The present invention discloses devices and methods for performing intravascular procedures without cardiac bypass. The devices include various embodiments of temporary filter devices, temporary valves, and prosthetic valves. The temporary filter devices have one or more cannulae which provide access for surgical tools for effecting repair of the cardiac valves. A cannula may have filters of various configurations encircling the distal region of the cannula, which prevent embolitic material from entering the coronary arteries and aorta.The temporary valve devices may also have one or more cannulae which guide the insertion of the valve into the aorta. The valve devices expand in the aorta to occupy the entire flow path of the vessel. In one embodiment, the temporary valve is a disc of flexible, porous, material that acts to filter blood passing therethrough. A set of valve leaflets extend peripherally from the disc. These leaflets can alternately collapse to prevent blood flow through the valve and extend to permit flow.The prosthetic valves include valve fixation devices which secure the prosthetic valve to the wall of the vessel. In one embodiment, the prosthetic valves have at least one substantially rigid strut, at least two expandable fixation rings located about the circumference of the base of the apex of the valve, and one or more commissures and leaflets. The prosthetic valves are introduced into the vascular system a compressed state, advanced to the site of implantation, expanded and secured to the vessel wall.

The present invention relates to the discovery of new class of hydrolysable amino acid derivatives and absorbable polyester amides, polyamides, polyepoxides, polyureas and polyurethanes prepared therefrom. The resultant absorbable polymers are useful for drug delivery, tissue engineering, tissue adhesives, adhesion prevention, bone wax formulations, medical device coatings, stents, stent coatings, highly porous foams, reticulated foams, wound care, cardiovascular applications, orthopedic devices, surface modifying agents and other implantable medical devices. In addition, these absorbable polymers should have a controlled degradation profile.

A feed additive includes at least one of p-thymol, a salt derivative and an ester derivative thereof for animals.

The present invention provides drug conjugates comprising 5-aminolevulinic acid (ALA), an aldehyde and a carboxylic acid that may function as a histone deacetylase inhibitor (HDACI). These conjugates may serve as co-drugs which release a plurality of active species in vivo. The novel drug conjugates may be used, for the treatment or prevention of cancer in PDT-dependent and/or PDT-independent (nonPDT) treatments, as well as for cosmetic uses. In addition the present invention provides novel uses for both the novel and known compounds. According to some embodiments, the present invention provides drug conjugates (co-drugs) comprising (i) ALA, (ii) an aldehyde and (iii) a carboxylic acid that may function as a histone deacetylase inhibitor (HDACO for the treatment of anemia and/or for the induction of erythropoiesis.

The invention provides certain bis-acylated hydroxylamine derivative compounds, pharmaceutical compositions and kits comprising such compounds, and methods of using such compounds or pharmaceutical compositions. In particular, the invention provides methods of using such compounds or pharmaceutical compositions for treating, preventing, or delaying the onset and/or develop of a disease or condition. In some embodiments, the disease or condition is selected from cardiovascular diseases, ischemia, reperfusion injury, cancerous disease, pulmonary hypertension and conditions responsive to nitroxyl therapy.

A compound of Formula (I): or a pharmaceutically acceptable salt of the compound. Also described are pharmaceutical formulations thereof and methods of using the same.

A phenyl alkyl carbamate derivative compound and a pharmaceutical composition containing the compound are provided. More specifically, the phenyl alkyl carbamate derivative compound and a pharmaceutically acceptable salt thereof, a composition for muscle relaxation containing the phenyl alkyl carbamate derivative compounds and/or pharmaceutically acceptable salt thereof as an active ingredient, and a method of muscle relaxation comprising administering a pharmaceutically effective amount of the phenyl alkyl carbamate derivative compound and/or a pharmaceutically acceptable salt thereof to a subject in need of to a subject in need of, are provided.

The present invention relates to norbornene-ester-based derivatives, to a method for preparing same, and to the uses thereof. This compound may be used as a plasticizer which can replace a phthalate-based plasticizer.

A catalyst for synthesis of lactic acid and it derivatives is provided. The catalyst includes SnY2.mH2O and at least one of NH4X or quaternary ammonium salts, wherein X and Y are selected from F—, Cl—, Br—, I—, CH3SO3—, C6H5SO3—, CH3C6H4SO3— or CN—, m represents an integer of 1 to 15. A method for synthesis of lactic acid and it derivatives with the above catalyst is also provided. By using the above catalyst and method, it is capable of converting carbohydrate-containing raw material to lactic acid and its derivatives directly in a more efficient and economical way.

Phosphoranimide-metal catalysts are disclosed. The catalysts comprise first row transition metals such as nickel, cobalt or iron. The hydrocarbon-soluble catalysts have a metal to anionic phosphoranimide ratio of 1:1, and have no inactive bulk phase and no dative ancillary ligands. The electronic state of the clusters can be adjusted to optimize catalytic activity for a range of commercially important reductive transformations, including hydrodesulfurization. A method of synthesis of these catalysts by anionic metathesis of a halide substituted precursor followed by oxidation is also disclosed.

A method of removing at least a portion of a silicon oxide material is disclosed. The silicon oxide is removed by exposing a semiconductor structure comprising a substrate and the silicon oxide to an ammonium fluoride chemical treatment and a subsequent plasma treatment, both of which may be effected in the same vacuum chamber of a processing apparatus. The ammonium fluoride chemical treatment converts the silicon oxide to a solid reaction product in a self-limiting reaction, the solid reaction product then being volatilized by the plasma treatment. The plasma treatment includes a plasma having an ion bombardment energy of less than or equal to approximately 20 eV. An ammonium fluoride chemical treatment including an alkylated ammonia derivative and hydrogen fluoride is also disclosed.

Provided are a novel 1,2-bis(dialkylphosphino)-4,5-(methylenedioxy)benzene derivative that forms a metal complex having particularly high asymmetry induction capacity and catalytic activity on β-dehydroamino acids, a method for manufacturing the same, a metal complex having this 1,2-bis(dialkylphosphino)-4,5-(methylenedioxy)benzene derivative as a ligand, and an asymmetric hydrogenation method using this metal complex. A 1,2-bis(dialkylphosphino)-4,5-(methylenedioxy)benzene derivative represented by general formula (1). (In the formula, R1 and R2 represent an alkyl group having 1-10 carbon atoms, and R1 and R2 have different numbers of carbon atoms.)

A method of manufacturing a compound or a salt thereof expressed with a formula (III) below, characterized by causing a compound or a salt thereof expressed with a formula (I) below and a compound or a salt thereof expressed with a formula (II) below to react in the presence of carbonate and copper salt or in the presence of hydroxide salt, carbonate, and copper salt.

A process for the manufacture of dialkyl furan-2,5-dicarboxylate (DAFD) vapor composition by feeding furan-2,5-dicarboxylic acid (“FDCA”) to an esterification reactor and in the presence of an alcohol compound such as methanol, conducting an esterification reaction to form an esterification vapor containing DAFD, unreacted alcohol compound, 5-(alkoxycarbonyl)furan-2-carboxylic acid (ACFC), and water, and continuously passing the esterification vapor through an ACFC condensing zone, that can be integral with the esterification reactor, in which at least a portion of the ACFC in the esterification vapor is converted to a liquid phase condensate, and continuously discharging the esterification vapor from the ACFC condensing zone as a DAFD vapor. There is also a DAFD vapor composition containing DAFD, water, unreacted alcohol, and by-products.

A compound with a diphenylmethane moiety having an inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) being present in the intestine and kidney is disclosed. A pharmaceutical composition including the compound as an active ingredient, which is useful for preventing or treating metabolic disorders, particularly diabetes is disclosed. A method for preparing the compound, and a method for preventing or treating metabolic disorders, particularly diabetes, by using the compound is provided.

Lactic acid equivalents are recovered from a starting lactide stream by catalytically racemizing a portion of the lactide in the stream at a temperature of 180° C. or below. This increases the proportion of two species of lactide (i.e., at least two of S,S-, R,R- or meso-lactide) at the expense of the third species. The racemized mixture so obtained can be separated to recover some or all of one or more of the lactide species from the remaining lactide species, by a process such as melt crystallization or distillation. Impurities in the starting lactide stream usually are retained mostly in the remaining meso-lactide, so a highly purified S,S- and/or R,R-lactide stream can be produced in this manner. Such a purified S,S- and R,R-lactide stream is suitable for polymerization to form a polylactide.

The present invention relates to the preparation of cyclopropane derivatives, in particular 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-4,8-dihydro-1H-purin-6-one, especially via the [(1S,7R)-4-phenyl-3,5-dioxabicyclo[5.1.0]octan-1-yl]methanol intermediate.

The present invention relates to a compound of formula (I) including any stereochemically isomeric form thereof, wherein the substituents are as defined in the specification and the claims; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof; provided that the compound is other than or a pharmaceutically acceptable salt thereof. The claimed compounds are useful for the treatment of a disease, the treatment of which is affected, mediated or facilitated by activating the GHS1A-r receptor. The invention also relates to pharmaceutical compositions thereof and processes for the preparation thereof.

A process for the production of 1,4-butanediol and tetrahydrofuran by catalytic hydrogenation of dialkyl maleates includes the following steps: a) hydrogenating a stream of dialkyl maleate in a first stage of reaction over suitable catalysts to produce dialkyl succinate;b) further hydrogenating the dialkyl succinate in a second stage of reaction, by using a different suitable catalyst, for producing mainly 1,4-butanediol, together with gamma-butyrolactone and tetrahydrofuran as co-products. In both stages of reaction the conditions, as hydrogen/organic feed ratio, pressure and temperature, are such to maintain the reactors in mixed liquid/vapor phase.

The invention provides a method for synthesizing 7-Acetyleno quinone methide compounds that is safe and inexpensive. The method avoids the need for extremely cold reaction temperatures and unlike the prior art does not require any highly explosive materials. The method comprises the steps of: a) performing a condensation reaction between 3,5-di-tert-butyl-4-hydroxybenzaldehyde and a secondary amine thereby forming a secondary amine quinone methide intermediate;b) removing water from the secondary amine quinone methide intermediate by azeotropic distillation;c) adding the dehydrated secondary amine quinone methide intermediate to an organic medium containing a metal acetylide to form a Mannich base intermediate; andd) adding a release agent to the Mannich base intermediate to yield a 7-Acetyleno quinone methide.

A way to formulate prasterone to both increase its oral bioavailability, and decrease the variability of its oral bioavailability. In contrast to the approach taught by the prior art, the instant approach is amenable to scale-up to commercial scale. Further, the resulting product is amenable to analysis using standard, known quantitative analytical techniques; thus, unlike the prior art approach, the instant approach may be used to manufacture a product in conformity with applicable regulatory standards.

The present invention relates to novel 4-pregenen-11β-17-21-triol-3,20-dione derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals, as modulators of glucocorticoid or mineralocorticoid receptors. The invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat disorders associated with glucocorticoid or mineralocorticoid receptor modulation.

Provided are compounds of Formula I wherein R1, R2, Y, Z and G are as defined herein, that are useful in the treatment and/or prevention of diseases mediated by deficient levels of glucokinase activity, such as diabetes mellitus. Also provided are methods of treating or preventing diseases and disorders characterized by underactivity of glucokinase or which can be treated by activating glucokinase.

The disclosure provides compounds and methods of using Apogossypolone derivatives for treating diseases and disorders. In particular, the disclosure provides compounds of Formula I: or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and provides methods for the preparation of compounds of Formula I; and methods for treating cancer, autoimmune diseases, and inflammation by administering a compound of Formula I.

The present invention provides for a practical, universal and efficient method to ligate two large macromolecules (e.g., proteins) using the alkyne-azide 1,3-dipolar cycloaddition reaction to produce a conjugated macromolecule, such as a multivalent scFv. The present invention also provides for conjugate macromolecules comprising a plurality of macromolecule components cross-linked through at least one linking group comprising at least one 1,2,3-triazole moiety, wherein at least 50 percent of the macromolecule components in the conjugate macromolecule has only one site available for cross-linking.

The present invention discloses novel process for the preparation of (2R)-2-acetamido-N- benzyl-3-methoxypropanamide of Formula I involving novel intermediates of Formula-XIX and Formula-XX.

To provide a novel vitamin D3 derivative useful as a therapeutic agent for osteoporosis. Provided is a vitamin D3 derivative represented by the following formula (1) or a medicinally acceptable solvate thereof: wherein R1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkylcarbonyloxyalkyl group with each alkyl having 1 to 6 carbon atoms, or an arylcarbonyloxyalkyl group with the aryl having 6 to 10 carbon atoms and the alkyl having 1 to 6 carbon atoms; R2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms or, together with the other R2 and the carbon atom to which they are bound to, may form a cyclic alkyl group having 3 to 6 carbon atoms; R3 represents an alkyl group having 1 to 6 carbon atoms or, together with the other R3 and the carbon atom to which they are bound to, may form a cyclic alkyl group having 3 to 6 carbon atoms; X represents an oxygen atom or a methylene group; and n represents an integer of 1 or 2.

Tissue slices and whole organisms offer substantial challenges to fluorescence imaging. Autofluorescence and absorption via intrinsic chromophores, such as flavins, melanin, and hemoglobins, confound and degrade output from all fluorescent tags. An “optical window,” farther red than most autofluorescence sources and in a region of low hemoglobin and water absorbance, lies between 650 and 900 nm. This valley of relative optical clarity is an attractive target for fluorescence-based studies within tissues, intact organs, and living organisms. Novel fluorescent tags were developed herein, based upon a genetically targeted fluorogen activating protein and cognate fluorogenic dye that yields emission with a peak at 733 nm exclusively when complexed as a “fluoromodule”. This tool improves substantially over previously described far-red/NIR fluorescent proteins in terms of brightness, wavelength, and flexibility by leveraging the flexibility of synthetic chemistry to produce novel chromophores.

A compound of the formula (1) wherein the substituents are as defined in claim 1, are useful as a pesticides.

Benzoyl derivatives of the formula I where the variables have the following meanings: R1, R2 are hydrogen, nitro, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or C1-C6-haloalkylsulfonyl;R3 is hydrogen, halogen or alkyl;R4, R5 are hydrogen, halogen, cyano, nitro, alkyl, alkoxy, alkylthio, dialkylamino, phenyl or carbonyl, it being possible for the 6 last-mentioned radicals to be substituted;X is O, S, NR9, CO or CR10R11;Y is O, S, NR12, CO or CR13R14;R15 is pyrazole which is unsubstituted or substituted, linked in the 4-position and has attached to it in the 5-position a hydroxyl or sulfonyloxy radical; and the agriculturally useful salts thereof; processes and intermediates for the preparation of the 3-heterocyclyl-substituted benzoyl derivatives; compositions comprising them; and the use of these derivatives or compositions comprising them for controlling undesirable plants.

Methods, systems, and computer readable media for monitored application of mechanical force to samples using acoustic energy and mechanical parameter value extraction using mechanical response models can be used for determining mechanical property parameters of a sample. An exemplary method includes applying acoustic energy to a sample to apply a mechanical force to the sample, measuring a response by the sample during the application of the acoustic energy, measuring a recovery response of the sample following cessation of the application of the acoustic energy, and determining a value for at least one additional mechanical property parameter of the sample based on the response measured during application of the acoustic energy and the recovery response measured following cessation of the application of acoustic energy.

Provided herein are methods, processes and apparatuses for non-invasive assessment of genetic variations.

A method and a system for producing a change in a medium disposed in an artificial container. The method places in a vicinity of the medium at least one of a plasmonics agent and an energy modulation agent. The method applies an initiation energy through the artificial container to the medium. The initiation energy interacts with the plasmonics agent or the energy modulation agent to directly or indirectly produce the change in the medium. The system includes an initiation energy source configured to apply an initiation energy to the medium to activate the plasmonics agent or the energy modulation agent.

A method and a system for producing a change in a medium. The method places in a vicinity of the medium at least one energy modulation agent. The method applies an initiation energy to the medium. The initiation energy interacts with the energy modulation agent to directly or indirectly produce the change in the medium. The system includes an initiation energy source configured to apply an initiation energy to the medium to activate the energy modulation agent.

A centrifuge includes a vacuum pump machine configured of an auxiliary vacuum pump and an oil diffusion pump for exhausting gas inside a rotary chamber to outside, in which a rotor rotates at high speed. In the centrifuge, a thermistor for detecting a temperature of oil and an oil surface inside a boiler of the oil diffusion pump is provided inside the boiler, and power of a heater is adjusted with the temperature detected by the thermistor, so that a degree of vacuum inside the rotary chamber is stably reduced from atmospheric pressure to a high vacuum state. Besides, when the heater does not heat, a current is carried through the thermistor for self-heating, and it is determined from variation in a resistance value whether the oil exists or not at a position at which the thermistor 8 is placed.

An apparatus for separating at least two discrete volumes of a composite liquid into components, comprising a valve design that facilitates loading and unloading of sets of blood bags. The valves comprise a jaw mounted on a shaft, the jaw being adapted to apply radio frequency energy to seal a tube, a stepper motor section, and at least two position sensors. The valve sections are mounted on an upper plate, and the stepper motor sections are mounted on a lower plate. A main radio frequency coil is selectively electrically coupled to each of the valves through a multiplexing switch.

The invention is a method of processing tarry or resinous liquids. Tarry liquids include wet scrubber liquids containing tars and chars derived from gasification, pyrolysis or drying of biomass. Resinous liquids include those derived from processing coniferous biomass. Tarry or resinous liquid is processed by a horizontal axis centrifuge having a discharge chamber containing a scraper to prevent centrifuge clogging or fouling. The removed tar and char can be used as solid fuel or recycled to the gasification or pyrolysis process. Polymers, for instance cationic polymers, can be added to the tarry or resin containing liquid prior to centrifugation to assist in solids/liquids separation. Removed resin can be recycled for further use. Tar, char or resin depleted wet scrubber liquid can be recycled for further use or more easily treated prior to disposal.

Methods and apparatuses for activating colorant in selected regions of an article in which the colorant is incorporated are described. The colorant activation can create various desired visual aspects.

The present invention provides heat-sensitive coating compositions, which comprise a color developer of formula (1) or mixtures thereof wherein R1 can be hydrogen, C1-20-alkyl, C3-8-cycloalkyl, C2-10-alkenyl, aryl or SO3H, and R2 and R3 can be the same or different and can be hydrogen, halogen, C1-20-alkyl, C3-8-cyclo-alkyl, C2-10-alkenyl, aryl, OR6, NR7R8, SR9, SO3H or COOR10 and R4 and R5 can be the same or different, and can be hydrogen, halogen, C1-20-alkyl, C3-8-cyclo-alkyl, C2-10-alkenyl, aryl, OR6, NR7R8 or SR9, R6, R7, R8, R9 and R10 can be the same or different and can be hydrogen, C1-30-alkyl, C3-8-cycloalkyl, C2-10-alkenyl or aryl, wherein C1-20-alkyl can be unsubstituted or substituted with one or more C3-8-cycloalkyl, C2-10-alkenyl, phenyl, halogen, OR11, NR12R13, SR14, SO3H or COOR15, and aryl can be unsubstituted or substituted with one or more halogen, C1-10-alkyl, halogenated C1-10-alkyl, C3-8-cycloalkyl C2-10-alkenyl, phenyl, OR11, NR12R13, SR14, SO3H or COOR15, wherein R11, R12, R13, R14 and R15 can be the same or different and can be hydrogen, C1-10-alkyl, C3-8-cycloalkyl or C2-10-alkenyl, a process for the preparation of these compositions, a process of coating substrates with these compositions, substrates coated with these compositions, a process for preparing marked substrates using these compositions, marked substrates obtainable by the latter process, and certain color developers.

The present invention relates to a web substrate comprising an activatable colorant and at least one deformed region. A first activated color region is produced in the web substrate upon exposure to a first external stimulus and a second activated color region is produced within the first activated color region upon exposure to a second external stimulus. The second activated color region coincides with the deformed region.

The invention provides a phenolsulfonic acid aryl ester represented by formula (1) wherein each symbol is as defined in the description. The phenolsulfonic acid aryl ester is useful as a developer to provide a thermal recording material with good color-developing sensitivity, image density when printed at a low application energy (i.e., high start-up sensitivity), and heat and plasticizer resistance. The invention also provides a thermal recording material using the developer.

The invention relates to a so-called zero emission ‘AST-CNR/ITM system’ modular plant for removal of pollutants from flue gases produced by industrial processes. The plant comprises prefabricated modular elements with programmed and automatic operation, easy to mount and assemble on site without undergoing expensive plant stoppage. Each module or ‘reaction tower’ comprises a plurality of sections vertically arranged on top of one another, which carry out the following functions: Removal of particulate matter with treatment and removal of chemical pollutants, such as heavy metals, chlorides, fluorides Treatment and removal of SOx Treatment and removal of NOx Capture of CO2 Production of hydrogen Production of methanol. The various sections may be combined according to the requirements of the plant and of the flue gases to be treated.

Embodiments include methods of identifying a personalized cardiovascular device based on patient-specific geometrical information, the method comprising acquiring an anatomical model of at least part of the patient's vascular system; performing, using a processor, one or more of geometrical analysis, computational fluid dynamics analysis, and structural mechanics analysis on the anatomical model; and identifying, using the processor, a personalized cardiovascular device for the patient, based on results of one or more of the geometrical analysis, computational fluid dynamics analysis, and structural mechanics analysis of anatomical model.

Embodiments include methods of identifying a personalized cardiovascular device based on patient-specific geometrical information, the method comprising: generating a patient specific model of at least a portion of a patient's vasculature from image data of the patient's vasculature and one or more measured or estimated physiological or phenotypic parameters of the patient; determining pathology characteristics from cardiovascular geometry of the patient specific model; defining an objective function for a device based on design considerations and one or more estimates of hemodynamic and mechanical characteristics; optimizing the objective function, by simulating at least one change in devices and evaluating the objective function using fluid dynamic or structural mechanic analysis; and using the optimized objective function to either (i) select a device from a set of available devices or (ii) manufacture a desired device.

An apparatus, system and method are introduced for preserving privacy of data in a dataset in a database with a number n of entries. In one embodiment, the apparatus includes memory including computer program code configured to, with a processor, cause the apparatus to form a random matrix of dimension m by n, wherein m is less than n, operate on the dataset with the random matrix to produce a compressed dataset, form a pseudoinverse of the random matrix, and operate on the dataset with the pseudoinverse of the random matrix to produce a decompressed dataset.

A proposed feature vector for a first deign is received and an existing feature vector for an existing design is retrieved for a given task. The proposed design is evaluated against the existing design using task-based scores associated with each design and based on their performances for the given task.

Vacuum deposited thin films of material are described to create an interface that non-preferentially interacts with different domains of an underlying block copolymer film. The non-preferential interface prevents formation of a wetting layer and influences the orientation of domains in the block copolymer. The purpose of the deposited polymer is to produce nanostructured features in a block copolymer film that can serve as lithographic patterns.

A magnetic data storage medium may include a substrate, a magnetic recording layer, a protective carbon overcoat, and a monolayer covalently bound to carbon atoms adjacent a surface of the protective carbon overcoat. According to this aspect of the disclosure, the monolayer comprises at least one of hydrogen, fluorine, nitrogen, oxygen, and a fluoro-organic molecule. In some embodiments, a surface of a read and recording head may also include a monolayer covalently bound to carbon atoms of a protective carbon overcoat.

One or more temporal stimulation parameters of vagus nerve stimulation (VNS) are selected to substantially modulate one or more target physiological functions without substantially modulating one or more non-target physiological functions. In one embodiment, a stimulation duty cycle is selected such that VNS is delivered to the cervical vagus nerve trunk to modulate a cardiovascular function without causing laryngeal muscle contractions.

Methods and devices for determining optimal Atrial to Ventricular (AV) pacing intervals and Ventricular to Ventricular (VV) delay intervals in order to optimize cardiac output. Impedance, preferably sub-threshold impedance, is measured across the heart at selected cardiac cycle times as a measure of chamber expansion or contraction. One embodiment measures impedance over a long AV interval to obtain the minimum impedance, indicative of maximum ventricular expansion, in order to set the AV interval. Another embodiment measures impedance change over a cycle and varies the AV pace interval in a binary search to converge on the AV interval causing maximum impedance change indicative of maximum ventricular output. Another method varies the right ventricle to left ventricle (VV) interval to converge on an impedance maximum indicative of minimum cardiac volume at end systole. Another embodiment varies the VV interval to maximize impedance change.