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To understand the thermodynamic difficulties of the reduction of - - carbon dioxide (or of the carboxyl group) breast cancer 2b prognosis cheap alendronate 35mg online, it is useful to review some fundamental facts of the thermochemistry of organic compounds womens health partnership indianapolis indiana alendronate 35mg amex. The Standard Bond Energies the energy of a homopolar single bond is menstruation 4 days cheap alendronate 70mg without a prescription, to a first approximation pregnancy signs and symptoms cheap alendronate 70 mg online, independent of the nature of other groups to which the bonded atoms are attached pregnancy xx massage cheap alendronate 35mg without a prescription, and the energy content of a nonionic molecule is women's health magazine uk back issues purchase alendronate 70 mg with visa, to the same approximation, the sum of these bond energies. However, secondary influences often cause considerable deviations from additivity. For example, the standard energy of an oxygen-hydrogen bond is 110 kcal, However, the energies one-half the total energy of the water molecule. We now is see that the heat of first combustion of an approximation, by its organic If the heats of combustion of a number of organic comlevel. However, because of the variations in the C O bonds mentioned above, the energies of some dismuand isomerizations reach - 10, or even - 20 kcal, as illustrated by table 9. As a result, the energy of hydrogenation of C^O bonds in carboxylic acids and in free carbon dioxide Carbon-carbon double bonds is positive (c/. Conjugation between a C=0 and a C=C bond has no marked effect on the hydro(A stabilizing genation energy of the former (c/. Large deviations from this rule may occur in the hydrogenation of ions (in system No. Instead of the free energy of hydrogenation, the oxidizing power often these potenis characterized by the oxidation-reduction potential, Eq. In chapter dioxide, Some photosynthesis was described as hydrogen transfer from water to carbon in chapter 5, a similar definition was applied to bacterial photosynthesis. The exchange of hydrogen atoms for hydroxyl radicals (once postulated by Franck as the primary process in photosynthesis, cf. The oxidation-reduction potentials, on the other hand, are free energies of reduction, Usted in table 9. If this transfer is associated with the addition or loss of hydrogen ions (hydrogenation being interpreted as a transfer of an equal number of electrons and H"*" ions), the normal potentials are dependent on pH. The potentials of systems the addition of hydrogen atoms (without binding or loss of same way as the potential of whose reduction consists in H"*" ions) change with pH the hydrogen electrode. For systems whose hydrogenation involves a change in ionization, the oxidationreduction potentials increase more (or less) rapidly than the potential of the hydrogen electrode. Thus, a reductant whose reduction creates an aromatic system should be thermodynamically able to reduce bicarbonate or carboxyl even without the help of Hght. Catalysts can improve kinetic reversibility, but cannot affect the static reversibility. The normal ferric iron potentials of systems based on the conversion of ferrous iron into relative stabilization of the oxidant and reductant by complex and as high as 4- 0. No complex iron compounds are known which are thermodynamically capable of reducing carbon dioxide or carboxyl group in a neutral medium. In chapter 6, mention was made of hydrogenase, an enzyme capable of reacting the potential of this enzyme must be close to reversibly with molecular hydrogen. Its chemical nature is Its potential, although considerably higher than that of all known as yet unknown. The Role of Phosphorylation difficult to In the case of decarboxylation, we found that the least respiration mechanism, particularly that of oxalacetic acid. In stage A of scheme a hexose molecule of a triose, which, in stage B, are oxidized to into two molecules two molecules of pyruvic and enol-pyruvic acid). In stage C, a transformation of two molecules of pyruvic acid leads to the regeneration of one of them, and the disintegration of the other one into three carbon dioxide molecules (liberated through the intermediary of specific "decarboxylases") and ten hydrogen atoms, which are transferred through specific "dehydrogenases" to oxygen as the final acceptor. The potentials of these carbonyl-carboxyl systems in neutral solution lie, according to table 9. The "dehydrogenases," which accept the hydrogen atoms from glyceraldehyde and acetaldehyde, are pyridinium nucleotides, whose potentials Ue between + 0. Thus, the hydrogen transfer from the aldehydes to the dehydrogenases should liberate a considerable amount of free energy, and thus be practically irreversible. It was shown by Meyerhof, Warburg, and coworkers that, in conse- quence of the phosphorylation of glyceraldehyde, practically all the free energy of its oxidation by pyridine nucleotide is retained in the oxidation product (enol-phosphopyruvate) and Lipmann has demonstrated a similar effect of phosphorylation on the transformation of pyruvic acid; into carbon dioxide and acetic acid. The main purpose of the oxidation of this storage is to make possible the utilization energy by the contractile system. Since both;; the oxidation and the transphosphorylation are reversible, the net rate of these processes is regulated by the rate of the terminal, exergonic, myosin-catalyzed dephosphorylation; in this way, the rate of respiration is accelerated or slowed down depending on the amount of work performed by the muscle. Only 30-35 triose are stored in the three high-energy kcal out of the 330 kcal combustion energy available in a phosphate molecules created in the two oxidation steps considered above. The other 90% are liberated in subsequent reaction steps, that is, according to scheme 9. Some of these processes may also be coupled with phosphorylations or transphosphorylations, and Indications their energy made available in this way for muscular work. In the respiration of dialyzed muscle extracts, five or six glucose molecules were found to be phosphorylated to diphosphates simultaneously with the oxidation of one glucose molecule to carbon dioxide. In this way, as much as 20-25% of the combustion energy of glucose could be converted into phosphate energy, to be utilized for muscular work. The remaining 75-80% is liberated in the downward slide of the hydrogen atoms from reduced dehydrogenases (whose potentials lie between + 0. Some evidence speaks in favor of phosphorylations also being associated with these stages of respiration (in which the largest part of the combustion energy is liberated), but the nature and extent of these phosphorylations is as yet unknown. Phosphorylation and Photosynthesis We found, in the preceding section, that phosphorylation permits the oxidation of carbonyl groups to carboxyl groups without dissipation of energy (and may have the same effect also on other steps in the Thus, phosphorylation transfer of hydrogen from sugars to oxygen). We shall now see that phosphorylation could also be used in the interpretation of the carbon dioxide reduction in this was first suggested by Ruben (1943), who thought photosynthesis. Chapter 7) have reduction potentials of the order of those of the pyridinium nucleotides {i. One could, however, also more fundamental importance, in analogy with the expansion of the phosphorylation theory of respiration (page 226). They attempted to support it by an experimental investigation of the phosphorus metabolism of Chlorella, which leads to the following results: 1. Chlorella cells are capable of utilizing phosphorylated compounds of a carboxyl attribute to the phosphorylation a for respiration in the dark. Dried Chlorella cells can be used for the preparation of a "Lebedev juice" which will catalyze the esterification of inorganic phosphate (in the presence of glucose, fluoride and pyruvate). The phosphorylated compounds contained in Chlorella appear to commonly occur in animal and most bac- 4. A 90-minute illumination of Chlorella, in the presence as well as in the absence of carbon dioxide, does not change appreciably the relative contents of inorganic and organic phosphorus in the cells. A significant tion of organic phosphate which materials, this change can be noted in the composition of the fracis precipitable by barium. In the absence of carbon dioxide, the relative amount of "resistant" phosphorus was large in the dark, but decreased upon illumination. The results under ^ and ^ prove that Chlorella does have a phosphorus metabolism which is almost a trivial result, in consideration of the universal participation of phosphates in the metabolism of most if not all organisms. The results under 3 indicate, however, that the paths of the phosphorus metabolism of Chlorella may be significantly different from that of the animal tissues and bacteria. The result under 4 represents a failure to prove a photochemical con(It was hoped that, in the version of inorganic into organic phosphate. Although these results are interesting as first steps towards the investigation of the phosphorus metabolism of Chlorella, they obviously do not represent effective arguments in favor of the "phosphate storage" hy- - Until more positive evidence is provided, we more convincing a general argument against Phothis hypothesis, which can be derived from energy considerations. The difficulty of the phosphate storage theory appears most clearly when one considers the fact that, in weak light, eight or ten quanta of one molecule of carbon dioxide (cf. If each quantum would produce one molecule of highenergy phosphate, the accumulated energy would be only 80-100 kcal light are sufficient to reduce per einstein -while photosynthesis requires at least 112 kcal per mole, and probably more, because of losses in irreversible partial reactions. The phosphate storage hypothesis appears somewhat less improbable when applied to chemosynthesis. One may assume that the oxidation of hydrogen, sulfur, ferrous iron or other substrates by oxygen proceeds in easy steps (as in the oxidation of glucose in the muscle), each step being coupled with the production of a high-energy phosphate, and that the energy of these phosphates is utilized later to transfer hydrogen, by In the case of reducsimilar easy steps, from water to carbon dioxide. However, the metabolism of "iron bacteria" is not well known, and in the better investigated cases of hydrogen, sulfur or thiosulfate bacteria, the reductants have comparatively high potentials, and the intermediate dissipation of their oxidation energy in the of 10 kcal each appears implausible. It was found above that no quinonoid-benzenoid or ferri-ferro system is likely to have the required high Systems of the type of hexadiene-benzene, while sufficiently potential. I H i i Free radicals should be violent oxidants and strong reductants at the same I time. These estimates, derived from standard bond strengths, may be approximately correct for simple radicals whose energies are not strongly affected by resonance; but may be far off the mark for radicals of a more complex structure. The general tendency in reaction kinetics is to resolve chemical respectively; cf. Michaelis suggested that hydro- genations and dehydrogenations of organic compounds take place in single steps, with one hydrogen atom (or one electron) transferred at a this mechanism would be impossible (except at high temperafree radicals had the high energies calculated from standard bond strengths. Reversible oxidation-reduction systems, the formation of free radicals in oxidation-reduction processes was discovered in 1931 by Friedheim and Michaelis, and by Elema, working with the same bacterial Further investigations, mainly by Michaelis and coworkers (for dyestuflf, pyocyanine. If Ei > Et, Kd > 1, and the maximum proportion of the semiquinone is less than one-third. In the triphenyl methyl radical, for example, the structure usually assumed, PhsC i is supplemented by a number the o-quinonoid forms, of other "resonating" structures, including Ph2C^<^ -^ and the p-quinonoid forms, As mentioned acetic acid, etc. To enable an oxidation-reduction to proceed smoothly at room temperature, it is sufficient for the energy of the semiquinone to be not larger than 10 kcal; this is compatible with a dismutation constant as not high as effect. Among "monovalent" organic systems, whose potentials have been measured, we find, for example, the porphyrexide, with a potential of - 0. Free Radicals in Photosynthesis and Chemosynthesis wide range of stability of free radicals has In the first several consequences for the mechanism of photosynthesis. Let us consider, as an illustration, the thionine-ferrous iron the first product of the light reaction is the reaction (of. Michaelis, Schubert, and Granick 1940; Granick, Michaehs, and Schubert 1940; and Michaelis and Granick 1941). Thus, in the formation of one molecule of leuco thionine, by the cooperation of two light quanta, according to the mechanism (7. In chapter 7, two alternative hypotheses were suggested for the mechanism by which eight quanta could be used to move four hydrogen atoms from water to carbon dioxide: a twice repeated photochemical activation of the same four hydrogen atoms (as in Schemes how and 7. As mentioned on page 166, the "energy dismutation" theory is supported mainly by the analogy between the photosynthesis of green plants and the chemosynthesis of hydrogen bacteria, for which it offers a simple explanation. Our suggestion is that this branching occurs in the oxidation of the intermediate H2X. The highest ratio between the rates of autotrophic reduction of carbon dioxide and of autoxidation is found when hydrogen serves as a According to Ruhland (1924), one molecule of hydrogen is reductant. Gaffron (1944) concluded, from experiments on adapted algae, that the limiting value of this ratio is 2 (c/. In other words, out of twelve hydrogen atoms which enter into the enzymatic apparatus, four are "promoted" and react with carbon dioxide, while eight are "degraded" - by union with oxygen. Ill for the interpretation of chemosynthesis with hydrogen as a reductant by substituting molecular hydrogen for H2Y as a hydrogen donor, and molecular oxygen for Z as the "promoting" oxidant. We between oxygen and carbon dioxide, both hydrogen atoms go to oxygen, while in the second one they are shared between oxygen and carbon dioxide: (9. V photosynthesis, 6,3,1,2, {4,3} -photoretoo complicated, we have adopted duction, 6 {4,8}-chemosynthesis. Ill, that is, we have written out the oxidation-redaction systems participating in the metabolism of adapted algae, and indicated by numbered arrows the hydrogen transfers occurring between them. Speculations in this are encouraged by the conclusion of Hill (1939) and Hill and Scarisbrick (1941) (c/. However, it is doubtful whether they can be positive enough to allow the complex in the ferrous form to reduce the hydrogenase (whose potential at pH 7 must be about + 0. In chapter 11, we shall consider the possibility that a ferrous iron compound serves as reductant in the primary photochemical process. This compound must have an exceptionally negative potential (even below that of free ferrous ions) in order to be able to recover its electron from water. However, it may be worth while to keep in mind the possibility that the photochemical process in photosynthesis may be the transfer of electrons from an iron (or other metal) complex of an exceptionally positive potential. On page 158, we suggested that the rest of the reduction process may be ascribed to dismutations (cf. Pushing the analogy with respiration still further, one could suggest that an alternation of hydrogenations and carboxylations continues until a triose. Experimental Evidence Regarding the Mechanism of Reduction of Carbon Dioxide In respiration and fermentation, speculations of the type presented above, are corroborated by experimental evidence isolation of inter- - mediates, substitution tests, reactions of isolated enzymes and so forth. Attempts to identify the intermediates in photosynthesis by ordinary analytical methods will be dealt with in chapter 10. They have produced numerous data (some of which may yet prove to be related to photosynthesis), and have led to prolonged controversies (for instance, concerning the occurrence of formaldehyde in plants), but did not yet reveal a single chemical compound clearly associated with photosynthesis, either as an intermediate or as a catalyst. Recently, some information concerning the nature of intermediates was obtained from experiments with radioactive carbon. Similar experiments were also carried out by Ruben and coworkers with illuminated plants. Ruben, Hassid, and Kamen (1939) illuminated barley leaves for 1^70 minutes in the presence of C*02. The leaves were then extracted with warm water and analyzed as quickly as possible. More extensive experiments were carried out with Chlorella suspensions by Ruben, Kamen, Hassid, and Devault (1939), Ruben, Kamen, and Hassid (1940), and Ruben, Kamen, and Perry (1940). Figure 24 shows that the uptake of radioactive carbon in light proceeds for over an hour at a constant rate of about 0. The radioactive-carbon content of the algae is expressed in arbitrary units, one unit corresponding to the uptake of 6. It is not precipitated by protein-coagulating agents (heat, trichloroacetic It is colorless acid), or by reagents which precipitate basic amino acids.
What Fisons urges is a type of hindsight revaluation of what its patent counsel should perhaps have said if the intention were indeed to convey the multiple considerations it now seeks to advance women's health center of oregon purchase 70 mg alendronate amex. It cannot be gainsaid that "suitable for oral administration" is too cryptic and too inartful a phrase to prescribe to the relevant reading public-persons skilled in the art-or menopause dryness order alendronate 70mg on line, indeed menstrual nausea vomiting buy discount alendronate 35 mg line, to any objective reader the congeries of meanings now sought to be attributed to that phrase breast cancer drug alendronate 35mg for sale. As Morton Grove points out womens health subscription generic 70 mg alendronate visa, drugs are routinely administered orally despite their being unstable pregnancy news cheap 70mg alendronate with amex, horrid-tasting, highly toxic and without therapeutic activity (M. For example, solutions made extemporaneously by pharmacists and used in a very short period of time need not be stable, yet they may be "suitable for oral administration" (M. Similarly, Morton Grove has pointed to various drugs that are administered orally yet are horrid tasting, such as dicloxacillin and potassium chloride (M. Emmet Clemente, n6 such a drug is "suitable for oral administration"-it just might not be a successful product (M. But this Court then follows its customary practice of limiting any later usage of the title "Dr. X" to anyone who is a medical doctor, using simply "X" to refer to the possessor of any different doctorate. Joel Zatz ("Zatz") in arguing that toxicity is relevant to determining whether a solution is "suitable for oral administration" (F. F 5): To be suitable for oral administration, pharmaceutical solutions must satisfy the requirements of oral preparations generally, as well as those related specifically to solutions. This requirement excludes certain ingredients that may be commonly used for other delivery routes. For example, ophthalmic and other topical products may contain as a preservative benzalkonium chloride, a substance not generally used orally. F 5): Another requirement for a pharmaceutical solution suitable for oral administration is that it be therapeutically active and efficacious. For example, a drug may be efficacious when injected intravenously but, because of breakdown in the gut by enzymes, lose its activity when administered orally. While the patentees clearly contemplated that their solution would have greater stability than previously developed oral formulations and, in its preferred embodiment, would be sweetened so as to be more palatable, those limitations cannot be read into the broader language in claim 1 (see Kemco Sales, 208 F. As for toxicity and efficacy, the written description is virtually silent on those issues in any event. Because the formulations set forth in those patents would not cause certain death or debilitating harm if taken orally, Fisons suggests that the Examiner recognized that "suitable for oral administration" means more than that and allowed Patent 774 to issue on that ground. But Fisons also pointed to a variety of other purported differences between its proposed patent and the prior art. Regarding the Pittman Patent, Fisons noted not only that it is for a different use but also that it suggests an alcoholic solution of a different steroid (id. Regarding the Ayer Patent, Fisons noted that its compounds "mainly intended for topical application rather than oral administration" concern steroids structurally different from prednisone and that its compounds intended for oral administration are suspensions containing ethanol and no sequestering agent (id. As for the Chow Patent, Fisons noted that its formulations use different steroid compounds (id. Fisons did not argue that the Pittman, Ayer and Chow formulations are unsuitable for oral administration or argue that its patent is distinguishable from the prior art on that basis alone. Thus it would be inappropriate to narrow the meaning of the claim terms in light of those sources in any event (Johnson Worldwide Assocs. It does not carry the extra baggage sought to be loaded onto the phrase by Fisons. We need not evaluate this argument because, even assuming its correctness, such a limitation would have been an obvious modification over the prior method claims, as we will discuss infra. Bristol cites cases such as General Foods and Symbol Technologies as supporting the proposition that there is no double patenting where one can practice the invention claimed in the earlier-issued patents without infringing the inventions claimed in the later-issued patent or vice-versa. Bristol contends that because the claims in the prior method patents may be practiced without infringing the composition claims, we need not inquire further into obviousness-type double patenting. Bristol contends that saline in the claims in the prior method patents was used only for administration at levels isotonic with body fluids. They assert that under the appropriate "obvious modification" inquiry, the only new limitation of the composition claim, "protected from light," is an obvious modification of the claims in the method patents in light of prior art references such as Perumareddi that teach the light sensitivity of platinum complexes. We agree with the defendants that the district court did not err in concluding that double patenting existed here. General Foods and Symbol Technologies do not entitle Bristol to a threshold cross-infringement test or patent term extension test. In General Foods, we first stated that the two patents at issue did not claim the same invention and then found that "under an obviousness-type double patenting analysis, neither claimed process is a mere obvious variation of the other. Thus, we made the "obvious modification" inquiry that is required by precedent to resolve obviousness-type double patenting issues. In Symbol Technologies, we first dismissed the double patenting challenge on the ground that 35 U. We then decided, in the event that the safeguard of § 121 did not apply, that the differences between the claims at issue would not have been obvious. Finally, we stated as a matter of policy that the decision did not allow the unlawful extension of the patent grant. However, the policy rationale upon which Bristol relies does not supplant the case law requirement that a court determine whether or not the claims at issue would have been obvious variations over the prior claims, an inquiry that we conducted in both General Foods and Symbol Technologies. In that case, the United States Patent and Trademark Office had held the claims invalid because one could not practice the invention of the prior claims without infringing the later claims. We affirmed the rejection, but on the ground that each additional limitation led only to an obvious modification of the device in the prior claims. Likewise, in this case, the proper obviousness-type double patenting test inquiry is whether each additional limitation leads to an obvious modification of the invention of the prior claims. Nevertheless, even though the claims do not define the same invention, there is no per se nonobvious distinction between a method of using a device and the device itself. In this case, as in Lonardo, the same invention is not claimed twice, but there is no nonobvious variation between the claimed composition and the composition to be used in the claimed methods. We also conclude that "suitable for therapeutic administration by injection in solution therefor" is not a patentable distinction over those claims. We do not agree that a complex "suitable for therapeutic administration" requires a degree of purity greater than that already required by the claims of the method patents. Those claims are directed to treating malignant animal tumor cells by parenteral administration in an amount sufficient to cause regression of the tumor. Those method claims are also necessarily directed to the administration of therapeutic compositions because they are intended to cause regression of tumor cells. Although we may not use the disclosure of the prior patent as prior art in a double patenting analysis, it may be used to interpret the meaning of the claim. Here, where Bristol asserts that the saline in the composition claims has a unique significance - maintenance of therapeutic properties after storage - that is lacking in the method claims, and the significance of saline is not evident from the claims themselves, we may look to the specification to construe how saline is used in each claim. The patents share the same written description, which indicates that saline was used to stabilize the solutions for the brief period of time between preparation and administration in the inventions of the various patents. A reading of the claim, the specification, and the prosecution history fails to produce a clear definition of the meaning of the phrase "suitable for therapeutic administration by injection in solution therefor. In reviewing the extrinsic evidence, the Court must construe the claim through the eyes of a "person of ordinary skill in the field of the invention. We have discovered that complex compounds of platinum cause regression of malignant tumors in animals. More specifically, the present invention is a method for treating malignant tumors in animals which comprises parenterally administering to an animal affected with a malignant tumor a solution containing a complex compound of platinum in an amount sufficient to cause regression of the tumor. Plaintiffs contend that the phrase "suitable for therapeutic administration by injection in solution therefor" means that "the claimed therapeutic composition is in solution, or dissolves in a volume to become a complete solution, that is sterile and substantially free from harmful impurities, and that retains substantially the same therapeutic properties and characteristics that it possessed at the time of its manufacture. Defendant Pharmachemie asserts that the phrase means "that the complex is capable of being put into a water or other solvent-based solution. Thus, plaintiffs claim that while the complex must be capable of dissolving in liquid, it must be suitable for therapeutic administration. To achieve this result, plaintiffs contend that "the claimed composition must be sterile, substantially free from harmful impurities and must retain its therapeutic properties over time. For example, transdermal and inhalation are two additional methods of parenteral administration. The three defendants also refer to the dictionary definition and seem to take the same view as the plaintiffs. Defendants assert that they are not altering their previous definition of "suitable for therapeutic administration by injection in solution therefor" as meaning "that platinum complex is capable of being put into solution in water or other media for parenteral administration. Defendants note that the parties have agreed on both the claim terms "therapeutic composition" and "therapeutic effective amount" and, as a practical matter, this settled the dispute as to meaning of "therapeutic. Similarly, defendant Pharmachemie avers that the emphasis on sterility and pyrogen-free comes from the testimony of an oncological pharmacist and the Court has already found that pharmacy is not the relevant art. Whether "therapeutic" incorporates sterility and pyrogenicity freedom is another issue. DeSombre at the Markman hearing held on February 2, 1998 at 122-123 ("Q: And before you inject a therapeutic agent into an animal you normally make sure that the solution is as pure as possible? Q: And when you test anti-tumor agents, you want to test the chemical in as pure a condition as possible? You would use, for example, a sterile isotonic saline as the diluent for substance. You would not have gone to the extent you would use for human experiments, for example, actually doing bacterial cultures to see whether the injectant contained any bacteria; but you would be normally cautious to make sure that you were not harming the animal, which would, in fact, impinge on the results of your experiment. Q: And you would not consciously allow material to degrade therapeutic compositions before you injected it into animals? However, the idea that the inventors would conduct animal experiments without first conducting sterility tests seems counterintuitive, since unknown impurities could prevent the reproducibility of the experiment from one test batch of mice to another. Anderson, an oncological pharmacist, whose testimony the Court found was irrelevant to the discussion at hand because he applied the relevant art of pharmacy rather than cancer research. Lastly, the stipulated agreement that the phrase "therapeutically effective amount" means "an amount sufficient to have an effect as an antitumor agent" and that "a therapeutic composition" means "a composition that is an effective antitumor agent" does not necessarily imply that the word "therapeutic" contained in the phrase "suitable for therapeutic administration by injection in solution therefor" must encompass a sterile and pyrogen-free substance. Because the extrinsic evidence reveals that cancer researchers did not ensure bacteria free solutions prior to injecting the platinum complexes into mice, the solutions are not required to be sterile. This is not to say that the complexes are harmful to the subject, but rather the substance is as pure as possible short of ensuring its sterility. Thus, upon reviewing all the intrinsic and extrinsic evidence of record, this Court finds that the phrase "suitable for therapeutic administration by injection in solution therefor" must be construed as meaning "a tumor reducing platinum complex that is capable of being placed into solution or other nonharmful media for parenteral administration. DeSombre, reveals that cancer researchers did not perform sterility and pyrogenicity tests before injecting the platinum complexes into mice. Therefore, in conclusion, this Court finds that the phrase "suitable for therapeutic administration by injection in solution therefor" must be construed as meaning "a tumor reducing platinum complex that is capable of being placed into solution or other nonharmful media for parenteral administration. Instead, they contest the limitation, if any, imposed by the phrase in the preambles to independent claims 1 and 15 "suitable for use in a biosensor. Generally, a claim preamble, when read in the context of the entire claim, recites claim limitations only if "the claim cannot be read independently of the preamble and the preamble must be read to give meaning to the claim or is essential to point out the invention. Indeed, when discussing the "claim" in such a circumstance, there is no meaningful distinction to be drawn between the claim preamble and the rest of the claim, for only together do they comprise the "claim. In the case at bar, the preamble statement "suitable for use in a biosensor" does not merely state a purpose or intended use for the claimed structure. Rather, the phrase informs the construction of the remainder of the claims by defining the matrix coating. The body of the claims is directed to an article that cannot be divorced from the intended field of use. It is only under the conditions imposed by the phrase "suitable for use in a biosensor" that the elements of the claims perform the functions by which they are defined. Thus, the statement at issue is "necessary to give life, meaning, and vitality" to the claims. The phrase is "meshed with the ensuing language of the claim" because it defines the conditions under which the matrix coating is to be employed. Those conditions must be such that the charged groups actually function to bring about a concentration of oppositely-charged ligands that are then covalently bound via the reactive groups. The statement further requires that the quantity of charged groups be that which would bring about a sufficient concentration of biomolecules to produce a useful signal for biosensor purposes. Consequently, the claims can be understood only in the context of this preamble statement, which constitutes a limitation on the claims. For the reasons discussed above, the Court finds that "super-purifying said smoke to reduce taste imparting components below thresholds for imparting smoke odor and taste" is supported by the disclosures made in the specifications. Thus, according to plaintiffs, the composition of the "surface active material" must be determined or measured for infringement purposes before it is made into a "pharmaceutical composition. Thus, according to defendants, the phrase "surface active material," as used in the patents, covers both the solid lung surfactant extract material before the physiological saline is added to form a "pharmaceutical composition" and the "pharmaceutical composition" itself, since the "pharmaceutical composition" also has surface tension reducing properties. For example, the addition of water causes a hydrolosis process that increases the amount of free fatty acids. Both the claim language and the language in the specifications show that the term "surface active material," as used in Claim 1 of the patents, means the lung surfactant extract material in dry form before it is suspended in physiological saline to form a "pharmaceutical composition" and that the chemical composition of the "surface active material" must be determined for infringement purposes before it is made into a "pharmaceutical composition. Claim 7 and Claim 9 provide as follows: Claim 7 A pharmaceutical composition useable for the treatment of hyaline-membrane disease comprising an effective amount of surface-active material as set forth in claim 1 and a pharmaceutically acceptable non-toxic carrier thereof. Claim 9 A pharmaceutical composition useable for the treatment of respiratory distress syndrome comprising an effective amount of a surface active material as set forth in claim 1 and a pharmaceutically acceptable carrier thereof. As defined by the patentee, the "pharmaceutical composition" inventions covered by Claims 7 and 9 are made by combining the "surface active material" set forth in Claim 1 of the patents with a pharmaceutically acceptable carrier, such as physiological saline. Thus, according to the patent claims themselves, the "surface active material" is only a part or subset of - 1846 - Jump to: A B C D E F G H I J K L M N O P Q R ST UVW XY Z the "pharmaceutical composition. The only way Claims 7 and 9 make sense as written is if "surface active material" means the lung surfactant extract material before it is suspended in physiological saline to form the "pharmaceutical composition. Clearly, the patentees intended to give the terms "surface active material" and "pharmaceutical composition" distinct meanings.
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When considering wireless networking womens health orlando cheap alendronate 35 mg without a prescription, you need to keep in mind the capabilities and requirements for using breast cancer chemo drugs order 35 mg alendronate mastercard, managing and supporting these devices women's health clinic portlaoise generic 35 mg alendronate free shipping. Smartphones Smartphone A telephonic device that provides similar capabilities to a personal computer breast cancer clothing cheap alendronate 35 mg visa. A smartphone is a variety of cell phone that provides some computing capabilities womens health redding ca 35 mg alendronate fast delivery. Several different tools are available that allow users access to wireless networks triple negative breast cancer order alendronate 35mg overnight delivery. The primary difference between a smartphone and a mobile phone is that a smartphone comes with an independent operating system, thus giving it similar capabilities to a computer. Using this operating system, developers can create applications specific to the device. A few popular smartphone operating systems are: · BlackBerry: this operating system was introduced in 1999 as an e-mailready pager. Today, however, the BlackBerry provides a cell phone as well as the same application capabilities as other smartphones. BlackBerrys support multitasking and built-in interoperability with various business applications like Microsoft Exchange and Lotus Domino, which allows for easily synchronizing with business tools like e-mail, calendaring, and contact lists. The iPhone was one of the first Smartphones that used a multi-touch technology and a web browser. With the multi-touch technology, the iPhone is able to interact with the user through touch and motion. You can manually enter commands through the touch interface and the iPhone can interpret your entry to access your requested action. Android A smartphone operating system that allows developers to create applications for smartphones. Each of the Smartphone operating systems supports various applications including: · Productivity applications: these types of applications include small versions of popular business productivity applications like the Microsoft suite of tools including Word, Excel, and PowerPoint. Most Smartphones are capable of downloading and installing applications without the use of a computer. However, many Smartphones have accessories that allow you to mimic a full computing experience. A tablet is a portable personal computer generally with a touchscreen input and a built-in wireless adapter. Similar to Smartphones, Tablets come equipped with an independent operating system that allows users to add applications based on their needs. Users use tablets for a variety of applications, including taking notes in meetings, showing diagrams in closed sessions, 398 Chapter 10: Wireless, Remote, and Wide Area Networking updating files while traveling, and, of course, playing a game or two. Because tablets can be connected through wireless networking, users can be allowed access to network resources, like printers and fax machines, as well. The iPad has a similar interface to the iPhone in that it supports multi-touch interactions. Some of the big draws for this tablet is that users can read books, watch movies, listen to music, play games, and surf for web content. Still other manufacturers are in the process of developing other tablet devices that will provide similar functionality to the iPad, but with unique operating systems. Manufacturers will build their devices around several different possible operating systems, including Mee-Go by Nokia and Android. Services like this provide an interface for merchants to make goods and services available for clients to bid on. In general, you can think of cloud computing as being any service that is offered outside of a company and is available to users from many different areas. When looking at cloud computing, you need to consider three components: the front end, the back end, and middle ware. To access services in the cloud the front end must have: · Access to the network containing the cloud: this access usually is to the Internet. On the back end lies the infrastructure including the servers, storage devices, applications, etc. Because of the nature of cloud computing, service providers generally warehouse robust systems capable of providing the processing power necessary to deliver services. Additionally, the service provider is responsible for ensuring services are available to clients at any point so they generally maintain a high level of redundancy. You have, too, if you have an e-mail account outside of your company, like Hotmail, Yahoo Mail, or Gmail. To get to any of these e-mail services, you have to use your own hardware, like your laptop, to access the network containing the services. You also have to use special software to access the service, usually a web browser. On the back end the e-mail provider provides the e-mail capability along with the security features that allow you to access your e-mail account, and prevents others from unauthorized access. The service provider also provides all the storage necessary to store your e-mail until you clean out your inbox. When considering service providers, take the time to find out how they plan on securing your data and restricting access to those you authorize. The middleware is responsible for allowing communications between systems within an interaction between the front and back ends. Middleware is a specialized software application that administers the interaction between the front end and back end. With the middleware a central server can monitor traffic and route requests appropriately. There are a number of smartphone models available today from various manufactures, but only a few operating systems. Section 10-4 · Various smart devices are available today that provide smaller, handheld platforms on which to perform many computer type activities, including accessing wireless networks. Section 10-2 · Remote access generally requires one or more remote access server and a set of clients requiring access. Which packet-switched connection method supports the highest bandwidth connections? Which protocol is used for Windows client dial-in remote access to a Windows server? You are designing a remote access solution for a company with three sets of requirements: · Field service personnel need as flexible a connection method as possible that will work from nearly any location-five users total. Researcher time requirements vary depending on whether they are gathering information or processing the data. When configuring support for field service personnel, what is needed at the client end? The office will be set up as part of the same Windows Active Directory domain as the main office. What are your options to correct the problem if the connection becomes saturated as the remote office grows? Reliability and access to data in any location are critical concerns, and a failure at any one location should not prevent other locations from communicating. You want to be able to specify the exact topology used to connect with remote offices with a determinate path between the offices. You estimate the current peak bandwidth requirements as 1 Mbps between each office and the other four offices. Requirements can vary from month to month and are their highest at end of quarter and end of year. How well does a circuit-switched solution meet your requirements (explain your answer)? How well does a direct circuit solution meet your requirements (explain your answer)? How well does a packet-switched solution meet your requirements (explain your answer)? The people trying to attack your computers and the people trying to protect them are in an ongoing race. Our discussion is limited to an overview of the subject, focusing on a few key topics. Not only could the subject of security more than fill a book, most of the topics introduced in this chapter could easily justify a book in itself. Our discussion of security starts by explaining why security is important and with a look at risk analysis. Next, we move on to practical subjects that apply directly to security: management activities like managing user accounts, resource access permissions, user rights, and guidelines for managing passwords. The chapter looks at network threats with an emphasis on threats originating from the Internet and how you can use firewalls to protect a network. Finally, it talks about malicious software and ways to protect a computer from its effects. Most of our examples in this chapter focus on the Windows family of operating systems and Windows networks. Not only is corporate espionage rampant, but also information such as valid names, e-mail addresses, and even credit card numbers are worth a great deal when passed into the wrong hands. The other is to detect these occurrences when they do happen, taking whatever steps are necessary to recover, minimize the damage, and prevent it from happening in the future. More recent summaries show the number of incidents declining slightly, but the financial impact of each incidence increasing. About 90 percent reported they suffered a measurable financial loss due to a security problem, with the average loss about $200,000. Most recent results reported by various organizations indicate that this 95 percent is still accurate for attempts to breach security, though some industry experts believe successful attempts have fallen off slightly. Malware infection continued to be the most commonly seen attack, with about two-thirds of respondents reporting it, and it appeared to be on the rise. By and large, respondents did not believe that the activities of malicious insiders (as opposed to non-malicious insiders) accounted for much of their losses due to cybercrime. Slightly more than half of the respondents said that their organizations do n ot use cloud computing. Ten percent, however, say their organizations not only use cloud computing, but also have deployed cloud-specific security tools. In 1998, the European Union passed strong data privacy laws that fined companies for disclosing information about their customers. Confidentiality refers to the protection of data from unauthorized disclosure of customer and proprietary data. Figure 11-2 identifies some potential threats to a computer center, data communication circuits, and attached computers. In general, your goals in response to security threats are ensuring business continuity and preventing unauthorized access. Business continuity planning refers primarily to ensuring availability, with some aspects of data integrity. One concern is disruptions, which are the loss of or reduction in network service. They can be caused by device failures, such as a failing hub or switch, or by a result in the data destruction. For example, a virus (a malicious program that attaches itself to another program and then propagates copies of itself) may destroy files that users need. Natural or manmade disasters such as fires, floods, earthquakes, mudslides, tornadoes, or terrorist attacks can destroy large parts of the buildings and networks in their path. Unauthorized access relates primarily to confidentiality, but also to integrity, because someone with unauthorized access may change important data. Unauthorized access is external attackers gaining access to organizational data files and resources from across the Internet. However, most unauthorized access incidents involve employees, if not as the attacker, then as the source for passwords or other information. A curious intruder may explore the system, gaining knowledge that has little value, and perhaps leaving behind some sort of calling card. A more serious intruder might be a competitor bent on industrial espionage who attempts to gain access to Confidentiality A term that refers to protection of data from unauthorized disclosure. Availability A term that refers to providing continuous access to the critical data and the operation of an organizations hardware and software so that there is no interruption of service. Business continuity planning Ensuring availability and integrity; keeping the business running when disruptions occur. Unauthorized access Access by unauthorized personnel that violates confidentiality and/or integrity. Worse still, the intruder could change files to commit fraud or theft, or could destroy information to injure the organization. Though still a third of our sample, breaches linked to business partners fell for the first time in years. The median size of breaches caused by insiders is still the highest, but the predominance of total records lost was attributed to outsiders. Ninety-one percent of all compromised records were linked to organized criminal groups. A growing percentage of cases and an astounding 94 percent of all compromised records in 2009 were attributed to Financial Services. Doing so assigns levels of risk (how likely they are to occur and the amount of damage they could cause) to various threats to network security by comparing the nature of the threats to the controls designed to reduce them. Identifying Network Assets Network assets Any hardware or software of value on a network. Start by identifying network assets, which are any things of value on the network (hardware or software).
A) the velocity of blood flow within each segment of the circulatory system is inversely proportional to the total cross-sectional area of the segment womens health 75150 cheap 70mg alendronate. Because the aorta has the smallest total cross-sectional area of all circulatory segments breast cancer umbrella cheap alendronate 70 mg overnight delivery, it has the highest velocity of blood flow menstrual bleeding for a month generic alendronate 35mg line. B) Filtration rate is the product of the filtration coefficient (Kf) and the net pressure across the capillary wall women's health big book of yoga amazon generic alendronate 70 mg with amex. The net pressure for fluid movement across a capillary wall = capillary hydrostatic pressure - plasma colloid osmotic pressure - interstitial colloid osmotic pressure - interstitial hydrostatic pressure womens health specialists of dallas generic alendronate 70mg mastercard. In this example pregnancy pillows purchase 35 mg alendronate with amex, vessel A has the highest vascular resistance (100 mm Hg/1000 ml/min, or 0. C) the transport of oxygen across a capillary wall is proportional to the capillary surface area, capillary wall permeability to oxygen, and oxygen gradient across the capillary wall. Thus, a twofold increase in the oxygen concentration gradient would result in the greatest increase in the transport of oxygen across the capillary wall. A twofold increase in intercellular clefts in the capillary wall would not have a significant impact on oxygen transport because oxygen can permeate the endothelial cell wall. A) Atrial natriuretic peptide is released from myocytes in the atria in response to increases in atrial pressure. C) the capillaries have the largest total cross-sectional area of all vessels of the circulatory system. The venules also have a relatively large total cross-sectional area, but not as great as the capillaries, which explains the large storage of blood in the venous system compared with that in the arterial system. C) An increase in perfusion pressure to a tissue results in excessive delivery of nutrients such as oxygen to a tissue. The increase in tissue oxygen concentration constricts arterioles and returns blood flow and nutrient delivery toward normal levels. A 50% reduction in renal artery pressure would be below the range of renal autoregulation and would result in a decrease in the glomerular filtration rate. B) An increase in plasma colloid osmotic pressure would reduce net filtration pressure and capillary filtration rate. Increases in capillary hydrostatic pressure and interstitial colloid osmotic pressure would also favor capillary filtration. An increase in venous hydrostatic pressure and arteriolar diameter would tend to increase capillary hydrostatic pressure and capillary filtration rate. D) An increase in sodium intake would result in an increase in sodium excretion to maintain sodium balance. Conversely, potassium excretion would only transiently increase after an increase in sodium intake. C) the rate of lymph flow increases in proportion to the interstitial hydrostatic pressure and the lymphatic pump activity. A decrease in plasma colloid osmotic pressure would increase filtration rate, interstitial volume, interstitial hydrostatic pressure, and lymph flow. A decrease in arteriolar diameter would decrease capillary hydrostatic pressure, capillary filtration, and lymph flow. Thus, a reduction in nitric oxide production would result in an increase in arterial pressure. A decrease in the production of these factors would tend to decrease arterial pressure. E) the brain has tight junctions between capillary endothelial cells that allow only extremely small molecules such as water, oxygen, and carbon dioxide to pass in or out of the brain tissues. B) the factors that determine the net movement of glucose across a capillary wall include the wall permeability to glucose, the glucose concentration gradient across the wall, and the capillary wall surface area. Thus, an increase in the concentration difference of glucose across the wall would enhance the net movement of glucose. E) An increase in atrial pressure of 10 mm Hg would tend to decrease venous return to the heart and increase vena cava hydrostatic pressure. Plasma colloid osmotic pressure, interstitial colloid osmotic pressure, arterial pressure, and cardiac output would generally be low to normal in this patient. A) An increase in renal arterial pressure results in increases in sodium and water excretion. Normally, glomerular filtration rate would be normal or slightly increased in response to an increase in renal artery pressure. However, in the absence of an intact tubuloglomerular feedback system, an important renal autoregulatory mechanism, an increase in renal artery pressure would result in significant increases in glomerular filtration rate. C) the vascular compliance is proportional to the vascular distensibility and the vascular volume of any given segment of the circulation. The compliance of a systemic vein is 24 times that of its corresponding artery because it is about 8 times as distensible and has a volume about 3 times as great. C) the difference between systolic pressure and diastolic pressure is called the pulse pressure. The two main factors that affect pulse pressure are stroke volume and arterial compliance. Pulse pressure is directly proportional to the stroke volume and inversely proportional to the arterial compliance. Net filtration pressure = capillary hydrostatic pressure - plasma colloid osmotic pressure + interstitial colloid osmotic pressure - interstitial hydrostatic pressure. B) Moving from a supine to a standing position results in pooling of blood in the lower extremities and a fall in blood pressure. The fall in arterial pressure activates the arterial baroreceptors, which in turn increases sympathetic nerve activity and decreases parasympathetic nerve activity. The increase in sympathetic activity constricts renal vessels and reduces renal blood flow. D) Reduction in perfusion pressure to a tissue leads to a decrease in tissue oxygen concentration and an increase in tissue carbon dioxide concentration. Both events lead to an increase in arteriolar diameter, decreased vascular resistance, and increased vascular conductance. B) Because oxygen is lipid soluble and can cross the capillary wall with ease, it has the fastest rate of movement across the capillary wall. The ability of lipid-insoluble substances such as sodium, albumin, and glucose to move across a capillary wall depends on the permeability of the capillary to lipid-insoluble substances. Because the capillary wall is relatively impermeable to albumin, it has the slowest rate of net movement across the capillary wall. A) An increase in capillary wall permeability to water would increase capillary filtration rate, whereas increases in arteriolar resistance, plasma colloid osmotic pressure, and interstitial hydrostatic pressure would all decrease filtration rate. D) the tendency for turbulent flow occurs at vascular sites where the velocity of blood flow is high. E) Total peripheral vascular resistance = arterial pressure - right atrial pressure ч cardiac output. C) Interstitial hydrostatic pressure in a muscle capillary bed is normally negative (-3 mm Hg). A) the two main factors that affect pulse pressure are stroke volume and arterial compliance. Increases in stroke volume increase pulse pressure, whereas an increase in arterial compliance decreases pulse pressure. Hemorrhage and decreased venous return would decrease stroke volume and pulse pressure. D) the primary mechanism whereby solutes move across a capillary wall is simple diffusion. C) Movement of the leg muscles causes blood to flow toward the vena cava, which reduces venous hydrostatic pressure. An increase in right atrial pressure would decrease venous return and increase venous hydrostatic pressure. Pregnancy and the presence of ascitic fluid in the abdomen would tend to compress the vena cava and increase venous hydrostatic pressure in the legs. A) Nitric oxide is a vasodilator that is believed to play a role in regulating blood flow. Infusion of a nitric oxide donor into the brachial artery would increase arteriolar diameter and decrease arteriolar resistance. The decrease in arteriolar resistance would also result in an increase in capillary hydrostatic pressure and filtration rate. The increase in filtration rate leads to an increase in interstitial hydrostatic pressure and lymph flow. D) In persons with decompensated heart failure, the kidneys retain sodium and water, which causes a weight gain and an increase in blood volume. This effect increases the mean systemic filling pressure, which also stretches the heart. The excess blood volume often will overstretch the sarcomeres of the heart, which will prevent them from achieving their maximal tension. An excess central fluid volume also results in orthopnea, which is the inability to breathe properly except in the upright position. A) During progressive hemorrhagic shock, the vasomotor center often fails, thus reducing sympathetic output. Decreased blood flow throughout the body causes acidosis because of decreased removal of carbon dioxide. In progressive shock due to hemorrhage, capillary permeability increases and mean systemic filling pressure decreases. C) With an overdose of furosemide there is a large loss of sodium and water from the body, resulting in dehydration and sometimes shock. The optimal therapy is to replenish the electrolytes that were lost as a result of the overdose of the furosemide. C) Severe vomiting can lead to a large loss of sodium and water from the body, resulting in dehydration and sometimes shock. C) the formula for resistance to venous return is mean systemic filling pressure - right atrial pressure/ cardiac output. In this example the mean systemic filling pressure is 7 mm Hg and the right atrial pressure is 0 mm Hg. Using these values in the previous formula indicates that the resistance to venous return is 1. Note that this formula only applies to the linear portion of the venous return curve. A) During increases in sympathetic output to maximal values, several changes occur. First, the mean systemic filling pressure increases markedly, but at the same time the resistance to venous return increases. Venous return is determined by the following formula: mean systemic filling pressure - right atrial pressure/ resistance to venous return. During maximal sympathetic output, the increase in systemic filling pressure is greater than the increase in resistance to venous return. Therefore, in this formula the numerator has a much greater increase than the denominator, which results in an increase in the venous return. The formula for cardiac output is oxygen absorbed per minute by the lungs divided by the arterial-venous oxygen difference. In this problem, oxygen consumption of the body is 240 ml/min, and in a steady-state condition, this would exactly equal the oxygen absorbed by the lungs. Therefore, by inserting these values into the equation, we see that the cardiac output will equal 12 L/min. A) A shift to the right in the cardiac output curve involves an increase in the normal intrapleural pressure of -4 mm Hg. Taking a patient off of a ventilator, decreasing intrapleural pressure to -7 mm Hg, and breathing against a negative pressure will shift the cardiac output curve to the left. C) Several factors can cause the cardiac output to shift to the right or to the left. Playing a trumpet or positive pressure breathing tremendously increases the intrapleural pressure, thus collapsing the atria and shifting the cardiac output curve to the right. Breathing against a negative pressure will shift the cardiac output curve to the left. E) the plateau level of the cardiac output curve, which is one measure of cardiac contractility, decreases in several circumstances. Some of these circumstances include severe cardiac tamponade, which increases the pressure in the pericardial space, and increasing parasympathetic stimulation of the heart. Increased sympathetic stimulation of the heart increases the level of the cardiac output curve by increasing heart rate and contractility. B) Cardiac output increases in several conditions because of increased venous return. Cardiac output decreases in patients with hypovolemia, severe aortic regurgitation, and polycythemia. The hematocrit level is high in polycythemia, which increases resistance to venous return. D) Mean systemic filling pressure is a measure of the tightness of fit of the blood in the circulation. Mean systemic filling pressure is increased by factors that increase blood volume and decrease the vascular compliance. Therefore, an decreased venous compliance, not an increased compliance, would cause an increase in mean systemic filling pressure. Norepinephrine administration and sympathetic stimulation cause arteriolar vasoconstriction and decreased vascular compliance, resulting in an increase in mean systemic filling pressure. Increased blood volume and skeletal muscle contraction, which cause a contraction of the vasculature, also increase this filling pressure.