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US6236887B1 - Drug-device combination for controlling the contractility of muscles - Google Patents
Drug-device combination for controlling the contractility of muscles Download PDF
cardiac muscle
excitatory
Shlomo Ben-Haim
Nissim Darvish
Yuval Mika
Maier Fenster
Impulse Dynamics NV
1996-09-17 Priority to IL11926196A priority Critical patent/IL119261D0/en
1996-09-17 Priority to IL119261 priority
1997-07-09 Application filed by Impulse Dynamics NV filed Critical Impulse Dynamics NV
1997-07-09 Priority to PCT/IL1997/000232 priority patent/WO1998010829A1/en
2000-12-27 Assigned to IMPULSE DYNAMICS NV reassignment IMPULSE DYNAMICS NV ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BEN-HAIM, SHLOMO, DARVISH, NISSIM, FENSTER, MAIER, MIKA, YUVAL
2007-06-12 Assigned to DRUMBEAT LIMITED reassignment DRUMBEAT LIMITED SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: IMPULSE DYNAMICS N.V.
2007-08-30 Assigned to BANK HAPOALIM B.M. reassignment BANK HAPOALIM B.M. SECURITY AGREEMENT Assignors: IMPULSE DYNAMICS N.V.
2007-09-10 Assigned to JOHNSON & JOHNSON DEVELOPMENT CORPORATION reassignment JOHNSON & JOHNSON DEVELOPMENT CORPORATION SECURITY AGREEMENT Assignors: IMPULSE DYNAMICS N.V.
2009-03-18 Assigned to MEDINVEST CAPITAL S.A R.L. reassignment MEDINVEST CAPITAL S.A R.L. SECURITY AGREEMENT Assignors: IMPULSE DYNAMICS N.V.
2015-04-08 Assigned to SANDLEFORD PARK LIMITED, AS SECURITY AGENT reassignment SANDLEFORD PARK LIMITED, AS SECURITY AGENT ASSIGNMENT OF TRADEMARK AND PATENT SECURITY AGREEMENT Assignors: MEDINVEST CAPITAL S.A.R.L., MORGAN STANLEY BANK INTERNATIONAL LIMITED
2019-04-24 Assigned to IMPULSE DYNAMICS N.V. reassignment IMPULSE DYNAMICS N.V. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: BANK HAPOALIM B.M.
2019-04-24 Assigned to IMPULSE DYNAMICS N.V. reassignment IMPULSE DYNAMICS N.V. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: JOHNSON & JOHNSON INNOVATION - JJDC, INC., FORMERLY KNOWN AS JOHNSON & JOHNSON DEVELOPMENT CORPORATION
2019-04-24 Assigned to IMPULSE DYNAMICS N.V. reassignment IMPULSE DYNAMICS N.V. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: SANDLEFORD PARK LIMITED
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A61N1/3627—Heart stimulators for treating a mechanical deficiency of the heart, e.g. congestive heart failure or cardiomyopathy
A61N1/365—Heart stimulators controlled by a physiological parameter, e.g. heart potential
A61N1/36514—Heart stimulators controlled by a physiological parameter, e.g. heart potential controlled by a physiological quantity other than heart potential, e.g. blood pressure
A61N1/36564—Heart stimulators controlled by a physiological parameter, e.g. heart potential controlled by a physiological quantity other than heart potential, e.g. blood pressure controlled by blood pressure
A61B2017/00243—Type of minimally invasive operation cardiac
A61B17/02—Surgical instruments, devices or methods, e.g. tourniquets for holding wounds open; Tractors
A61B2017/0237—Surgical instruments, devices or methods, e.g. tourniquets for holding wounds open; Tractors for heart surgery
A61B2017/0243—Surgical instruments, devices or methods, e.g. tourniquets for holding wounds open; Tractors for heart surgery for immobilizing local areas of the heart, e.g. while it beats
A61N1/36014—External stimulators, e.g. with patch electrodes
A61N1/36557—Heart stimulators controlled by a physiological parameter, e.g. heart potential controlled by a physiological quantity other than heart potential, e.g. blood pressure controlled by chemical substances in blood
A61N1/368—Heart stimulators controlled by a physiological parameter, e.g. heart potential comprising more than one electrode co-operating with different heart regions
An apparatus for the combined drug/electric-stimulation treatment of a cardiac muscle comprises circuitry (S) for creating a non-excitatory electric potential between at least two points (R1, R2) located in the vicinity of a muscle (H). A method for the combined drug/electric-stimulation treatment of a cardiac muscle, using the apparatus, involves controlling the start time, duration, and magnitude of the electric current flowing between said at least two points, to impart a desired change in cardiac muscle performance.
This application is a filing under 35 U.S.C. § 371 of PCT patent application No. PCT/IL97/00232, filed Jul. 9, 1997, which i based in part on commonly assigned U.S. provisional patent application Ser. No. 60/026,392, filed Sep. 16, 1996, now abandoned.
The present invention relates to the field of medicine. More particularly, the invention relates to means for controlling the contractility of muscles in patients treated with drugs which influence the cardiovascular system.
Many activities of the human body involve the contraction of muscles. For instance, movement of the limbs, breathing activity, etc. The most complex and vital muscular activity of the human body is that of the heart, which functions as a pump and which, by contracting at the required times and in the required manner, controls the flow of blood throughout the body.
The heart is composed of different parts, which contract differently and with different timing, in order to permit the aforementioned pumping activity. The contraction of the heart is controlled by electric stimuli, which are generated at the cellular level by chemical reaction. However, it is well known in the art to control the timing of the contraction of the cardiac muscle, by the action of externally applied electric stimuli, through the so-called "pace maker".
In a copending PCT patent application No. PCT/IL97/00012, filed Jan. 8, 1997 by the same applicants herein, the specification of which is incorporated herein by reference, there is described a method and apparatus for modifying the force contraction of at least a portion of a heart chamber, which comprises applying a non-excitatory electric field, for a predetermined period of time, at a delay after activation, which causes the force of contraction to be increased. Substantial increases in the force of contraction are obtained, typically—but non-limitatively—in the order of 5%-50%. This increase in cardiac output is useful in order to obviate cardiac insufficiency due to a variety of pathological situations, e.g., the reduction of cardiac output due to the implantation of a pace maker, the insufficiency due to the results of the malfunctioning of a portion of the cardiac muscle, etc.
In another copending PCT/IL patent application, entitled "Apparatus and Method for Controlling the Contractility of Muscles", filed by the same applicants herein on the same day as the present application and identified as Attorney's Docket 4224/WO/97, the specification of which is incorporated herein by reference, there is described a method and apparatus for decreasing the force contraction of at least a portion of a heart chamber, which comprises applying a non-excitatory electric field of a polarity inverse of that required for obtaining an increase of muscle contractility, for a predetermined period of time, at a delay after activation, which causes the force of contraction to be decreased. The ability of reducing the contractility is of importance in a variety of situations, e.g., during surgery or as an aid in healing of hibernated areas of a heart after myocardial infarct.
Several severe diseases of the cardiac muscle cannot be treated effectively without the aid of drugs. However, many drugs used in therapy have a deleterious, side-effect in that they reduce the contractility and cardiac output of the heart and may cause life threatening arrhythmias. Some illustrative examples of drugs used in the treatment of congestive heart failure (CHE) are given below.
Congestive heart failure (CHF) is a complex clinical syndrome characterized by impaired ventricular performance, exercise intolerance, a high incidence of ventricular arrhythmias, and shortened life expectancy. Virtually all forms of heart disease can lead to heart failure, with coronary artery disease, hypertension, and diabetes mellitus being the most common in the U.S.
CHF can be broadly subdivided into two distinct forms (although several other classification schemes have been used). Distinguishing between the two forms is often difficult: 1. Diastolic dysfunction or diastolic heart failure; and 2. Systolic dysfunction or systolic CHF.
Changes in the structure and biochemical properties of the myocardium and peripheral vasculature occur during the development of CHF and these changes can contribute to further impairment of cardiovascular function. Many different drugs are used in the therapy of CHF, which affect the cardiac muscle, whether directly or indirectly, by causing changes in the cardiovascular system.
Recent studies indicate that metoprolol, a commonly used beta-blocker which can cause up-regulation of beta-1 receptors, can restore catecholamine responsiveness to patients with dilated cardiomyopathy.
Captopril, an ACE inhibitor that is commonly used to treat heart failure, has been shown to increase lymphocyte Gs and increase myocardial beta-1 receptor density.
Digitalis (cardiac glycosides): has been used clinically for over 200 years to treat heart failure and edema (dropsy), but its present use in treating CHF is controversial. Digoxin is the most widely used preparation of digitalis (half-life=1-2 days), although digitoxin (half-life=7 days) is also used in situations where long half-life may be an advantage.
However, Digoxin may be toxic at relatively low dosages, since it may cause arrhythmia and conduction problems, but the art has so far failed to provide means by which the desirable therapeutic effect of Digoxin or similar drugs may be maintained at low dosages, so as to avoid toxicity problems.
Beta-Adrenergic agonists: beta1-adrenergic agonists (dopamine, dobutamine, prenalterol, xamoterol) have been used to treat acute and chronic heart failure, but have limited usefulness in chronic CHF because of their arrhythmogenic effects, short duration of action, the development of tolerance, and necessity of parenteral administration.
Dobutamine is a moderately selective beta1-adrenergic agonist that lacks vasoconstrictor activity and causes minimal changes in heart rate. It is frequently added to nitroprusside when blood pressure is adequate to increase cardiac output.
Prenalterol and xamoterol are partial beta1-adrenergic agonists that may simultaneously stimulate beta1-receptors and block the receptors from stimulation by endogenous catecholamines, thereby protecting against beta1-receptor down-regulation.
Cyclic nucleotide phosphodiesterase (PDE-III, cGMP-inhibitable PDE) inhibitors: There are several agents that increase myocardial and vascular smooth muscle cAMP through inhibition of cyclic nucleotide phosphodiesterase PDE-III, cGI PDE) activity. These agents should therefore simultaneously increase cardiac output and reduce afterload.
The bipyridines, amrinone and mirinone, are potent PDE-III inhibitors that can be given orally or parenterally. They can be given orally, are generally well-tolerated, but can have significant non-cardiac side-effects (nausea, vomiting, thrombocytopenia).
Ca+ Channel Blockers: Ca+ channel antagonists are widely used in many types of heart diseases, including cardiac insufficiency, and cause direct arterial vasodilatation by the inhibition of Ca+ current. Ditiazem and Verapamil exhibit negative inotropic, chronotropic and dromotropic effect on cardiac function. Some of these drugs, such as Verapamin, have life threatening side effects, such as altering the A-V node conduction.
Anti-Arrhythmic Drugs: In cardiac insufficiency, and in other ischemic diseases, many patients suffer from arrhythmia. Drugs acting on the chronicity are known to cause many side effects.
It is therefore clear that it is highly desirable to be able to reduce the dosage of such drugs, whenever possible, or to obviate side effects and problems which they may cause.
It has now been surprisingly found, and this is an object of the present invention, that it is possible to obviate the aforementioned drawbacks of drugs used in the therapy of heart diseases, by applying a non-excitatory signal of the type described above, which increases the contractility of the cardiac muscle and its output. It has further been found that this can be achieved without generating adverse effects and/or without adversely affecting the activity of the drug which is administered to the patient.
It is an object of the invention to provide apparatus for the combined drug/electric-stimulation treatment, which can be used as a treatment aid for a patient in need of a medicine which impairs heart muscle contractility.
It is another object of the invention to provide a method for treating a patient in need of a drug which may impair the contractility of the heart muscle.
It is yet another object of the invention to provide apparatus useful in therapy, by means of which the dosage of drugs having potentially harmful side effects can be reduced or, alternatively, by means of which the dosage can be increased while keeping side effects within an acceptable range.
It is still another object of the invention to provide apparatus which cooperates with such drugs, its activity being related to the amount of the drug present at a given time in the patient's blood.
Other objects and advantages of the invention will become apparent as the description proceeds.
In one aspect, the invention relates to an apparatus for the combined drug/electric-stimulation treatment of a cardiac muscle, comprising circuitry for creating a non-excitatory electric potential between at least two points located in the vicinity of a muscle.
According to a preferred embodiment of the invention, the apparatus comprises circuitry for controlling the start time of the electric potential generated between said at least two points. According to another preferred embodiment of the invention the apparatus comprises circuitry for controlling the duration of the electric potential generated between said at least two points. According to still another preferred embodiment of the invention the apparatus comprises circuitry for controlling the magnitude of the electric potential generated between said at least two points.
In a preferred embodiment of the invention the circuitry for creating a non-excitatory electric potential between said at least two points comprises one or more electrode. A variety of different electrodes can be used, which will be easily recognized by the skilled person. An illustrative example of suitable electrodes are carbon electrodes.
In another aspect, the invention is directed to apparatus for the combined drug/electric stimulation treatment, comprising circuitry for causing a non-excitatory electric current to flow between at least two points located in the vicinity of a muscle.
According to a preferred embodiment of the invention, the apparatus comprises circuitry for controlling the start time of the electric current flowing between said at least two points.
According to another preferred embodiment of the invention, the apparatus comprises circuitry for controlling the duration of the electric current flowing between said at least two points.
According to still another preferred embodiment of the invention, the apparatus comprises circuitry for controlling the magnitude of the electric current flowing between said at least two points.
In a preferred-embodiment of the invention the circuitry for causing a non-excitatory electric current to flow between said at least two points comprises one or more electrode, e.g., carbon electrodes.
In another aspect the invention is directed to means and methods for counteracting proarrhythmic effects of drugs.
In the context of the present invention, by "non-excitatory current", or "non-excitatory potential", or "non-excitatory signal", it is meant to indicate a signal which does not cause a propagating action potential in the muscle cells (which may start a new pacing or contraction of the muscle). In other words, the non-excitatory electric stimulation effected by a non-excitatory electric pulse is such that it does not induce propagating activation potentials in the cardiac muscle cells. Rather, such pulses affect the response of the heart muscle to the action potentials, by modulating cell contractility within selected segments of the cardiac muscle. As described in the abovementioned PCT patent application PCT/IL97/00012, the inventors have found that by applying non-excitatory electrical stimulation pulses of suitable strength, appropriately timed with respect to the heart's electrical activation, the contraction of the selected segments can be increased or decreased, thus increasing or decreasing the stroke volume of the heart.
There may be various reasons for a signal to be non-excitatory. Two main types of non-excitatory signals to be used in conjunction with the invention are: 1) A signal which, independently of its magnitude, is applied during the refractory period, and therefore does not cause a new contraction, even though its magnitude may be above threshold values for pacing; 2) A signal which is sub-threshold for pacing and, therefore, no matter when given, does not cause a new contraction to take place.
While a DC current is typically used as the base line for the non-excitatory signal, it is possible to supply a signal which is a complex signal for instance, a signal generated by superimposing an AC current on the DC base signal so as to generate a waveform of varying envelope. Any suitable signal can be superimposed, having any shape, e.g., square wave or sinusoidal wave, as will be apparent to the skilled person. Thus, according to one preferred embodiment of the invention the apparatus further comprises means for superimposing on a DC signal one or more waveforms of given frequency and amplitude, thereby to generate a complex signal.
The apparatus of the invention can be provided in different forms, e.g., as an insertable device or an extra corporal device or an implantable device.
According to a preferred embodiment of the invention, the circuitry for controlling the start time and/or duration of the electric potential is synchronized to heart activity, for instance, it can operate not at every beat of the heart, e.g., every 1, 2 or 3 beats of the heart.
According to a preferred embodiment of the invention the non-excitatory electric current is a DC electric current, and the apparatus may further comprise circuitry for superimposing on the DC signal one or more waveforms of given frequency and amplitude, thereby to generate a complex signal.
The apparatus employed to carry out the method of the invention can be of different construction, as will be apparent to the skilled person., One example of apparatus suitable for carrying out the invention is described in detail and claimed in a copending PCT patent application of the same applicants herein, entitled "Cardiac Output Controller", filed on the same day as the present application and identified as Attorney's Docket 27068, the description of which is incorporated herein by reference. Another example of suitable apparatus, coupled to a pacemaker device, is the subject of another copending PCT patent application of the same applicants herein, entitled "Cardiac Output Enhanced Pacemaker", filed on the same day as the present application and identified as Attorney's Docket 27181, the specification of which is also incorporated herein by reference. However, as said, the invention is not intended to be limited to any particular construction of device used to carry it out.
In another aspect, the invention is directed to apparatus for the combined drug/electric-stimulation treatment of a cardiac muscle, comprising:
means for creating an electric potential between at least two points located in the vicinity of the cardiac muscle;
means for causing a non-excitatory electric current to flow between said at least two point; and
means for controlling the start time, duration and magnitude of the electric current flowing between said at least two points.
According to a preferred embodiment of the invention the apparatus comprises:
means for creating an electric potential between at least a pair of electrodes in the vicinity of the cardiac muscle at at least two root locations;
means for causing a non-excitatory electric current to flow between said at least two root locations; and
means for controlling the start time, duration and magnitude of the electric current flowing between said at least two root locations.
By "root location" it is meant to indicate the vicinity of the muscle where the electrodes are located, which may be distinct from the area which is affected by the current flowing between them. As will be appreciated by the skilled person, due to the very complex nature of the electric behavior of the cardiac muscle, it is possible that positioning an electrode at a given location will affect another, more remote portion of the muscle. Therefore, the root location is not necessarily the center or any other portion of the treated area, but it is only a location, near the muscle, where an electrode will be positioned.
The invention is further directed to a method for the combined drug/electric stimulation treatment of a cardiac muscle, comprising a) administering to a patient in need thereof a drug which affects the cardiovascular system and which affects the cardiac muscle, or a mixture of two or more such drugs, b) creating a non-excitatory electric potential between at least two points located in the vicinity of the muscle, and c) controlling one or more of the parameters consisting of start time, duration, magnitude and polarity of the non-excitatory electric potential created between said at least two points.
In another aspect the invention is directed to a method for the combined drug/electric stimulation treatment of a cardiac muscle, comprising a) administering to a patient in need thereof a drug which affects the cardiovascular system and which affects the cardiac muscle, or a mixture of two or more such drugs, b) causing a non-excitatory electric current to flow between at least two points located in the vicinity of the muscle, and c) controlling one or more of the parameters consisting of start time, duration, magnitude and polarity of the non-excitatory electric current flowing between said at least two points.
The signal supplied to the patient according to the method of the invention is of the same type as described above with reference to the apparatus.
The change in cardiac muscle contractility and of electrophysiological characteristics of the cardiac muscle obtained by the method of the invention can be exploited for a variety of therapeutic purposes. According to one preferred embodiment of the invention, it is designed at least partially to compensate for cardiac muscle contractility decrease induced by said drug or mixture of drugs. According to another preferred embodiment of the invention it is designed at least partially to compensate for cardiac muscle contractility increase induced by said drug or mixture of drugs. According to still another preferred embodiment of the invention the change in cardiac muscle contractility is designed to add to and/or amplify the cardiac muscle contractility increase or decrease induced by said drug or mixture of drugs.
In another aspect the invention is directed to a method for reducing the dosage of a cardiovascular drug which affects cardiac muscle contractility. Thus, drugs such as Digoxin, and other proarrhythmic drugs, which as explained above have serious side effects, can be administered in substantially lower dosages, while at the same time achieving the same or even an improved effect on cardiac muscle contractility.
Thus, according to a preferred embodiment of the invention there is provided a method for the combined drug/electric-stimulation treatment of a cardiac muscle, comprising:
administering to a patient in need thereof a drug which affects the cardiovascular system and which affects the cardiac muscle, or a mixture of two or more such drugs;
providing an electric potential between at least a pair of electrodes in the vicinity of the cardiac muscle at at least two root locations;
causing a non-excitatory electric current to flow between said at least two contacting locations; and
controlling the start time, duration and magnitude of the electric current flowing between said at least two root locations, so as to impart the desired change in cardiac muscle contractility.
The invention further encompasses a kit for the treatment of cardiovascular diseases, comprising a drug or a combination of two or more drugs, and an apparatus according to the invention, as herein described.
Additional apparatus according to the invention comprises circuitry for controlling its activity as a function of calculated and/or actual level of a given drug or combination of drugs in the patient's blood.
The apparatus of the invention is further useful for reducing the dosage of pro-arrhythmic drugs, and, for counteracting side-effects of pro-arrhythmic drugs.
Further therepeutic flexibility can be provided by another preferred embodiment of the invention, in which the apparatus comprises timing circuitry for activating it at predetermined times during the day.
As will be appreciated by the skilled person, the actual set of operating parameters used (current, length of pulse, number of electrodes, lag after pacing signal, etc.), will be dependent on the specific use made of the invention, and the skilled person will be able to devise the optimal set of parameters for a given application. Some non-limitative operating ranges in which cardiac muscle reacts according to the invention are given here for the sake of illustration only, it being understood that operation outside such ranges is of course possible under various conditions: Current: 0.01-10 mA; Length of Pulse: 1-998 milliseconds with a pacing of 1 Hz, and 1-498 milliseconds with a pacing of 2 Hz; Delay after Pacing Signal: 1 milliseconds and above. Where no pace maker is used, the delay is preferably calculated from the natural pacing of the patient's heart, or from the local activation time.
While a variety of electrodes can be used, and the invention is in no way limited to any particular type of electrode, particularly preferred suitable electrodes for this purpose are, e.g., carbon electrodes.
The above and other characteristics and advantages of the invention will be more readily apparent through the following detailed description of preferred embodiments thereof with reference to the appended drawings, wherein:
FIG. 1 shows the effect of the application of an NT-signal to a rabbit papillary muscle in the presence of Caffeine;
FIG. 2 shows the effect of the application of an NT-signal to a rabbit papillary muscle in the presence of Ryanodine;
FIG. 3 shows the effect of the application of an NT-signal to a rabbit papillary muscle in the presence of Nifedipine;
FIG. 4 shows the effect of the application of an NT-signal to a rabbit papillary muscle in the presence of both propranolol and adrenaline;
FIG. 5 shows the effect of the application of an NT-signal to a rabbit papillary muscle in the presence of adrenaline;
FIG. 6 shows the effect of the application of an NT-signal to a rabbit papillary muscle in the presence of Diltiazem;
FIG. 7 shows the effect of the application of an NT-signal to a rabbit papillary muscle in the presence, of Digoxin; and
FIG. 8 is a schematic representation of an apparatus according to one embodiment of the invention.
The following terms and abbreviations, used throughout this specification, are defined below, for the sake of clarity:
b.p.m.=Beats per minute
HMC=Hypertrophic Cardiomyopathy
I.M.=Intramuscular
IV=Intra Venous
LV=Left Ventricle
LVP=left ventricular pressure
NT Signal=Non-Excitatory Signal
RV=Right Ventricle
VF=Ventricular Fibrillation
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The invention will now be illustrated through detailed experiments. Experiments in vitro were carried out using isolated rabbit papillary muscle, and the protocol for its isolation is detailed below.
The following equipment which will be referred to hereinafter, is now briefly described for the sake of clarity
Plugsys system: The plugsys system is an incorporating plug in modules for measuring, controlling and data processing in connection with recorders and computers. In general, it functions as an amplifier which increases the sensitivity of the measuring of biological signals. One such device, used in the experiments described herein, is manufactured by HSE, Germany.
Millar: This device (manufactured by Millar Instruments, U.S.A.), is a micro manometers transducer that can be connected to a battery operated bridge (which is the interface box) and the output can be digitized using an A/D converter. In another mode of operation the transducer is connected through a DBA (plugsys DC Bridge Amplifier), which is an amplifier connected to transducers to measure pressure force (manufactured by HSE, Germany).
ISOLATED PAPILLARY MUSCLE PROTOCOL
Animals: New Zealand white rabbits (males) from Israel (Yokneam) or an hybrid of New Zealand White and local albino rabbits (males, AniLab, Rehovot) are kept in room temperature, 2-3 per cage (35×55×65 cm), under natural light conditions. Daily feeding of dry food (Rabbit Mix-Code 590), and unlimited water supply. The cages and the room are cleaned daily,
A. for solution making: Scales (by Mettler toledo, model P8303, Max 310 gram, d=1 mGram) magnetic stirrer. by Freed electric. Weights 10 Kg (d=50 gram) by Moznei Shekel, Gas tanks with mixed 95% O2+5% CO2″ pressure regulators, pH meter by Mettler toledo, model 320 PH, ice machine 45 Labotal.
B. for the in-vitro papillary muscle preparation
Dissection chamber (HSH, Hugo Sachs Elektronik, Germany), Steered organ bath type 813 (I-18E) including temperature controller type 319, Force Transducer type F30 with amplifier type 660 and calibration unit (HSE), Stereoscope (Olympus), Digital micro manipulator (HSB), Manipulator, Anti-vibration table (IMC, U.S.A.), Faraday cage, Fiber optic illuminator (HSE), Current and Voltage clamp amplifier (axon Instruments, U.S.A.), stimulators (Grass instruments, U.S.A.), Micro-pipette puller by Narishige (model pp-83, Japan) Current source ISO 10 and ISO-50 (home made) supplying 10 and 50 mA correspondingly and Oscilloscope, 20 MHz (Gould, England), Computers: PowerPC 9500/I50, (Apple, U.S.A.), or Pentium, 160 MHz, Data Acquisition Boards: PC-AO-2DC, 16 bite, or the PCI-M10 8, 12 bite board by National Instrument, software: LabView for windows, by National Instrument (U.S.A.). Data acquisition and analysis program are home made, The program includes data acquisition and on-line analysis, programmable experiment execution, programmable signal output. The off-line analysis program analyze different parameters of muscle twitch and action potentials.
The Krebs-Heseleit Solution (KHS) was prepared using materials from Sigma (Israel): 0.32 g/lit KCl (4.5 mM), 6.99 g/lit NaCl (118.0 mm, 2.01 g/lit NaHCO3 (24.0 mM), 0.285 g/lit MgSO4·7H2O (1.19 mM, 0.16 g/lit KH2PO4 (1.18 mM), 2.0 g/lit Glucose (11.0 mM), and 0.37 g/lit CaCl2·2H2O (2.52 mM), added after bubbling with a 95% O2+5% CO2 gas mixture for 20 minutes.
Solution preparation: Distilled water (ion exchange column Zilion, Israel and ultra filtration by EasypurLF, Israel) are used to prepare the KHS stock solution (X 20, 5 L). The chemicals listed above except CaCl2 are used. The stock solution expire after 1 week of refrigeration, For each day of experiment fresh solution is prepared (5 L) out of the stock solution, CaCl2 is added, and the solution is bubbled (95% O2/15% CO2) for 20 min. and titrated to a pH of 7.4. Bubbled KHS at room temperature is used for perfusion of the papillary muscle kept in the Steiert organ chamber. Ice cold (4 C), bubbled EKS is used for the dissection of the papillary muscles.
Anesthesia and heart dissection: animal is brought from the cage to a scale for measuring body weight, The animal is anesthetized by 1Vembutal 1-1.2 mg 1 Kg body weight I.P, using −5 cc syringe and 23 Gage needle. The level of anesthesia is checked by the animal reflex to a pinch. When the animal is deeply anesthetized, the skin over the chest is cut off and the chest wall is cut exposing the heart. Using seizures and a forceps the pericardium is cut and the heart is dissected out by cutting all the blood vessels, Immediately after cutting, the heart is placed in an ice cold and oxygenated KHS.
Papillary muscle dissection: The heart is transferred to a fresh ice-cold KHS and than to the dissection chamber, containing ice-cold continuously oxygenated KHS. The heart is fixed to a rubber pad with insect pins and than the left ventricle is opened exposing the papillary muscles. A silk (60) thread is tight around the tendon of the papillary muscle and the muscle is dissected out using fine twizers. The dissected muscle (length of 2-3 mm) is transferred to the organ bath and the heart is kept in the dissection chamber at 4° C. for further dissections of the other papillary muscles. The dissection of the papillary muscle last for 3-5 min.
The Steiert Organ Bath: The muscle is placed in an organ bath, and than fixed to the chamber by a plastic holder. The silk thread tight to the tendon is hooked to a rigid hook on the force transducer (on the opposite side) to give an isometric conditions. The papillary muscle is continuously perfused (7-12 ml/min,) with oxygenated KHS kept at a regulated temperature of 37° C.
Pacing and Stimulation:
Pacing stimuli (typically 1 Hz, 2 ms duration, and amplitude of 2 mA) are given by two Ag-AgCl electrodes which are part of the organ bath and are placed under the muscle. The electrodes are covered with AgCl layer, chlorodizing by 5 mA, 5 ms pulses during perfusion. Constant current stimuli (CCLU) are given to the upper part of the muscle using graphite electrodes (diameter of 0.5 mm fitted to a glass pipette) placed 2-3 mm apart along the fibers' line (contraction axis). The muscle length is adjusted to maximal isometric force and left for equilibration period of 30 min.
Drug administration:
We use the perfusion system for drug application by switching the feeding krebs solution bottle to the drug containing bottle. The drug is administered for a period of 30-80 minutes while monitoring the mechanical and electrophysiological response of the muscle every 10 minutes.
EXAMPLE 1 Stimulation in the presence of Caffeine
A rabbit papillary muscle was stimulated by an NT-signal in the presence of Caffeine 10 mM (Phosfodiesterase Inhibitor).
A rabbit papillary muscle was stimulated in Organ-Bath perfused by KHS (normal experimental medium) together with Caffeine 10 mM (which is a PDE inhibitor and also causes depletion of the internal cardiac Ca+ stores—Sigma, Mo, catalog No. C-8960) for 60 in before applying the NT signal
The NT-signal applied to the electrodes 4 produced an average increase in peak force of the control. Caffeine 10 mM when applied cause a significant reduction in the basal contraction force (33% decrease). It also reduced the increase in peak force in response to NT stimulation applied to the same preparat in the presence of Caffeine to an average increase of 15% in the muscle force, vs 60% increase in the control level.
Pacing: 1 Hz, 2 mS Duration, 1 mA current.
NT signal: 30 mS Delay, 60 mS Duration, 6 mA, with the polarity increasing muscle contractility.
Temp. 36.2° C.
The results are shown in FIG. 1.
EXAMPLE 2 Stimulation in the Presence of Ryanodine
A rabbit papillary muscle was stimulated in Organ-Bath perfused by KHS together with Ryanodine (a Ca-release suppresser from the Sarcoplasmic Reticulume). 100 nM (Sigma, Mo, catalog No. R-6017) for 60 min before applying the NT signal.
The NT-signal applied to this preparat produced an average increase in peak force of 60% in the control. Ryanodine 100 nM when applied cause a significant reduction in the basal contraction force (55% decrease). However when NT stimulation was applied to the same preparat in the presence of Ryanodine, it produced an average increase of 70% in the muscle force, compared to the new basal force.
NT Signal: 30 mS Delay, 60 mS Duration, 6 mA.
EXAMPLE 3 Stimulation in the Presence of Nifedipine
A rabbit papillary muscle was stimulated in Organ-Bath perfused by KHS together with Nifedipine (Ca-channel blocker commonly used in clinical treatment in ischemic heart disease mainly affecting the smooth muscle cells in vascular vessels). 1 μM (Sigma. Mo, catalog No. n-7634) for 10 minutes before applying the NT Signal.
The NT signal applied to this preparat produced an average increase in peak force of 30% in the control Nifedipine 1 μM when applied cause a significant reduction in the basal contraction force (70% decrease). However when NT stimulation was applied to the same preparat in the presence of Nifedipine an average of 35% increase in the muscle force was observed.
EXAMPLE 4 Stimulation in the Presence of Propranolol and Adrenaline
An experiment combining two drugs was carried out, the results of which are shown in FIG. 4. A rabbit papillary muscle was exposed for 5 minutes to propranolol (0.5 μM) and adrenaline (0.25 μM) in control Now amplitude trace) and activated by the NT signal (high amplitude trace).
The graph depicts twitches of papillary muscle after 5 min exposure to the above. The concomitant presence of the drugs decreased the overall muscle force. When the NT signal was applied, the contractile force increased by about 200%. The control trace reflects the clinical state of heart failure, with reduced contractility, high plasma catecholamine concentration, while there is down regulation of the Beta receptors.
pacing: 1 Hz, 2 mS duration, 3 mA.
EXAMPLE 5 Stimulation in the Presence of Adrenaline
An experiment was carried out on a rabbit papillary muscle, in the presence of adrenaline, and the results are shown in FIG. 5. This graph is composed from two different triles on the same papillary muscle (left, rabbit). In the control turning on the NT signal caused an increase of about 110%, then adrenaline, 0.5 μM was added to the perfusion chamber. The recording shown in FIG. 5 (on the right) was taken after 5 minutes perfusion with adrenaline. Adrenaline caused a 20% increase in the basal contraction force of the muscle. When the NT signal was turned on there was an additional 86% increase in the peak contraction force. This result indicates that high adrenaline concentration does not attenuate the increase in muscle contraction after NT signal stimulation.
Pacing: 1 Hz, 2 mS duration, 3 mA
NT signal was: 30 mS delay, 60 mS duration, 6 mA.
EXAMPLE 6 Stimulation in the Presence of Diltiazem
An experiment was carried out on a rabbit papillary muscle, in the presence of Diltiazem (a Ca-channel blocker commonly used in clinical treatment in ischemic heart disease), and the results are shown in FIG. 6.
A rabbit papillary muscle was stimulated in Organ-Bath perfused by KRS and 10 μM Diltiazem, (Lot 702663). The NT-signal applied to this preparat produced an average increase in peak force of 20% under these experimental conditions. The drug caused a significant reduction in the basal contraction force of the muscle.
EXAMPLE 7 Stimulation in the Presence of Digoxin
An experiment was carried out on a rabbit papillary muscle, in the presence of Digoxin, and the results are shown in FIG. 7.
There is a 115% increase in the NT-signal induced force on the control without the addition of the drug. Addition of Digoxin caused an increase of 38% of the basal contraction force. Applying the NT-signal on the Digoxin-treated muscle caused a further increase of 86% on the new basal level, after 19 minutes treatment with Digoxin The combined Digoxin-NT signal treatment is synergistic, and the increase in muscle contraction, as compared to the single contributions of each treatment, is 20%, as shown in the graph.
Pacing: 1 Hz, 2 mS, 3 mA.
NT Signal: 1 Hz, delay 30 mS, duration 60 mS.
Referring now to FIG. 8, a schematic representation of an apparatus according to one embodiment of the invention is seen. In this scheme, a portion of a cardiac muscle, H, is brought into closed positioned relationship with two electrodes, E1 and E2, the ends of which are positioned at root position R1 and R2, respectively. The electrodes receive the voltage and current from a signal generator S, the construction of which is conventional and well know to skilled persons, and which is therefore not described here in detail, which in turn receives power from a power line, PL, connected to an autonomous power source or to the mains, as the case may be. The activity of the power signal generator S is controlled by a controller, C, which may be a microprocessor, or which may be an external controlling device, e.g., a PC or the like computer. The controller C controls the parameters of the signal generated by the signal generator, such as current intensity, frequency and timing, and may use both preset parameters (e.g., the frequency of pulse generation) and feedback input, e.g., from apparatus which monitors heart or other parameters, or from a pace maker which supplies the pacing signal. These input signals are collectively schematically indicated in the figure as FB. Of course, the apparatus is only schematically shown, for the sake of brevity. And the skilled person will easily be able to devise many different kinds of apparatus suitable to supply the signal needed in carrying out the invention.
All the above description and examples have been given for the purpose of illustration and are not intended to limit the invention in any way. Many modifications, can be carried out in the invention: for instance, many different drugs can be used in conjunction with an NT-signal, or different combinations of drugs can be used; furthermore, different signals can be employed, all without exceeding the scope of the invention.
1. A method for the combined drug/electric stimulation treatment of a cardiac muscle, comprising a) administering to a patient in need thereof a drug which affects the cardiovascular system and which affects the cardiac muscle, or a mixture of two or more such drugs, b) creating a non-excitatory electric potential between at least two points located in the vicinity of the muscle, and c) controlling one or more of the parameters consisting of start time, duration, magnitude and polarity of the non-excitatory electric potential created between said at least two points.
2. A method for the combined drug/electric stimulation treatment of a cardiac muscle, comprising a) administering to a patient in need thereof a drug which affects the cardiovascular Stem and which affects the cardiac muscle, or a mixture of two or more such drugs, b) causing a non-excitatory electric current to flow between at least two points located in the vicinity of the muscle, and c) controlling one or more of the parameters consisting of start time, duration, magnitude and polarity of the non-excitatory electric current flowing between said at least two points.
3. A method according to claim 2, wherein the non-excitatory electric current is a DC current.
4. A method according to claim 3, further comprising generating a complex signal by superimposing on the DC signal one or more waveforms of given frequency and amplitude.
5. A method according to any one of claims 2 to 4, wherein the flow of the non-excitatory DC electric current is synchronized to heart activity.
6. A method according to claim 5, wherein the non-excitatory DC electric current flows not at every beat of the heart.
7. A method according to claim 6, wherein the non-excitatory DC electric current flows every 1, 2 or 3 beats of the heart.
8. A method for the combined drug/electric-stimulation treatment of a cardiac muscle, comprising:
providing means for creating an electric potential between at least two points located in the vicinity of the cardiac muscle;
providing means for causing a non-excitatory electric current to flow between said at least two point; and
controlling the start time, duration and magnitude of the electric current flowing between said at least two points so as to impart a desired change in cardiac muscle contractility.
9. A method according to any one of claims 1, 2, and 8, wherein the change in cardiac muscle contractility is designed at least partially to compensate for cardiac muscle contractility decrease induced by said drug or mixture of drugs.
10. A method according to any one of claims 1, 2, and 8, wherein the change in cardiac muscle contractility is designed at least partially to compensate for cardiac muscle contractility increase induced by said drug or mixture of drugs.
11. A method according to any one of claims 1, 2, and 8, wherein the change in cardiac muscle contractility is designed to add to and/or amplify the cardiac muscle contractility increase or decrease induced by said drug or mixture of drugs.
12. A method according to any one of claims 1, 2, and 8, for reducing the dosage of a cardiovascular drug which affects cardiac muscle contractility.
13. A method according to any one of claims 1, 2, and 8, for reducing the dosage of a cardiovascular drug which affects the electrophysiological characteristics of the cardiac muscle.
14. A method for the combined drug/electric-stimulation treatment of a cardiac muscle, comprising:
15. A method according to claim 14, wherein the means for causing a non-excitatory electric current to flow, are synchronized to heart activity.
16. A method according to claim 15, wherein the means for causing a non-excitatory electric current to flow operate not at every beat of the heart.
17. A method according to claim 16, wherein the means for causing a non-excitatory electric current to flow operate every 1, 2 or 3 beats of the heart.
18. Apparatus for the combined drug/electric-stimulation treatment of a cardiac muscle, comprising:
means for causing a non-excitatory electric current to flow between said at least two points;
means for controlling the start time, duration and magnitude of the electric current flowing between said at least two points; and
means for superimposing on the DC signal one or more waveforms of given frequency and amplitude, thereby to generate a complex signal.
19. Apparatus according to claim 20, comprising:
means for causing a non-excitatory electric current to flow between said at least two root locations;
means for controlling the start time, duration and magnitude of the electric current flowing between said at least two root locations; and
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Belonging Essay Peter Skrzynecki; Belonging Essay Peter Skrzynecki. 1008 Words Oct 6th, 6 Pages Belonging Essay To a certain extent the different groups we belong to define who we are, however there are times when a certain group can separate you from belonging. 2018 Bartleby. com Go back to bartleby 2018 Bartleby. com Belonging Band 6.
Belonging is knowing who you are, through trials and struggles that you will be familiar with yourself and can understand the reasons for your uniqueness. Belonging is not only about being accepted into a circle, but earning that place.
Not just a member, but a leader. No man is an island, yet despite the most basic human Do you find it difficult to write essays about belonging? Firstly, read our post on How to write band six essays!.
Then, read the following band six response for further guidance, or Download it as a word document. This sample HSC English essay received a Oct 20, 2009 Sample of Band 6 essays I personally believe that English Advanced is the most difficult subject to study for, as it is virtually impossible to read a band 6 Creative writing pictures belonging band 6.
September 19, 2018 0 Comment. Wrote way too much for both essays and didn't get to finish my conclusion for the 40 marker. How to write an essay. In the last part of our Guide, we looked at how essays work and discussed the structure and planning of an essay.
If you havent read it, you should go check that out first. In this part, well get into the nittygritty of writing the essay and give you some tips for producing Band 6 responses in exam conditions.
This is one of the most important lessons you will need to apply when figuring out how to write a band 6 essay during your HSC year. Writing an essay that directly responds to the question and demonstrates that you really know what you are talking about is Writing essays seems like all you do throughout the senior years, so by the time HSC rolls around you should be able to smash out an awesome Band 6 response!
Of course, sometimes things dont go exactly the way we plan.


(b) terminal voltage per phase.
(c) frequency of armature current.
(d) generated voltage per phase.
(d) varies with rotor speed.
(a) open-circuit and zero power factor tests.
(b) zero power factor and slip tests.
(c) open and short circuit tests.
(d) short circuit and slip tests.
(b) sum of the output of two.
(c) both low and high speed application.
(b) magnitude of the load current.
(c) power factor of the load.
(c) operating at high rpm.
(a) voltage drop due to armature reaction.


How do I make the most of my practice time?
First off there is a huge difference between playing and practicing.
Playing things that you already know is not practicing in my mind. Practice should be about learning something new. Not playing the same ole stock licks.
You need a plan. A simple "practice" plan. Make a list, things you want to improve on, goals, both short term and long term.
Break your routine down into simple small chunks.
An egg timer or the alarm on a phone will help you stay on the course.
Remember practice should be just that, practice. Having a practice schedule helps.
Now with all this being said. There is absolutely nothing wrong with just playing! Running though things you know and enjoy. Most of all have fun!
One last thought. You should play at a little everyday, just to keep your hands in shape.
It's funny for me practice is almost zen like, very close to Meditation. I almost guilty if I don't play or practice everyday.
Nothing happens overnight. It takes desire, discipline and dedication to improve as not only a guitar player but a musician.


Yaaaaas! One of my favorite new segments to the show (jk they're all my favorite, lemme stop). Tune in to find out exactly how I plan on using these very special panel interview episodes to spread some epic messages and info and how I plan on spilling all of the tea. Woot Woot!


"Interesting," I thought. I hadn't seen anything about the governor using the short-message service. You, the sharp News Cut reader, need no hint about the significance of 2012. I sort of dismissed the number; we all remember what it was like to have myname1998@hotmail.com accounts, right?
It had to be a fake. Then things… disappeared.
Shortly after receiving an e-mail from Twitter telling me that TimPawlenty2012 was now following me, the account ceased to be. Grab your tinfoil hat.
If this was someone purporting to be Tim Pawlenty, it's highly unlikely that Twitter closed down the account. Support requests are notoriously slow, and fake Twitter personalities exist for many high-profile people. If you're creating a fake Tim Pawlenty, you're likely doing it for the exposure, not to cultivate two dozen followers and close up shop.
The messages are a typical slice of what you might expect out of a communications lackey — success stories, challenge-tackling and politically conscious messages of bipartisanship. If this someone really was Pawlenty, and Pawlenty really was a "potential presidential candidate," it would make sense to test drive a few Web 2.0 tools before ramping up a campaign, especially when the political posturing for potential President 45 has already begun.
Click on the image below to see the full feed, minus one status.
While we can probably assume the account wasn't actually being staffed by Tim Pawlenty himself, if it was someone within the governor's office or political circle, it wouldn't be unreasonable to assume that this person would have inside knowledge of Pawlenty's political aspirations.
Of course, none of this is really new, but it is news if it's straight from the horse's Twitter.
What do you think, Twitter users? Real or fake?
I'm waiting on a call back from Pawlenty's communications people.
5:07 p.m.: Pawlenty Communications Director Brian McClung responds via email.
No. Our office is not associated with any such Twitter account.
8:30 p.m.: Twitter Pawlenty wasn't disappeared after all. The account has been moved to twitter.com/TimPawlentyMN. The question remains. Who's office is associated with the Twitter account?
I'm waiting on a message back from TimPawlentyMN.
The person behind the account says he/she is "just someone from Minnesota giving updates on behalf of Tim Pawlenty." Mystery solved then, I guess. At least it was a fun distraction from the budget news.
If he was the real Tim, he'd be drinking up your attention, not running from it.
Fake and here's why: I can guarantee you that Tim Pawlenty is not tech-savvy enough to make a "tinyURL" to post to a twitter feed.
@Jennifer, Tim's technological aptitude notwithstanding, Twitter coverts web addresses that are longer than 30 characters to TinyURL addresses automatically.
I am guessing someone was playing around with this and thought only a few insiders would see it. Bob now that you have it everyone will. No different than Palin saying if God tells her to she will run in 2012.
Oh! maybe God did it.
Jennifer, amazingly twitter makes the tiny urls FOR you, it's pretty cool and automatic.
Maybe we'll end up with battling Pawlenty tweeters!
This continuing partisanship is so discouraging. Just listened to minority leader Seifert spewing partisan on the budget, i.e. " I won't be voting for any of it". Hoping dems will hang themselves with budget cuts next time voting rolls around. We don't need partisanship, we don't need a campaigning governor, we need brave leaders who put MN best interests first!
OMG, What a nightmare to wake up November 7th 2012 and find that our absentee governor whose mandate to govern Minnesota included a landslide 20,000 vote win in his last race because Judy Dutcher didn't know what E85 was. Now there's a convoluted chain of events not unlike Sarah Palin's rise to 'fame'. Ask anyone at Wizmo where Palenty was 'vice president of looking out the window' and no one will remember him or what he did. What a phoney this flim flam man is.


The Sylvan Teak Dining Arm Chair boasts attractive, modern lines and durable construction from sustainably harvested V-Legal teak wood. Smartly sized, the Sylvan chair is extremely comfortable without being a space hog like some dining arm chars. Tailored and manicured in all the right places the Sylvan dining chair has a unique modern style while maintaining traditional sensibilities. Recommended for use with or without a cushion. Stackable design. Sold with optional Sunbrella seat cushion complete with ties. By Harmonia Living.


text:
AAA: Cheaper gas means more holiday travel
About 70,000 more North Carolina residents will travel over the upcoming Labor Day weekend than a year ago, primarily because of cheaper gas, according to AAA Carolinas.
RALEIGH, N.C. — About 70,000 more North Carolina residents will travel over the upcoming Labor Day weekend than a year ago, primarily because of cheaper gas, according to AAA Carolinas.
AAA said the proximity of Hurricane Earl to the Outer Banks could reduce its forecast of an 8.1 percent increase in holiday travel. Travelers heading to the coast should pay close attention to forecasts, warnings and evacuations before hitting the road, the organization said.
Gas prices statewide average $2.58 for a gallon of regular unleaded, down 11 cents from the summer peak on Aug. 11 and 16 cents lower than Memorial Day gasoline prices, AAA said.
An estimated 930,000 North Carolina residents are expected to travel during the holiday weekend, despite continued high unemployment and economic uncertainty, said David Parsons, president and chief executive of AAA Carolinas.
"Travel by Carolinians has been increasing all year, and this holds true for the last vacation of the summer," Parsons said in a statement.
Atlanta, Myrtle Beach, Charleston, Asheville, Raleigh, Savannah and Washington, D.C., rank as the most popular destinations, according to AAA Vacations, which tracks hotel bookings and TripTik routings.
The state Department of Transportation will suspend most road construction projects between 4 p.m. Friday and 9 a.m. Tuesday to make travel easier during the holiday.
The only exceptions are the repaving work on Glenwood Avenue in Raleigh, a project to replace the U.S. Highway 17 Business bridge over the New River in Jacksonville and work on the Cashie River Bridge on U.S. 17 in Bertie County, DOT officials said.
Previous work on westbound Interstate 40 in Haywood County will be halted from 5 p.m. Thursday through Monday evening, opening all four lanes near the Tennessee border, officials said.
AAA forecasts that air travel also will rise by 3.9 percent over the holiday, despite higher airfares. AAA's Leisure Travel Index reports the lowest round-trip rates are 9 percent higher this year, to an average of $179 for the top 40 U.S. air routes.
Island evacuations start as Earl strengthens
Thanksgiving travel
NCHSAA releases finalized dual team wrestling playoff brackets

redpajama_set_name: RedPajamaCommonCrawl


IEC 62304 defines a rather light set of constraints for class A software. Many connected objects or back-office servers processing medical data are low risk devices (when they're qualified of medical devices). If we put apart the case of devices used for close-loop, or remote monitoring (or the like), most of standalone software in back-office (services) or used remotely (standalone web apps or mobile apps) will present failures with negligible consequences for the patient. As such, most of standalone software will be in class A (a conclusion that I verified empirically).
For class A software, it's usual to do the bare minimum to be compliant: software requirements, functional tests, a bit of risk assessment with acceptable risk prior to mitigation actions, a bit of SOUP management, and voilà! It won't be enough to prove that standalone medical device software is secure.
Thus, cybersecurity requires to bring additional documentation: security risk assessment, mitigation actions, and evidence of their effective implementation. Where are we going to find these evidences?
In software requirements, of course, but also in architectural design, possibly in detailed design, and in unit/integration/verification tests. This sounds more like class B than class A.
More, we can mimic the section 5.5.4 of IEC 62304, applicable to class C only, by including additional cybersecurity tests requirements like application of OWASP 13 Top-10 to verify good coding practices. For this kind of tests, tools like static analyzers or methods like peer code reviews are usually implemented. These tools and methods are more frequent for class C software development, than for class B and A.
High safety risk devices will require a limited cybersecurity overhead. If essential performance relies on software, device connectivity will be limited. The cybersecurity documentation will represent a limited amount of work, compared to device safety documentation.
Low safety risk devices will require a significant cybersecurity overhead. Software safety documentation is poor, thus the cybersecurity overhead will represent a significant amount of work, compared to device safety documentation.
This comparison is not valid for high-risk devices designed for connectivity, like an hypothetical close-loop system, which loop goes through a remote server. It's the worst case, reserved to manufacturers with enough resources to support the design and maintenance of such device.
Connecting a medical device to a network is not trivial, especially if that network is not a controlled network, like public or home network. The cybersecurity requirements established by the FDA guidances in the US, and in the new Medical Device Regulation in the EU have significant consequences on the cost of documentation to bring evidences of compliance.
The cost is significant for IEC 62304 class A software, which requires documentation closer to class B than class A.


text:
layout: changelog
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  * Adds coveralls to the repo, to track code coverage and display a badge in the README
  * Updates the disconnect function on the RTM client to support both an error message and a code or reason for the disconnect, e.g. `account_inactive`
  * Updates the message-handlers for `team_xxx` events to set the team back to the data-store once changes are made

redpajama_set_name: RedPajamaGithub


text:
Have We Got the Relationship Between Museums and Collectors All Wrong?
March 5, 2018 by Marion Maneker
Bendor Grosvenor has an important piece in the Financial Times that goes far beyond its specific subject, David Cannadine's report on the crisis in British museum collecting. Grosvenor picks apart the institutional sclerosis that makes museums poor collectors but exemplary stewards.
Buying an artwork requires institutional energy, which not all museums possess. Museums are one of the last unreformed public services in Britain, where almost everything is decided by committee, and decisions can take an age, if they are taken at all. A few years ago I sold a portrait to a national museum for what should have been an easily digestible £8,000. But the process took more than six months (which is fairly standard). I wouldn't be surprised if the museum spent more on staff time than on the picture.
Grosvenor's argument goes on to suggest that museums do best when they partner with private collectors who can loan works either long-term or for exhibitions. He's not naive. He understands the popular suspicion of lenders who might be trying to enhance the stature of their works. (Caveat collector!)
Those fears are overblown, Grosvenor says. And the best hope for re-invigorated museums is engaging with collectors. That's a lesson that will become increasingly important as the number of private museums and collections grow.
The collecting crisis in British museums — and why private loans are part of the solution (Financial Times)
Art Agency Partners Revenue Revealed
How Pictures Get Lost
How to Buy Art
Nahmad: Museums Market Our Art
When Jack Met Craig and They Went After John
What Patrons Owe Artists


2. Prep vegetables. Add the zucchini, carrots, pepper, and cabbage into one or two large bowls. Toss with hands to combine.
3. Prepare the dressing by processing all dressing ingredients in a mini processor (or simply whisk by hand). The dressing may seem a bit thin at first, but it thickens as it sits.
4. Top bowls with edamame, green onion, hemp seeds, and sesame seeds. Pour on Thai Sauce and enjoy!
1. Place rice noodles in a large pot of boiling hot water for about 10 minutes (read instructions on package), then drain and set aside.
3. Pour very hot water into a shallow dish or skillet and immerse rice paper to soften for about 10-15 seconds.
4. Transfer rice paper to a damp cutting board or damp towel and gently spread out edges into a circle. It may take a little practice, so don't feel bad if your first few attempts are not successful.
5. To the bottom third of the wrapper add a small handful of vermicelli noodles and layer veggies. (I also like to add the Avocado Mango Salsa to give a little bit of sweetness) From the bottom gently fold over once, tuck in edges, and continue rolling until seam is sealed.
1. Mash Avocado into a mixing bowl and add mango, red onion, tomato, jalapeño and Thai Chilli Sauce.
2. Mix together and serve with spring rolls.
1. Preheat oven to 350F. In a small bowl, whisk together the ground flax and water and set aside.
3. In a large microwave safe bowl, add chocolate chips and Earth Balance then melt in microwave for about 45 seconds until melted. Stir well then add in flax egg, sugar, and vanilla.
4. Pour wet mixture over dry mixture and stir well. Now fold in the walnuts.
5. Scoop batter onto greased/oiled pan and spread with hands until smooth and even.
6. Bake for 33-34 minutes at 350F and allow brownies to cool in pan for about 1.5 hours. Make sure you are careful when cutting as they are very crumbly! Enjoy with Coconut whip cream, cinnamon, and cardamon.
1. Place a can of coconut milk in freezer for 2 hours.
2. Take can out of freezer and let thaw for about 30 minutes.
3. Scoop off the coconut fat that is on top and put into a mixing bowl, leave the liquid contents in the can. With a hand mixer whip together icing sugar and coconut fat until desired consistency.
4. Serve on top of brownies and enjoy!
I feel forever grateful for living in such a beautiful place. The Alberta Slalom Canoe Kayak Team traded in their paddles for skis for the annual winter ski camp that took place in the Canadian Rockies. We had four amazing days of skiing, running, hiking and exploring. My goal was to reach 100 km's by the end and I exceeded that at 102 km's!! It involved a lot of hard work with spectacular mountain sunrises and crisp fresh air.
Here is a little snippet I put together to sum up our camp. The video consists of locations: Canmore Nordic Centre, Lake O'Hara, Cascade Fire Road, Grotto Canyon, and Mount Shark.
It is the time of the year when Canada is graced with the brisk air and snow days. This year Team Canada decided to change it up and head down under to New Zealand and Australia.
Canoe slalom athletes have been put into a unique situation when it comes to traveling with our boats where all Canadian airlines and many international airlines not taking boats on flights. This has put us in a major dilemma as to how we travel to our international training camps and competitions.