2013
|Device for simultaneous measurement and recording of oxygen consumption dynamic change of small animal
|Apr 1, 2012
|Jul 18, 2012
|Device for automatically monitoring breath state of animal in sealed anoxic environment in real time
|U.S. Classification
|International Classification
|Cooperative Classification
|European Classification
|Apr 29, 1987
Owner name: VESTAR, INC., A DE CORP.
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Owner name: NEXSTAR PHARMACEUTICALS, INC., COLORADO
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Owner name: NEXSTAR PHARMACEUTICALS, INC., COLORADO
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MH Apartments Opera Rambla: Find photos, reviews, information, amenities and compare prices for 3 stars hotels in Barcelona, Spain.
Centrally positioned, MH Apartments Opera Rambla allows for easy access to Barcelona's best tourist attractions. Only a short walk from La Rambla, it offers comfortable apartments equipped with a refrigerator, a kitchenette and a coffee maker.
Hotel description
This 3.5-star property provides a tour desk, free Wi-Fi and a lift. Additionally, the multilingual staff are on hand to provide assistance.
Apartments at MH Apartments Opera Rambla Barcelona are comfortable and feature an in-room dining area, a dishwasher and a microwave. Each one features a flat-screen TV with satellite / cable channels, as well as a private en suite.
MH Apartments Opera Rambla is located in the heart of Barcelona's entertainment district with restaurants, cafés and nightlife on the doorstep. Guests can also visit the Picasso Museum, Placa de Catalunya and Palau de la Musica Catalana.
Hotel features
Air Conditioned, Refrigerator, Cable / Satellite TV, Coffee / Tea Maker, Microwave, Hair Dryer, TV, CD Player, DVD Player, En suite, Private Bathroom
Elevator / Lift, Multilingual Staff
Tour Desk, Bath / Hot Tub
High-speed Internet, Internet Connection (wireless)
Private Toilet
Availability and Prices
Booking Site
Room Type
Per room
Per night
Per night
Users who viewed MH Apartments Opera Rambla also viewed these 3 stars Barcelona hotels:
Rambla & Catalunya Hostel
Rambla Catalunya n 84, Barcelona
Rambla Catalunya n 84, Barcelona
Inglaterra Hotel Barcelona
Carrer De Pelai, 14, Barcelona
Carrer De Pelai, 14, Barcelona
Hotel Catalonia Sagrada Familia
Aragón, 569 bis, Barcelona
Aragón, 569 bis, Barcelona
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text: Home Shows & Schedule Food Detectives Moldy Cheese Food Detectives Hosted by Ted Allen Email MainEpisodes Moldy Cheese A delicious piece of bleu cheese has Ted Allen wondering—what makes moldy cheese okay to eat? And when you burn your tongue, does it cause any permanent damage? Finally, the Food Detectives team hits the street to find out if so-called "dirty water hot dogs" are as dirty as you think. (Episode: OF0206) Previous Episode Liquid Smoke Next Episode Small Plate Club


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- 1/4 pound sliced bacon
- 1 small onion, chopped
- 2 garlic cloves, minced
- 4 ears corn, kernels cut off and cobs discarded
- 1 large fresh jalapeno chile, seeded and finely chopped
- 1 (10-ounce) package frozen baby lima beans, thawed
- 1/2 pound okra, cut into 1/3-inch-thick slices
- 3/4 pound cherry tomatoes (1 pint), halved
- 2 tablespoons cider vinegar
- 1/4 cup chopped fresh basil
- Salt and freshly ground black pepper
Cook bacon in a large skillet over moderate heat until crisp. Drain on paper towels, leaving fat in skillet.
Add onion to skillet and cook over moderate heat, stirring, until softened. Add garlic and cook, stirring, 1 minute. Stir in corn, jalapeno, lima beans, okra, and tomatoes and cook, stirring, until vegetables are tender, about 7 minutes. Stir in vinegar, basil, salt, and pepper, and adjust seasonings, to taste. Serve succotash with bacon crumbled over the top.
Recipe courtesy of Gourmet Magazine
Cooking Tips
More Recipes and Ideas
Succotash with Grilled Scallops and Parsley Drizzle
Recipe courtesy of Ellie Krieger
Succotash Salad
Recipe courtesy of Patrick and Gina Neely
Succotash Salad
Recipe courtesy of Katie Lee


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Everything you always wanted to know about me
Do you really want to look back on wedding photos and know that you tortured your poor friends who took the time to be in your wedding? We didn't think so. The Barrymore Dress will have your bridesmaids thanking you for being in the wedding party and getting to wear such a killer dress. This is a long, backless dress with flutter sleeves and adjustable ties at the center back, so it will fit just right. Made from 100% viscose.View sizing chart
IT'S ONLY NATURAL. This is made of viscose. It's a natural fiber and therefore biodegradable -- which is super important because petroleum-based synthetics like polyester can take over 200 years to decompose. Talk about a hand-me-down. This viscose is woven in a mill free of harmful substances such as heavy metals, dyes, and formaldehydes. It's weird when you wear formaldehyde anyway.
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Garment care
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PHILADELPHIA — A boyhood fantasy came to life under an evening sky burnished by a chilly wind. More than 46,000 fans stood roaring at Citizens Bank Park in 38-degree temperatures as a national television audience sat in warm homes holding its breath.
Henrik Lundqvist, playing his first game outdoors since he was a child in Sweden, squared up as the Flyers' Danny Briere bore down on him on a penalty shot with 19.6 seconds remaining.
"There was a lot of pressure on me there," Lundqvist said.
Lundqvist was up for the moment that thousands of kids in icy Northern climes dream of as they drift off to sleep — "Will I stop a penalty shot?"
Lundqvist braced himself as Briere fired on his forehand, aiming his shot between Lundqvist's legs. Lundqvist closed his legs, and the puck bounced harmlessly off his left pad.Continue reading the main story
Lundqvist pumped his right arm in brief but emphatic celebration. Rangers fans roared. Flyers fans fell silent.
Lundqvist's save, the last of his 34, preserved a come-from-behind 3-2 victory Monday for the Rangers in the fifth Winter Classic, another milestone in the Rangers' magical season.
The win, their seventh in the last eight games, gave them 52 points in 37 games — the best record in the N.H.L.
"When it snowed in the second period, that was awesome," Lundqvist said. "The last time I played outside, I was 10. But it's still the same game — it really is."
There were several Rangers stars on an ice sheet that stretched from third base to first on the stadium field. Defenseman Marc Staal made a surprising return from the postconcussion syndrome that had sidelined him since last April 23. He logged a modest but effective 12 minutes 41 seconds and finished plus 1.
Another was Mike Rupp. A 6-foot-5 forward better known lately for fighting, he scored two goals that erased a 2-0 deficit, his second and third goals of the season.
After his first goal, at 14:51 of the second period, Rupp gave a salute, a mocking reference to the Flyers' Jaromir Jagr, who salutes after each of his goals.
"I was happy I had that goal, and that's kind of where I'll leave it," Rupp said.
Brad Richards scored the winner at 5:21 of the third period, 2:40 after Rupp's second goal. He forehanded a rebound past goalie Sergei Bobrovsky to cap a play started by Ryan Callahan, who led the Rangers with 11 hits, and Brandon Dubinsky, who had 10.
The Rangers' comeback marked the first time the Flyers had lost in regulation this season after leading at the second intermission. Their record in that situation is now 18-1-1.
It also gave the Rangers a 3-0 mark against the Flyers this season. If only one of those results were reversed, the teams would be deadlocked in the standings.
The first half of the game tended toward the dull side, as if in the torpor of a late winter afternoon. But the game awoke when Brayden Schenn, 20, scored his first N.H.L. goal 12:26 into the second period for the Flyers.
Schenn had returned from a concussion that sidelined him last month. Another Flyer who missed time in December with a concussion, Claude Giroux, made the score 2-0 at 14:21. It was the 18th goal and 46th point of the season for Giroux, the league's leading scorer. But 30 seconds later, Rupp used defenseman Andrej Meszaros as a screen to beat Bobrovsky, and the Rangers' rally was on.
The Flyers tried to come back over the last five minutes, but they were hampered by the absence of Jagr, who played only two shifts in the second period before leaving the game with swelling in his left leg from a previous injury.
"It's too bad that it happened in such a big game as today," Jagr said. "But that's part of life and part of sport."
With 20 seconds left, Briere was denied at the Rangers' right post when Lundqvist stuck out his toe. But the puck dribbled beneath, and defenseman Ryan McDonagh dived on it as it nudged the goal line.
The referees called McDonagh for covering the puck in the crease. Penalty shot for the Flyers. Lundqvist said he "couldn't believe" the call because, he and McDonagh said, the puck wound up under Lundqvist's pad.
Tortorella complained about that call and others, risking a fine in his postgame remarks.
"I'm not sure if NBC got together with the refs or what to turn this into an overtime game," he said, referring to the referees Ian Walsh and Dennis LaRue. "For two good refs, I thought the game was reffed horribly."
McDonagh said he was relieved when Lundqvist stopped Briere on the penalty shot. "He's the backbone of the team," he said.
After all the hype, all the trash talk and the buildup of the HBO series chronicling the Flyers-Rangers rivalry, the Winter Classic ended in a Rangers win.
In the dressing room after the game, Rangers defenseman Dan Girardi sat eating a Philly cheese steak.
"This is delicious," he said, savoring the taste of victory.Continue reading the main story


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With all this traveling in and out, back and forth around the maze that is the United States infrastructure, its easy to understand why auto insurance is required in order to own an operate a car. For car buyers, an effort needs to be made on the part of insurance companies to provide information on the different types of auto insurance available. These include bodily injury and liability, collision, comprehensive, full glace, liability, medical coverage, personal injury protection, and underinsured or uninsured motorist.
Liability insurance coverage is imperative to have as a driver. This insurance covers any injuries or damages to property that may occur during an accident. Two types of liability include bodily injury liability insurance and property damage liability insurance.
Medical insurance is different in that it focuses on the driver and passengers of the car. This will cover any medical treatment for the driver and the passengers. In addition, the medical insurance may or may not offer disability insurance and pain and suffering compensation.
Uninsured or under-insured drivers insurance will pay any costs that you or your passengers may experience if an accident should occur with a driver who is uninsured or underinsured.
Collision insurance deals with the cost of damage caused by a collision to your car that may affect the book value. Comprehensive deals more with damage caused by vandalism, natural disasters, theft or other kinds of damage.
There are several other types of car insurance. These include glass replacement insurance, towing insurance etc. These types of insurance are often not required and are not popular as they are often costly.
Now that you know what types of car insurance are out there, the next step is to find a credible insurance agent. The first place to investigate this is through family and friends. Referrals will help you sort those agents that you want to investigate further. You will want to speak with several different agents before you make your final decisions. Ask any and all questions you may have. That is what the agent is there for.
Auto insurance is a must for all automobile owners, which repay you in case your automobile is stolen or damaged in an accident. Most people complain about the high prices of auto insurance policy. Here we offer you some money saving tips with the help of which you can get the best car insurance quotes online as well as best auto insurance policy.
If you are a new car owner or your previous auto insurance policy needs a renewal then it's time for you to search for a new one. You will be surprised to know that different insurance company offers different premium for the same coverage. Thus, it is in your interest to find a low premium, more coverage best auto insurance policy. Local market search will be not enough, go to the websites of auto insurance companies and request for car insurance quote online.
Your credit history matters a lot for auto insurance companies. Reviews of insurance companies have shown a correlation between credit scores and risk to an insurance company. Thus, manage your credit score to a positive level before requesting for a car insurance quote online.
During the request for car insurance quote online keep an eye on discounts provided by auto insurance companies, mainly on their websites. With offered discounts, you can drop your premium.
If you have a life insurance policy or health insurance policy or any other insurance, it is recommended to ask the same insurance company for auto insurance. They will surely provide lower car insurance quote online, as you are their client.
By following all these recommendations, we are sure that you will be able to buy the best auto insurance policy to protect your car, truck or any other vehicle against theft or damage.


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Center for Comprehensive Health Practice, Inc.
Por el momento no tenemos ninguna oportunidad de voluntariado, trabajo o eventos.
Ingresa o regístrate para enterarte cuando nuevos avisos o eventos sean publicados!
Sobre nosotros
The Center for Comprehensive Health Practice (CCHP) is an interdisciplinary family-focused health center offering quality primary care, behavioral health treatment and supportive services in East Harlem, New York. Accredited by the Commission on Accreditation of Rehabilitation Facilities (CARF) and supported by the Office of Alcoholism and Substance Abuse Services (OASAS) and the National Health Services Corp (NHSC), CCHP serves many of New York City's most vulnerable and underserved communities.
CCHP's family-focused approach includes an array of specialty services: internal medicine, pediatrics, HIV/AIDS and HCV prevention and treatment, behavioral health, substance use treatment, health education, and our groundbreaking Early Childhood Development Center. For over 50 years, we continue to serve the imminent needs of the community, regardless of one's race, ethnicity, gender, religion, sexuality, age, or ability to pay.
Palabras clave
Información de contacto
Número de identificación del gobierno: 13-3484329
Email: Ingresa para ver las direcciones de email.
Página(s) web:
cchphealthcare.org facebook.com/cchphealthcare
1900 Second Ave, 9th Floor, New York, NY, 10029, US


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"We offer a unique combination of extensive inhalation device development capability and long experience from pharmaceutical product development."
Iconovo has signed an agreement for a licensing deal and a product development project with Amneal Pharmaceuticals that produce and market generic drug products. The agreement involves an adaptation of Iconovo's unique inhaler, ICOres™, as well as a development of a powder formulation to treat asthma and COPD. D


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William Blows Trace in a Chair
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Topic: Naming Rights
Come Super Bowl Sunday, Will the University of Phoenix Regret Its Naming Rights Deal?
As school faces scrutiny, $155 million deal highlights deep pockets
By Robert Klara on Jan. 23, 2015 - 8:00 AM EST
When the expected 184 million viewers tune in to Super Bowl XLIX on Feb. 1, they'll see more than just the Seattle Seahawks face off against the New England Patriots—they'll…
Jason Sadler Becomes Jason HeadsetsDotCom as Name Auction Ends
Change nets him $45,500
By David Gianatasio on Dec. 13, 2012 - 8:39 AM EST
What's in a name? $45,500, that's what. Jason Sadler will receive that amount for legally becoming "Jason HeadsetsDotCom" and promoting the name change through social media and other means next…
Social Media's Walking Billboard Now Selling His Name
Jason Sadler offers last name to highest bidder
By David Gianatasio on Nov. 30, 2012 - 1:25 PM EST
The name "Jason JLabAudio" has a certain ring to it—and some potentially serious bling to it. The currently named Jason Sadler stands to make $34,500 by changing his name to…
Sears Tower: No place for a brand name?
By Adweek Blogs on Jul. 24, 2009 - 10:33 AM EDT
Chicago's Sears Tower has become Willis Tower, thanks to a deal struck with London-based insurance broker Willis Group Holdings, and locals are not happy about it. In fact, they've…
Naming rights to agency stadium up for bid
By Adweek Blogs on Mar. 31, 2009 - 10:15 AM EDT
With apparently way too much time on its hands, Charlotte, N.C., ad agency BooneOakley is auctioning off the naming rights to its in-house basketball stadium. Wait, BooneOakley has an…


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Newegg.com - A great place to buy computers, computer parts, electronics, software, accessories, and DVDs online. With great prices, fast shipping, and top-rated customer service - once you know, you Newegg.
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This review is from: Acer C710-2487 Chromebook Intel Celeron 847 (1.1 GHz) 4 GB Memory 320 GB HDD 11.6" Chrome OS
Pros: Small, light, and has a long battery life. With Google Chromebook's you get access programs like Google doc's, spreadsheets etc. and not having to buy additional programs saves a lot of money
Cons: Chromebook's are "Internet browsers", meaning you cant download programs not on the Google market place. so no firefox T_T
Other Thoughts: if you do take it back and forth to class try using the offline feature so you can use google doc's when your schools free internet craps outREAD FULL REVIEW
This review is from: CORSAIR CX series CX430 430W 80 PLUS BRONZE Active PFC ATX12V & EPS12V Power Supply
Pros: Great power supply for the first time computer builders, and the cable sleeves keep your computer looking nice and clean
Cons: I wish it would come with a 2nd PCI-e power cable, but you can work around that
Other Thoughts: As a logistics manager at a shipping center i have seen lots of bad power supply units come in, but i have never seen a Corsair come in. these PS are made to lastREAD FULL REVIEW
This review is from: MSI 760GM-P34 (FX) AM3+ AMD 760G + SB710 Micro ATX AMD Motherboard
Pros: Nice budget mother board, has everything you need for a beginner build.
Cons: Do not use a Razor Naga or similar mouse for this Motherboard. There is an issue with the usb device software that causes the Bios to lock up leaving you staring at a blank screen for 10 minutes. (the computer will eventually boot)READ FULL REVIEW


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Check in from 15h / Check out prior to 11h
Ambassador Hotel Sudbury: Find photos, reviews, information, amenities and compare prices for 3 stars hotels in Sudbury, Canada.
Located in Sudbury, Ambassador Hotel Sudbury offers 3-star accommodation, as well as a Jacuzzi. It has a gym, as well as meeting rooms, massage services and a 24-hour reception.
Hotel description
A laundry service, babysitting/child services and a dry cleaning service are just some of the convenient services at the hotel. Honeymoon suites are on offer for those seeking some added luxury.
Equipped to ensure an enjoyable stay, rooms provide a refrigerator, a coffee maker and tea and coffee making facilities. A telephone, cable/satellite channels and a hair dryer are also provided.
A satisfying breakfast is served every morning at Ambassador Hotel Sudbury, and there are numerous cafés and eateries close by.
Ambassador Hotel Sudbury offers parking for guests and is an easy drive from New Sudbury Centre. Science North and Laurentian University are just a 20-minute car ride from the hotel.
Hotel features
Room Service, Restaurant, Pet Friendly, Air Conditioned, Non-Smoking Rooms, Refrigerator, Cable / Satellite TV, Coffee / Tea Maker, Hair Dryer, TV, Vending Machines
Business Center, 24 Hour Reception, Dry Cleaning, Babysitting / Child Services, Conference Room(s), Multilingual Staff, Wake-up Service, Meeting Rooms, Laundry service, Photocopier, Desk
Fitness Room/Gym, Massage / Beauty Centre, Jacuzzi, Massage
High-speed Internet, Internet Connection (wireless)
Nightclubs, Smoking Room
Availability and Prices
Booking Site
Room Type
Per room
Per night
Per night
Users who viewed Ambassador Hotel Sudbury also viewed these 3 stars Sudbury hotels:
BEST WESTERN Downtown Sudbury Centreville
151 Larch Street, Sudbury
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1500 Regent Street South, Sudbury
Artisan Upstairs Guesthouse
318 Jeanne D'arc Avenue, Sudbury
318 Jeanne D'arc Avenue, Sudbury
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Alero 2004 mpg for sale on US's largest classifieds sites (43 results)
2004 OLDSMOBILE ALERO GL - Contact Dealer
Lithia Ford of Klamath Falls (DA3312) Klamath Falls OR, 97603 ☎&n
2004 OLDSMOBILE ALERO GL - Contact Dealer
QR Code Link to This Post Lithia Ford of Klamath Falls (DA331
2004 OLDSMOBILE ALERO GL *Guaranteed Credit Approval *SAVE THOUSANDS*
Legendary MotorsAddress : 908 South Main St , Traer, IA 50675Have a question about this OLDSMOBILE ALERO?Call us at (319) 961-4573 / (319) 269-94002004 OLDSMOBILE ALERO GL Sedan - $2,900Make OLDSMOBILEModel
2004 Oldsmobile Alero
Up for sale is my 2004 Oldsmobile Alero. This is the GL2 trim model with a 3.4L V6 and 4-speed automatic. This car came to me from my dad who won it in a raffle in May 2014 in Wyoming. He gave it to my wife and I and we drove it in Michigan from July 2014 till now. It\'s been in Washington just over a
2004 Olds Alero 4dr
2004 Olds Alero 4dr, Silver exterior, gray interior. This car purchased with 30,000 miles on it from Crookston MN Pontiac Buick, GMC car dealership in 2004.. Very good condition. Now has 139277 miles on it. very dependable, great college car. 4 cylinder engine gets 30 mpg . 3000.00 or best offer
Year: 2004
2003 Oldsmobile Alero GL1
Mileage:146,573 Miles Exterior:Red Engine:2.2L I4 Transmission:Automatic 4-Speed Trim/Package:GL1 4dr Sedan Fuel Type:Gasoline MPG City/Hwy:21 city / 30 hwy~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ GIVE US A CALL! : (641)456-9828TEXT JORDE
Year: 2003, Make: Oldsmobile, Model: Alero
2004 Chrysler Pacifica
Mileage:148,193 Miles Exterior:White Engine:3.5L V6 Interior:Tan LeatherTransmission:Automatic 4-Speed Trim/Package:Fwd 4dr Wagon MPG City/Hwy:15 city / 21 hwyRUNS AND DRIVES GREAT . ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ GIVE US A CAL
2004 Oldsmobile Alero GL V6
2004 Oldsmobile Alero 6 Cylinder135k miles4 doorFront wheel bearings replaced recently.Great fuel mileage - 30 mpg All recent maintenance records. If interested please email. Asking $4500 obo.
2004 *Oldsmobile* *Alero* GL1 Sedan - $299 Down Back to School Sale!
2004 *Oldsmobile* *Alero* GL1 SedanOffered by: Approved Auto America — (502) 912-8750 — Call for more infoApproved Auto AmericaYear: 2004Make: OldsmobileModel: AleroSeries:
2004 Oldsmobile Alero GL1
FUEL EFFICIENT 34 MPG Hwy/24 MPG City! GL1 trim. CD Player, Alloy Wheels. 4 Star Driver Front Crash Rating. CLICK NOW!KEY FEATURES INCLUDECD Player. Aluminum Wheels, Keyless Entry, Remote Trunk Release, Bucket Seats, Front Disc/Rear Drum Brakes.EXPERTS ARE SAYING4 Star Driver Front Crash Rating. 4 St
2004 Oldsmobile Alero - $3900 (Georgetown)
Silver Olds Alero in really good condition. Gets about 30 mpg. Very low maintenance. Has current oil change/tune up. Has power sunroof and rear spoiler. Runs excellent! No engine or transmission problems. A/C blows cold and heater heats up very fast.Automatic transmission with cruise control. Huge tr
Year: 2004, Make: Geo
2004 Oldsmobile Alero - $4995 (Rigby)
I have a 2004 Oldsmobile Alero for sale. It has automatic everything, seats, tranny, windows. It has 115000 miles on it, pretty low! it gets 26 mpg in town and 28 on the highway. I am asking below what it is appraised for. If you are intreseted please call or text 208-821-5534 Location: Rigby it`
2004 Oldsmobile Alero - $4000 (Moorhead)
I really like this Alero but has to go to help on a down payment for a new truck. 2004 Alero GL, 3400 V6, auto trans with 83,000 miles on it. Gets 20+ mpg in town and 30+ mpg highway. Runs perfect, shifts perfect and drives like new still. Clean car, has a couple dents but nothing bad. Power everythi
2004 Oldsmobile Alero - $2150 (Remer)
2004 Oldsmobile Alero Trim: GL2 Miles: 190k Color: White Engine: 4-Cylinder 2.2L MPG: from 27 to 33mpg highway 4 Door, Automatic Transmission, Front Wheel Drive, Alloy Wheels, Air Conditioning, Cruise Control, Power Door Locks, Power Seats, Power Steering, Power Windows, Tilt Steering, AM/FM R
2004 Oldsmobile Alero - $6200 (McGregor, Mn)
2004 Oldsmobile Alero. Automatic. 3400 V6. call with any ?`s Adam 1-218-838-1234. Good mileage 26-28 mpg. 80,000 miles good shape. Location: McGregor, Mn it`s NOT ok to contact this poster with services or other commercial interests
2004 Oldsmobile Alero GL Sedan 82,000 miles - $4500 (Nampa)
2004 Oldsmobile Alero GL Sedan $4,500. EXCELLENT CONDITION! LOW MILES, LESS THAN 82,000 ORIGINAL MILES! SUPER CONDITION. POWER EVERTHING. DETAILS BELOW!!!
2004 Oldsmobile Alero (silver)
2004 Oldsmobile (Olds) Alero Price: $5,400 VIN: 1G3NL52F84C136702 Miles: just under 93,000 Engine: 4 cylinder gasoline Transmission: automatic Drive Type: 2 wheel drive - front Body Style: Sedan (4 door) Exterior Color: Silver Interior: gray cloth MPG
2004 Oldsmobile alero 30mpg - $3999 (Milwaukee )
Gray in and out 04 alero with 125k mile 4 slender means very good on gas around 30 mpg , drives good , just put $80 synthetic oil and new struts . If interested call 4145366767 to see at N Milwaukee .pics soon or text 224-522-2915 to send it to u . *Note : it`s a 2004 not 2012 Thanks for reading
2004 Oldsmobile Alero - $5500 (Winchester)
Oldsmobile: 2004 Alero 1 owner 4DR, GL package, sunroof, V6, Auto, Traction Control, ABS, Premium Wheels, Moon Roof, AM/FM CD Player. Silver outside gray interior. Good tires, new brake pads and rotors front and rear. New spark plugs. Excellent condition inside and out. Excellent mechanical conditio
2004 Oldsmobile Alero Sedan GL1
: FUEL EFFICIENT 34 MPG Hwy/24 MPG City! GREAT MILES 65,888! GL1 trim. CD Player, Alloy Wheels. 4 Star Driver Front Crash Rating. AND MORE!br /br /KEY FEATURES INCLUDEbr /CD Player, Aluminum Wheels Keyless Entry, Remote Trunk Release, Bucket Seats, Front Disc/Rear Drum Brakes, Vehicle Anti-Theft


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Hello! I am cute, new baby here for u!
whenever possible
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Potash is a mineral that contains potassium ("K") in water soluble form which is the third important plant nutrient after nitrogen ("N") and phosphor ("P"). The majority of the global potash supply comes from two regions: Saskatchewan in Canada and the Eurasian border region in Belarus and Russia. The four largest producers worldwide which hold more than 60% of the global market share are Uralkali (Russia), Potash Corporation of Saskatchewan (NYSE:POT) (Canada), The Mosaic Company (NYSE:MOS) ("USA"), and Belaruskali (Belarus). In July 2013, Uralkali announced that it will no longer export its products through the "Belarus Potash Corporation" ("BPC"), a distribution company which exported potash jointly with Belaruskali. The news let the shares of all major potash miners including Potash Corp. and Mosaic Co. tumble because of the fear of lower potash prices. Potash Corp., Mosaic Co., and Agrium (NYSE:AGU) jointly own the second large global potash export company "Canpotex" which manages transportation and distribution of Canadian potash outside Canada and the US.
The share price drop last summer made me curious whether this correction could be an interesting entry point to invest in potash miners from a contrarian viewpoint. However, after some research, I came to the conclusion that the risks are too high, mainly because there is still too much downside potential for the potash price.
Potash Corp.
Potash Corp. is operating in the three segments potash, nitrogen, and phosphate with potash being the largest and most profitable business. In 2012 and 2013 it stood for 41% of the company's sales and for 57% of its gross margin.
Potash Corp.'s turnover by segment in $M
Source: company website.
Product sales in all three segments grew by volume in 2013, but declined in value. Especially, potash prices have fallen during the course of 2013 and the deterioration has continued further in Q1 2014. It is also important to note that Potash Corp.'s realized sales prices in North America are much higher than in the rest of the world. COGS have been constantly reduced, but the reduction could not offset the price decrease, and gross margins per metric ton have become significantly lower.
Potash Corp.'s potash prices and margins per metric ton
Source: company website.
Potash Corp. pays a quarterly dividend of $0.35 which corresponds to a tempting yield of 3.8%. The last dividend raise has been in May 2013.
After reaching a record high in 2008, the stock dropped below $20 and now stands at $37 which is almost twice as high as at the end of 2008 when the global potash price was actually higher as it is today.
Mosaic Co.
Mosaic Co. is another leading global crop nutrient company. The phosphate segment is the larger of the company's two businesses (Mosaic Co. does not produce nitrogen fertilizers), but potash is much more profitable as it represents only 35% of sales but 62% of the operating earnings.
Mosaic Co.'s turnover by segments in $M
Source: company website.
Mosaic Co. has been confronted with the same difficult market environment, and sales and profits have declined in 2013. Despite a volume growth of 16% in the potash segment and sales growth of 7%, gross margin declined by 1% versus 2012. Similar to Potash Corp. the realized sales prices were higher in the USA than for the export business.
Mosaic Co.'s potash prices per metric ton
Source: company website.
Mosaic's share price development shows a similar pattern. The current quarterly dividend of $0.25 results in a dividend yield of only 1.6% - less than half of Potash Corp.'s yield.
Potash World-market Prices
Potash is the most important business segment for both Potash Corp. and Mosaic Co., and potash margins have been traditionally high in comparison to nitrogen and phosphate fertilizers. The potash market is dominated by a small number of players which has helped to maintain these margins in the past.
The world market spot price for potash has been more volatile than the prices of other fertilizers and has skyrocketed until February 2009 when reaching a record high of $872 per metric ton ("mt"). It then dropped sharply to a low of $312/mt in March 2010 and has recently fallen even below this level. The last monthly spot price for MOP, f.o.b. Vancouver end of April 2014 is $287/mt.
Potassium Chloride (MOP), Monthly Prices in $/mt, standard grade, spot, f.o.b. Vancouver
Source: quandl.com.
It is also important to mention that despite the fact that potassium is an essential crop nutrient, plants can tolerate the absence of potassium fertilization for a relatively long period of time. In other words the stop of nitrogen fertilization immediately has a negative impact on plant yield whereas most crops tolerate it if no potassium fertilizer is applied during a growing season with only small losses. This makes the potash price more vulnerable during a crisis as farmers can relatively easily skip potassium fertilization, at least for a certain period of time.
Supply and Demand Outlook
The long-term outlook for agriculture is very good. An increasing world population, the growing middle class in the emerging countries, and the use of a more crops for the production of bio-fuels requires that agricultural production increases. Fertilizers play an important role for agricultural productivity, consequently the global fertilizer demand will grow, however, studies show that potash supply will grow faster than demand.
The global potash demand is expected to grow from 32.7 million metric tons ("mmt") in 2013 to 37.6 mmt in 2017 (CAGR 3.6%) according to the "2013-2017 Fertilizer Outlook" of the International Fertilizer Industry Association (IFA).
These figures are confirmed by the Food and Agriculture Organization of the United Nations' (FAO) "Fertilizer Trends and Outlook" which forecasts a demand growth from 32.2 mmt in 2012 to 37.2 mmt in 2016 (CAGR 3.8%). The majority of the demand growth is expected to occur in Asia (72%) and only 2.5% in North America.
However, potash capacity and potash supply is expected to grow faster than its demand. IFA forecasts supply to grow from 41.7 mmt in 2013 to 49.7 mmt in 2017 (CAGR 4.5%). This scenario is already very conservative as it considers delays for all ongoing expansion projects and no new greenfield projects.
According to FAO's projections, potash supply will increase from 40.2 mmt in 2012 to 61.4 mmt in 2016 (CAGR 7.1%) and 56% of the new supply will come from North America!
Worldwide potash demand and supply 2013-2017 in mmt
Source: International Fertilizer Industry Association.
Worldwide potash demand and supply 2012-2016 in mmt
Source: FAO.
In any case, the supply grows at a faster rate than the demand, and both studies forecast an increasing overcapacity for the next years which will be in the range of 30-42% in 2016. The major capacity expansions take place in North America where no noticeable growth in potash demand is expected. Potash Corp. and Mosaic Co. as the major producers have also invested billions of dollars in new capacity which will become operational within the next years: Potash's nameplate capacity will increase from 13.9 mmt in 2013 to 18.1 mmt in 2015 after completion of the current expansion program, and Mosaic Co. has 2.0 mmt additional capacity under construction which will be completed by 2018. As a reaction to the unfavorable market environment both companies have already reacted, and delayed or suspended further projects or idled capacities.
In contrast to Potash Corp. and Mosaic Co. which are able to manage capacity utilization of existing operations to a certain extent, new players in Canada will be less flexible. The German Kali & Salz is realizing a major green field project, the "Legacy Project" which is expected to add 2.0 mmt capacity in the first stage in 2017, and further expansions are already projected. BHP Billiton Ltd. (NYSE:BHP), one of the major global mining companies which is not producing potash today plans to enter the market, and is working in Saskatchewan in a similar dimension with the "Jansen Potash Project." BHP has committed a total amount of $3.8B for this greenfield project until 2017.
My main concern for both Potash Corp. and Mosaic Co. is the uncertainty in the potash market. Potash prices have been reclining for almost two years, and I do not see that this trend has been stopped. Global capacities as well as supply are already higher than the demand. Despite lower prices, potash margins are still comparatively high so that prices may come down further. What happened last summer when one major player announced to gain market share at the expense of lower prices, shows how fragile this system is.
Very attractive potash margins in the past have also lead to new significant capacity expansions which will become operational during the next two to five years. The majority of the new capacity is added in North America where no market for additional products is. Consequently, the production from new mines has to find its way to the export market where prices are already lower than in the US or Canada. The fact that new large scale greenfield operations are also built in Canada by new market entrants which have to fill a certain capacity could also put pressure on the high margin North American potash market.
Although both Potash Corp. and Mosaic Co. do all they can to cope with the current market environment, and have taken measures to safeguard profitability to the extent possible, my conclusion is that for both Potash Corp. and Mosaic Co. the risks currently outweigh the chances. Even an attractive dividend yield (at least for Potash Corp.) does not justify buying the stock in the current situation.
Disclaimer: Opinions expressed herein by the author are not an investment recommendation, any material in this article should be considered general information, and not relied on as a formal investment recommendation. Before making any investment decisions, investors should also use other sources of information, draw their own conclusions, and consider seeking advice from a broker or financial advisor.
Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.


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As part of its annual market research report, The Custom Electronic Design & Installation Association (CEDIA) asked systems integrators (a.k.a. custom AV installers) how they see the demand for 4K/Ultra HD TV sales shaping up over the next 12 months. Survey participants said they expect the new high-resolution sets to account for only 11 percent of their TV sales, suggesting the need for content to catch up. Is an Ultra HD TV in the cards for you?


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Building On Sand
As out-of-towners, we know of other communities founded with high hopes of building Torah, but no longer exist today. In most of them the day school folded first and, within a short time, nothing Jewish remained.
It is a great struggle to enroll and keep Jewish students – especially those not affiliated with the Orthodox community. (Sadly, there are even shomer Shabbos children who may not graduate from day school!) Trying to recruit for day schools across the country is getting trickier and trickier. The economy has effected enrollment, but so has the lack of reverence for Judaism, which exists in a new generation of young parents who are barely traditional. Very few communities are immune to these trends.
Recently, there has been fear that the school's lay leadership may attempt to change the tone of our day school. Some of the officers have even urged the Judaic Studies staff to not emphasize Torah when speaking to perspective parents.
As teachers, we watched from the sidelines while this development played out. We had to consider if this city, the one in which we raised our family, was still suitable for us. It has been a tough time here, over the rainbow. At present, it seems the school will continue in its current direction. Our fear of needing to move has receded, and now we will wait to see how things play out. We hope the New Year brings us stability, and continued success in teaching Torah to the remnants of our people. We hope that here we will not just be building on sand.Penina Scheiner
About the Author: Penina Scheiner is a kindergarten teacher, writer, and busy wife and mom who lives over the rainbow with her husband and kids.
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Adam Levine Smolders on PEOPLE's Sexiest Man Alive Cover [PHOTO]
Blake Shelton is officially jealous, as Adam Levine's Sexiest Man Alive cover for PEOPLE has landed.
Blake Shelton is officially jealous, as Adam Levine's Sexiest Man Alive cover for PEOPLE has landed.
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