Described herein are implantable systems and devices, and methods for use therewith, that can be used to monitor and treat heart failure (HF). Such implantable systems preferably includes a lead having at least two electrodes implantable in a patient's left ventricular (LV) chamber. A plurality of different sensing vectors are used to obtain a plurality of IEGMs each of which is indicative of an evoked response at a corresponding different region of the LV chamber. For each of the IEGMs, there is a determination of one or more evoked response metrics indicative of a localized cardiac function at the corresponding region of the LV chamber. The evoke response metrics can be, e.g., paced depolarization integral (PDI) and/or maximum upward slope of an R-wave, but are not limited thereto. The patient's HF condition is monitored based on the localized cardiac function at the plurality of different regions of the LV chamber as determined based on the one or more evoked response metrics determined for each of the IEGMs.

Heart failure (HF) is a debilitating, end-stage disease in which abnormal function of the heart leads to inadequate blood flow to fulfill the needs of the body's tissues. Typically, the heart loses propulsive power because the cardiac muscle loses capacity to stretch and contract. Often, the ventricles do not adequately fill with blood between heartbeats and the valves regulating blood flow may become leaky, allowing regurgitation or backflow of blood. The impairment of arterial circulation deprives vital organs of oxygen and nutrients. Fatigue, weakness, and inability to carry out daily tasks may result.
Not all HF patients suffer debilitating symptoms immediately. Some may live actively for years. Yet, with few exceptions, the disease is relentlessly progressive. As HF progresses, it tends to become increasingly difficult to manage. Even the compensatory responses it triggers in the body may themselves eventually complicate the clinical prognosis. For example, when the heart attempts to compensate for reduced cardiac output, it adds muscle causing the ventricles to grow in volume in an attempt to pump more blood with each heartbeat. This places a still higher demand on the heart's oxygen supply. If the oxygen supply falls short of the growing demand, as it often does, further injury to the heart may result. The additional muscle mass may also stiffen the heart walls to hamper rather than assist in providing cardiac output.
Current standard treatment for HF is typically centered around medical treatment using ACE inhibitors, diuretics, and digitalis. It has also been demonstrated that aerobic exercise may improve exercise tolerance, improve quality of life, and decrease symptoms. Cardiac surgery has also been performed on a small percentage of patients with particular etiologies. Although advances in pharmacological therapy have significantly improved the survival rate and quality of life of patients, some HF patients are refractory to drug therapy, have a poor prognosis and limited exercise tolerance. In recent years cardiac pacing, in particular Cardiac Resynchronization Therapy (CRT), has emerged as an effective treatment for many patients with drug-refractory HF.
HF patients require close medical management to reduce morbidity and mortality. Because the disease status evolves with time, frequent physician follow-up examinations are often necessary. At follow-up, the physician may make adjustments to the drug regimen in order to optimize therapy. This conventional approach of periodic follow-up may be less satisfactory for HF, in which acute, life-threatening exacerbations can develop between physician follow-up examinations. It is well known among clinicians that if a developing exacerbation is recognized early, it can be more easily and inexpensively terminated, typically with a modest increase in oral diuretic. However, if it develops beyond the initial phase, an acute HF exacerbation becomes difficult to control and terminate. Hospitalization in an intensive care unit is often required. It is during an acute exacerbation of HF that many patients succumb to the disease. Early identification may also allow for pacing therapy from an implanted pulse generator.
In view of the above, it would be beneficial if a patient's HF condition can be chronically monitored. Additionally, it would be beneficial if therapy can be automatically delivered and adjusted to improve HF treatment. Further, it would be beneficial to facilitate the early termination of a developing HF exacerbation.
A properly time ordered ventricular electrical activation sequence and proper inter-ventricular and intra-ventricular delays (which can collectively be referred to as a proper ventricular electrical activation pattern) enable efficient contractions of the ventricular chambers of the heart, thereby contributing to efficient blood perfusion through both the lungs and the systemic circulation. However, in patients with right bundle branch block (RBBB), left bundle branch block (LBBB), or other ventricular conduction abnormalities, their ventricular electrical activation sequence and inter-ventricular and intra-ventricular delays are often adversely affected, which may adversely affect blood perfusion and, more generally, may adversely affect cardiac mechanical function. Accordingly, it would be desirable to be able to detect when a patient's ventricular electrical activation pattern deviates from a predetermined preferred pattern, and to increase compliance with the predetermined preferred pattern.
In a normal heart, cells of the sinoatrial node (SA node) spontaneously depolarize and thereby initiate an action potential. This action potential propagates rapidly through the atria (which contract), slowly through the atrioventricular node (AV node), the atrioventricular bundle (AV bundle or His bundle) and then to the ventricles, which causes ventricular contraction. This sequence of events is known as normal sinus rhythm (NSR). Thus, in a normal heart, ventricular rhythm relies on conduction of action potentials through the AV node and AV bundle.
Rhythms that do not follow the sequence of events described above are known as arrhythmias. Those that result in a heart rate slower than normal are known as bradyarrhythmias; those that result in a faster heart rate than normal are called tachyarrhythmias. Tachyarrhythmias are further classified as supraventricular tachyarrhythmias (SVTs) and ventricular tachyarrhythmia (VT). SVTs are generally characterized by abnormal rhythms that may arise in the atria or the atrioventricular node (AV node). Additionally, there are various types of different SVTs and various types of VTs that can be characterized. For example, a paroxysmal SVT can exhibit heart rates between approximately 140 beats per minute (bpm) and approximately 250 bpm. However, the most common SVTs are typically atrial flutter (AFL) and atrial fibrillation (AF). In addition, many SVTs involve the AV node, for example, AV nodal reentry tachycardia (AVNRT) where an electrical loop or circuit includes the AV node. Another type of SVT is an AV reentrant tachycardia (AVRT), where an AV reentrant circuit typically involves the AV node and an aberrant conducting bundle known as an accessory pathway that connects a ventricle to an atrium.
Atrial flutter (AFL) can result when an early beat triggers a "circus circular current" that travels in regular cycles around the atrium, pushing the atrial rate up to approximately 250 bpm to approximately 350 bpm. The atrioventricular node between the atria and ventricles will often block one of every two beats, keeping the ventricular rate at about 125 bpm to about 175 bpm. This is the pulse rate that will be felt, even though the atria are beating more rapidly. At this pace, the ventricles will usually continue to pump blood relatively effectively for many hours or even days. A patient with underlying heart disease, however, may experience chest pain, faintness, or even HF as a result of the continuing increased stress on the heart muscle. In some individuals, the ventricular rate may also be slower if there is increased block of impulses in the AV node, or faster if there is little or no block.
If the cardiac impulse fails to follow a regular circuit and divides along multiple pathways, a chaos of uncoordinated beats results, producing AF. AF commonly occurs when the atrium is enlarged (usually because of heart disease). In addition, it can occur in the absence of any apparent heart disease. In AF, the atrial rate can increase to more than 350 bpm and cause the atria to fail to pump blood effectively. Under such circumstances, the ventricular beat may also become haphazard, producing a rapid irregular pulse. Although AF may cause the heart to lose approximately 20 to 30 percent of its pumping effectiveness, the volume of blood pumped by the ventricles usually remains within the margin of safety, again because the atrioventricular node blocks out many of the chaotic beats. Hence, during AF, the ventricles may contract at a lesser rate than the atria, for example, of approximately 125 bpm to approximately 175 bpm.
Overall, SVTs are not typically immediately life threatening when compared to ventricular arrhythmias, examples of which are discussed below.
Ventricular arrhythmias, which originate in the ventricles, include ventricular tachycardia (VT) and ventricular fibrillation (VF). Ventricular arrhythmias are often associated with rapid and/or chaotic ventricular rhythms. For example, sustained VT can lead to VF. In sustained VT, consecutive impulses arise from the ventricles at a rate of 100 bpm or more. Such activity may degenerate further into disorganized electrical activity known as ventricular fibrillation (VF). In VF, disorganized action potentials can cause the myocardium to quiver rather than contract. Such chaotic quivering can greatly reduce the heart's pumping ability. Indeed, approximately two-thirds of all deaths from arrhythmia are caused by VF. A variety of conditions such as, but not limited to, hypoxia, ischemia, pharmacologic therapy (e.g., sympathomimetics), and asynchronous pacing may promote onset of ventricular arrhythmia. Further, there are various different types of VT, including, e.g., monomorphic VT and polymorphic VT, for which different types of therapy may be appropriate.
It has been common practice for an implantable cardioverter defibrillator (ICD) to monitor heart rate, or more commonly the ventricular rate, of a patient and classify the cardiac condition of the patient based on this heart rate. For example, a tachyarrhythmia may be defined as any rate in a range above a designated threshold. This range is then divided into ventricular tachycardia and ventricular fibrillation zones. The ventricular tachycardia zone may be further divided into slow ventricular tachycardia and fast ventricular tachycardia zones.
As described above, both SVTs and ventricular arrhythmias may lead to ventricular rates in excess of 100 bpm. In other words, ventricular rates of SVTs can overlap with rates of tachycardias of ventricular origin. These SVTs are often well tolerated and require no intervention. Further, physically active patients can have heart rates during exercise that overlap with their tachycardia rates. Accordingly, discrimination of VT from SVT, including increased heart rates due to exercise, may require more than just knowledge of a patient's ventricular rate. In other words, using heart rate as the sole criterion to classify the cardiac condition of a patient is often not sufficient.
To improve the specificity and accuracy of arrhythmia characterization, many ICDs can also examine the morphology of an intracardiac electrogram (IEGM), in addition to the heart rate. The shape of an intracardiac complex can include information on the origin and sequence of the heart's electrical activity. A normal intracardiac complex traverses the AV node and is conducted by specialized cardiac tissue throughout the ventricles. This results in a distinctive complex morphology. A tachycardia of ventricular origin often has a different morphology due to its ectopic origin and conductance through cardiac muscle tissue. As such, in addition to monitoring heart rate, some ICDs are capable of performing morphology discrimination to classify the cardiac condition of the patient. For example, a template based on the morphology of a "known" signal can be stored in the ICD. The "known" signal can be, for example, a signal collected during a period where a patient is known to exhibit a normal sinus rhythm. By comparing the morphology characteristics (e.g., number, amplitude, sequence and/or polarity of waveform peaks, as well as the area of the peaks) of an arrhythmia to the template, the ICD can calculate the match (or lack thereof) between the waveforms. For a further description of morphology discrimination, refer to U.S. Pat. No. 5,240,009 (Williams), entitled "Medical Device with Morphology Discrimination" and to U.S. Pat. No. 5,779,645 (Olson et al.) entitled "System and Method for Waveform Morphology Comparison," which patents are hereby incorporated by reference. These are just a few examples of morphology discriminator algorithms and parameters, which are not intended to be limiting.
Sudden onset and interval stability (also know as rate stability), are examples of other factors that can be monitored to improve the specificity of arrhythmia characterization. Also, the relationship between ventricular rate (V) and atrial rate (A) can be used to characterize an arrhythmia. For example, this can be part of a rate branch algorithm, which, depending on V and A, may follow one of three branches: a V<A rate branch; a V=A (within a specified tolerance) rate branch; and a V>A rate branch. If V<A, then morphology discrimination and/or interval stability may be available to distinguish VT from AF or AFL. If A and V are essentially the same (within a certain tolerance), then morphology discrimination and/or sudden onset may be available to distinguish VT from sinus tachycardia. If V>A, then an arrhythmia may be characterized as VT. Also, specific branches can be turned on or off. For example, if V is greater than the tachycardia threshold but essentially the same as A, and the V=A branch is turned off, then the algorithm can cause the WA branch to be followed, and the arrhythmia may be classified as VT. Additional details of an exemplary rate branch algorithm are provided in U.S. Pat. No. 6,636,764 (Fain et al.), entitled "Safety Backup in Arrhythmia Discrimination Algorithm," which is incorporated herein by reference. Also, atrioventricular association (AVA) can also be used to distinguish AFL from VT. In an exemplary AVA algorithm, the AV interval is measured from each ventricular sensed event to its preceding atrial event and an AVA Delta is then calculated as the difference between the second longest AV interval and the second shortest AV interval in a recent group of intervals. If the measured AVA Delta is less than a programmable AVA threshold parameter, the AV intervals are considered stable, which is indicative of SVT. If the measured AVA Delta is greater than or equal to a programmable AVA threshold parameter, the AV intervals are considered unstable, which is indicative of VT. More generally, the relative rate of the atria and ventricles and/or the timing relationship between atrial and ventricular events can be considered.
Typically an ICD is programmed to provide a therapy in response to an arrhythmia being detected, where the type of therapy corresponds to the type of arrhythmia that the ICD believes it has detected. For example, VT may be treated with a therapy consisting of low-energy pacing pulses designed to capture the ventricles. This therapy is referred to as ventricular anti-tachycardia pacing therapy (V-ATP). VT may also be treated with relatively low energy, synchronized cardioversion shocks. VF, on the other hand, is typically treated more aggressively with high energy shocks. SVT may not be treated, or may be treated using atrial ATP (A-ATP) or atrial defibrillation. Quite often, SVT is treated using medication, or ablation.
Inappropriate therapy is a huge problem for ICD patients. Inappropriate therapies, specifically inappropriate shocks cause great suffering among the ICD patient population. Patients receive a potentially life-saving device (the ICD) only to find out that it sometimes malfunctions and inflicts both pain and harm without any warning whatsoever. For a secondary prevention patient, this might be bearable since he or she has experienced and been saved from a lethal tachyarrhythmia in the past. For the primary prevention patient, however, without a history of arrhythmias who receives the ICD only based on a risk score, this is more difficult to bear.
Today only a few of the patients who are candidates for an ICD receive one. This is mostly an economic issue; although several studies indicate that an ICD is a cost effective treatment in indicated patients. However, if the performance of the devices improves, the willingness to put in an ICD, especially in young primary prevention patients, will increase.
Despite the numerous arrhythmia discrimination techniques that exist, examples of which were provided above, delivery of inappropriate therapy remains a major problem with ICDs today. For example, a common cause of inappropriate shocks in ICD devices are atrial arrhythmias that are conducted to the ventricles at a high rate. Accordingly, there is still a need for new, and preferably improved, arrhythmia discrimination techniques.

Devices, systems and methods to monitor and treat heart failure (HF)


An impact absorbing protective cap includes a rigid shell which fits on the head of the wearer. The shell is generally hemispherical in shape and terminates in a peripheral edge which defines an open space. An attenuator band is mounted to the inner surface of the shell generally at the peripheral edge for distributing lateral impact forces striking the outer surface of the shell. The attenuator band is made of flexible hard material and is in corrugated form with a series of undulations alternately disposed toward and away from the inner surface of the shell.

There are many occupations and activities which require the use of protective caps. In particular, such protective caps are a necessity in industrial environments. Protective caps are also used in other activities which might involve the application of force to the head, such as a batting helmet for baseball.
Much effort has been expended in designing protective caps capable of providing protection against vertical blows to the head. A particularly effective protective cap is manufactured by Fibre-Metal Products Co. which includes a rigid shell having an internal headgear and headband. The shell is provided with a suspension system which is designed to help protect the wearer against the impact from a vertical force. This is accomplished by having the shell flex upon an impact to the top of the shell so as to absorb part of the impact force. The smooth ribless surface may further reduce the force transmitted by a glancing blow. The reduced force passes to eight energy distributing points. In this protective cap there are no ribs or surfaces which create weak areas caused by interrupted material flow. The internal suspension also functions to absorb still more of the impact forces. The energy absorbing connections distribute the forces over a greater area of the head, thus reducing concentrations at any one point. Remaining impact forces, are passed to the body's natural shock absorbers.
While the above noted protective cap has proven to be very successful in providing protection against vertical impact forces, it would be desirable to provide a protective cap with some means to also help protect against laterally applied impact forces.


A method for enabling voice driven interactions among multiple interactive voice response (IVR) systems begins by receiving a telephone call from a user of a first IVR system to begin a transaction; and, automatically contacting, by the first IVR system, at least one additional IVR system. Specifically, the contacting of the additional IVR system includes assigning tasks to the additional IVR system. The tasks require input from the user and the additional IVR system is secure and separate from the first IVR system. Moreover, the tasks can include a transfer of currency and a transfer of local information.

1. Field of the Invention
The embodiments of the invention provide a system and method for enabling voice driven interactions among multiple interactive voice response systems, and more particularly to a system and method that controls tasks between multiple voice systems.
2. Description of the Related Art
Interactive Voice Response systems (IVRs) are used by many organizations to interact with their customers and clients. IVR's are typically resident within the domain of a single enterprise, and are used to communicate with a user in order to accomplish a transaction (banking queries, airline reservation, flight schedule, etc.). Voice-driven interfaces have become very popular in acting as front-ends for several backend applications (airline reservation, flight schedule, etc.)
Workflows (human, machine or software) are commonly used to efficiently accomplish tasks. A lot of automation has been possible due to standardization, such as business process execution language (BPEL), web service definition language (WSDL), etc. For several workflow or processes, there are points where a unit of the workflow has to interact with humans. This interaction may occur using any interface, but is usually predetermined; the most common being text/data based.
An IVR application has two main components: the telephony channel that handles the call, and the backend application logic that drives the content of the call. For cross IVR applications apart from the call context transfer, application context transfer also needs to be performed. Examples of a call context include caller identification and the dialed number. Examples of an application context include the IVR menu option in the source IVR, user details, and target IVR menu option to switch to. Traditional telecom protocols (such as those in public switched telephone network (PSTN) network) restrict the application context that can be sent 'in-band', i.e., along with the call.
In addition, people in remote areas need information. Most of this information is local—restricted to within the geographical area (a few nearby villages/towns). The Internet does not help since most of the truly local information is not available on the Internet. Moreover, remote areas typically do not have reliable Internet connectivity and residents having little exposure to technology neither have a PC, nor the skills to operate it. However, the mobile penetration has increased tremendously in the last few years. Furthermore, current banking methods are not economically viable for delivering banking solutions at reasonable rates to the remote and sparsely populated areas with low transaction volume. The embodiments herein provide a pervasive, cost-effective, user-friendly medium for information capture and delivery to non-tech savvy users in remote areas.

System and method for enabling voice driven interactions among multiple IVR's, constituting a voice workflow

International Business Machines Corporation


An adjustable shade (20) is used in combination with a stroller (22) carrying a child occupant. The stroller (22) has an integral canopy (26), and the adjustable shade (20) includes a top cover (36) which is configured to attach to the integral canopy (26). A front curtain (38) is coupled to the top cover (36) and extends downward from a front edge (52) of the top cover (36). First and second side curtains (40, 42) are coupled to the top cover (36) and extend downward from first and second lateral edges (54, 56) of the top cover (36). Adjustable shade (20) adjusts to a plurality of positions to effectively protect the child occupant from lateral and reflected rays of sunlight.

As is well known in the art, various problems and difficulties have been encountered in providing suitable sun shade devices for protecting infants and children when they are exposed to the sun. This is particularly true when an infant or young child occupies a baby carriage, stroller, or other conveyance device. Suitable sun shade devices are very important to the well-being of the child because sunlight can cause skin damage to the child or make the child occupant uncomfortable from the intense light and heat. Furthermore, when an infant is secured in a reclining or near-reclining position, the rays of the sunlight will often fall directly upon the infants' face and eyes causing damage to the eyes.
Many conventional conveyance devices, termed strollers herein, have integral canopies which are configured to protect a child occupant. While these canopies may protect the child from vertical rays of sunlight, these canopies are ineffective for protecting the child occupant from lateral and reflected rays of sunlight. Moreover, as the stroller moves around, the lateral and reflected rays of sunlight come in different directions according to the direction in which the stroller travels, making it difficult for an adult to effectively protect the child by using temporary means, such as strategically placed blankets or other shields.
One conventional baby carriage hood, or sun shade, has a support member for mounting the hood on a stroller. The support member includes a shaft which extends through the support member. The hood also has at least two hood ribs whose ends are bunched by the shaft in the manner of the pivot of a hand-held foldable fan. The ribs can then be unfolded and folded in the manner of a fan, and the unfolded angle thereof can be adjusted to any desired angle so as to shade the child occupant. Unfortunately, this sun shade does not completely enclose the child occupant of the stroller, hence the lateral and reflected rays of sunlight will still reach the child as the stroller travels about. Moreover, the attachment of the support member to a stroller precludes this prior art sun shade from being used on a variety of strollers.
Another prior art sun shade includes a self supporting frame for supporting a protective cover to protect a child occupant against the sunlight. The self supporting frame is secured to the handles of a conventional stroller and to structural elements of the stroller chassis. The self supporting frame then retains the protective cover around the chassis of the stroller to effectively protect the child occupant regardless of which direction the stroller travels.
Unfortunately, the self supporting frame structure is cumbersome to install, awkward to store, and does not allow quick and immediate access to the child occupant should the need arise. Another problem with the self supporting frame structure sun shade is that the child occupant is completely enclosed in a visually limiting protective cover. A child often feels separated or abandoned by his or her adult companion, for example his parent, if the child does not have an unimpeded view of that parent. This situation causes feelings of unhappiness or fear which leads to a fretful, crying baby or child. Moreover, the protective cover may also limit fresh air from passing through the stroller, so that the air under the cover is hot and stale. This situation results in further unhappiness for the child occupant due to the discomfort of the heat.
Yet another prior art sun shade is formed from a foldable material such as cardboard, plastic, and the like. The material is cut and scored to provided a preselected pattern which when folded into its fully assembled configuration, provides a means for attachment to a stroller for blocking sunlight. The canopy is configured to be installed at a position above and separated from a child in the stroller so that it allows quick and immediate access to the child occupant should the need arise. Unfortunately, this sun shade also does not completely enclose the child occupant of the stroller, hence the lateral and reflected rays of sunlight will still reach the child as the stroller travels about.


A peeling machine according to the present invention includes a cutter head and a feed mechanism having upper and lower feed rollers, and the feed mechanism includes a first holder that supports the lower feed roller, a second holder that supports the upper feed roller, a roller opening/closing driving mechanism, a synchronizing mechanism that has a pinion disposed in the same vertical plane as axes of the both feed rollers and first and second racks, and a grasping-force applying cylinder that applies a downward work grasping force to the second holder.

1. Field of the Invention
The present invention relates to a peeling machine for continuously cutting the outer peripheral surface of a round rod-like work, and in particular, to a feed mechanism for feeding the work to a cutter head.
2. Description of the Prior Art
Generally, a peeling machine includes a cutter head that rotates about a substantially horizontal mechanical center line to cut the outer peripheral surface of a round rod-like work, and a feed mechanism that holds the work on the mechanical center line between upper and lower feed rollers and feeds the work to the cutter head.
Japanese Unexamined Patent Publication No. H4 (1992)-226803 discloses various feed mechanisms for conventional peeling machines, and FIG. 8 shows one of the feed mechanisms. In FIG. 8, the feed mechanism includes a pair of upper and lower feed rollers 201, 202 that hold a round rod-like work W therebetween, and holders 203, 204 for supporting the feed rollers 201, 202, respectively, are supported by vertical respective guide rods 206, 206 so as to be vertically movable and to be driven by cylinders 210, 211, respectively. A synchronizing mechanism that moves the upper and lower holders 203, 204 in synchronization with each other is configured of a rocker lever 212, and a pair of connecting rods 220, 221 for connecting both ends of the rocker lever 212 to the upper and lower holders 203, 204.
With the configuration shown in FIG. 8, the synchronizing mechanism can change the position of the upper and lower feed rollers 201, 202 symmetrically in the vertical direction according to the works W having different diameters, thereby accurately holding the concerned work. Japanese Unexamined Patent Publication No. H4 (1992)-226803 also discloses a structure using a pair of upper and lower angle lever, as another example of the synchronizing mechanism.
In the feed mechanism shown in FIG. 8, the cylinders 210, 211 vertically move the holders 203, 204 for opening/closing the feed rollers 201, 202, and a grasping force to finally grasp the work W is derived from expansion/contraction of the cylinders 210, 211. That is, opening/closing of the upper and lower feed rollers 201, 202, positioning of the feed rollers 201, 202 with respect to the work, and grasping of the work with a predetermined pressure are all made by only controlling expansion/contraction of the cylinders 210, 211. However, with such configuration, it is difficult to rapidly open/close the feed rollers 201, 202, accurately position the feed rollers 201, 202, and grasp the work with an appropriate grasping force according to the diameter of the work. In other words, when the moving speed of the upper and lower holders is increased to improve the working efficiency, it becomes difficult to accurately position the feed rollers 201, 202, and suitably grasp the work with the appropriate grasping force according to the type of the work. Conversely, when the moving speed of the holders is decreased to enable grasping of the work with the appropriate grasping force according to the type of the work, working time increases, lowering the working efficiency.
When the grasping force with respect to the work is small, slippage between the work and the feed rollers occurs, inhibiting stable feeding. Conversely, when the grasping force with respect to the work is too large, for example, non-slip protrusions on the outer peripheral surfaces of the feed rollers may cause a transfer flaw on the surface of the work. Especially in cutting a soft material such as aluminum, the transfer flaw is likely to occur. Other feed mechanisms disclosed in Patent document 1 cause a similar problem.


A greatly improved flexible annular stapler for joining tubular organs is disclosed. The novel stapler features greater accuracy of operation and better control by the operator, as well as additional functions, such as internal illumination and viewing facility, and accomodation of a large number of accessories, such as fibroscopes and catheters. The novel stapler, moreover, features easy attachability of both stapling jaws and easy detachability of the head. The novel features are particularly useful for closed surgery. Also disclosed are novel methods and procedures for using a flexible annular stapler and the novel features disclosed herein--particularly under conditions of closed surgery.

The present invention relates to excision of a section of a hollow or tubular soft organ, such as the digestive tube, and rejoining the remaining ends and, more particularly, to methods for performing these operations under conditions of closed surgery, using a flexible annular stapling and cutting instrument. The invention also relates to an improved construction of such an instrument.
Various ailments of the digestive tube, particularly of the esophagus, the stomach, the small intestines and the colon, such as tumors, chronic inflammation or other disorders, often require excision of a portion of the tube, followed by rejoining of the remaining end segments, through anastomosis, to reestablish continuity of the tube. In some cases it is necessary to thus join one organ to another; for example, the cut end of the small intestines may be joined to the colon, or the cut end of the duodenum may be joind to the stomach. In some other cases, two organs or two portions of the same organ may be joined side-to-side (rather than end-to-end or end-to-side, as in the above cases). In the discussion to follow and in the claims, the terms "parts of hollow organs" or just "parts" will be used, for brevity, to collectively denote the two parts to be joined, and the terms "part of a hollow organ" or just "part"--to denote each of the two parts to be joined, whether they are truly two different hollow organs or two segments of the same hollow organ.
It has been common practice since the end of the '50s to use, for the purpose of the anastomosis, a suitable annular stapling and cutting instrument. An example of such an instrument, to be referred to herebelow as stapler, is depicted in FIG. 1A. The stapler basically consists of a tubular main body, at one end of which is an annular staple gun, while the other end serves as a handle and has a knob and activation levers thereon. A rod is slidably disposed inside the tubular body, protruding through the staple gun and terminating with a round head that contains an annular anvil. The staple gun contains a set of surgical stapling pins, arranged in one or two concentric circles and a circular knife inside these circles. On the face of the anvil are short grooves, one opposite each staple pin, with arc-like depth profile. During surgery, this stapler is used, for example, to rejoin end segments of the intestines after excision, by inserting it through a longitudinal cut in the side of the intestines and through the ends of both segments, then annularly folding and temporarily sewing one end over the face of the gun and one end over the anvil; the latter operation forms the ends into partially closed flange-like butts. Subsequently, by turning the knob, the head with the anvil is pulled toward the face of the gun, thus bringing the butts into mutual contact. Finally, by activating a lever on the handle, the staple pins are pushed through the flanges into the grooves in the anvil until they are bent tight; at the same time, the circular knife cuts away the inner disks of the two adjoining flanges, leaving an annular ring as the joint.
This, conventional, type of stapler has several shortcomings:
It always requires an extra, longitudinal, cut; for multiple excisions, multiple extra cuts are needed. PA0 It is not suitable for hard-to-reach or complicated portions of the intestiness, such as those inside the pelvis, nor for the duodenum; operation on the esophagus or the stomach is difficult. PA0 It is suitable almost only for end-to-end joints. PA0 The temporary sewing of the butt ends is difficult and the depth of the resulting flanges is small, thus risking leakage. PA0 (a) an elongated flexible tubular body; PA0 (b) a handle attached to a first end of the body; PA0 (c) a first jaw having an axial hole therethrough and two faces, a first face being attached to the second end of the body; PA0 (c) a flexible cable slidably disposed inside the body and through the hole, the cable consisting of two portions, a first portions defining an end segment, at least part of which protrudes from the second face of the first jaw; and PA0 (d) a second jaw, defining a head, being attachable to the end segment; PA0 (i) a housing attached to the second end of the body, PA0 (ii) an elongated externally threaded member disposed inside the housing and attached to the second portion of the cable, PA0 (iii) a turning assembly, which includes an internally threaded member that engages the externally threaded member, and a knob outside the housing, and PA0 (iv) a lever assembly, which includes a manually pressable lever; PA0 (a) providing a flexible annular stapler having two round jaws; PA0 (b) inserting the jaws into a first one of the two parts and advancing the jaws to where one jaw is inside the first part and the other jaw is inside the second one of the two parts, each jaw being substantially near the respective plane; PA0 (c) for each of the two parts, shrinking the opening so as to form an at least partially closed butt that encloses the respective one of the jaws; and PA0 (d) operating the annular stapler so as to pull the two the butts together and essentially combine the two annular areas into a combined annular area, to staple the two organs or segments to each other over the combined annular area and to cut away portions of the butts that are central to the combined annular area. PA0 (a) providing a flexible annular stapler having a flexible body, two round jaws and a flexible cable slidable through the body and through a first one of the jaws and having an end protrudable from the first jaw, the first one of the jaws being attachable to the body and the second one of the jaws being attachable to the end of the cable, both of the jaws being initially detached; PA0 (b) inserting the flexible body through the patient's body wall; PA0 (c) introducing the first jaw through the patient's body wall and attaching it to the flexible body; PA0 (d) introducing the second jaw through the patient's body wall and attaching it to the end of the cable; PA0 (e) having the first jaw inside the first one, and the second jaw inside the second one, of the two parts of hollow organs and having each of the two parts form an at least partially closed butt at or near the respective plane, the butt enclosing the respective one of the jaws; and PA0 (f) operating the annular stapler so as to pull the two butts together, to staple the two organs or segments to each other over an annular area and to cut away portions of the butts that are central to the annular area.
French patent FR 9204490 to the present applicant, which is incorporated into the present disclosure by reference, discloses a novel annular stapler that differs from the one described hereabove essentially in the following (see FIG. 1B for an external view and FIG. 1C for a longitudinal-sectional view): The main, tubular, body consists of a flexible hose 26, which can be of any length and to one end of which an anvil assembly 18 is attached. Through hose 26 is slidably disposed a flexible cable 21, one end of which is pointed and to which a head 11 is attachable. The other end of cable 21 is attached to a handle 30 by means of a long screw 52, engaged by a nut 51, which is connected to a knob 46 so that turning the knob causes the cable to slide along the hose and thus--the head to move with respect to the anvil. The head contains a cartridge with staple pins and a rigid hammer assembly 15 (to be refrred to as hammer) that includes fingers, to push the pins, and a circular knife. Hammer 15 is connectable to the end of cable 21 by a screw-like arrangement. Connected to the hammer through a spring is an annular base plate, which holds the cartridge of pins and has slots for passage of the pins. Cable 21, which may be hollow, has a flat outer surface, which matches a flat in the shape of a central hole in anvil 18 through which the cable slides; this is in order to keep the head angularly aligned with respect to the anvil prior to stapling. In handle 30 there is a window 54, through which a millimeter scale 42, attached to cable 21 is viewable, together with a fixed pointer. Operation of this stapler is similar to that of a conventional one, except that the stapling and cutting operation, after the two butts have made contact, is actuated automatically by continued turning of the knob (rather than activating a lever.
This novel stapler avoids the shortcomings of the conventional one, listed hereabove. In particular, it enables reaching any segment of the digestive tube--either through a natural opening (mouth or anus) or through a single, conveniently located cut. It also enables end-to-side or side-to-side joints.
Even so, the novel stapler of French patent FR 9204490 (to be referred to as the French patent) still has a few shortcomings and many as yet unrealized potentialities. One shortcoming is that in the disclosed construction there is an appreciable length of cable between the point at which the cable emerges from the anvil and the point at which it enters the head structure, even when these two components are at their closest approach. This may allow some twist in the cable and consequently some angular misalignment between the staple pins in the head and the grooves in the face of the anvil, which may cause malfunctioning of the stapling action. Likewise, because of uneven back pull of an intestinal butt, the faces of the two components may not be parallel, or may not be axially aligned prior to the stapling action, which, again, could cause malfunction. Another shortcoming of the instrument is in the operation of the handle; turning the knob may not be the optimal way to activate the stapling and cutting operation. Yet another shortcoming is the difficulty with which the head or anvil are are attachable or detachable, making such operations within the body, as would be advantageous in certain procedures, close to impossible.
The unrealized potentialities are mainly associated with a new possible mode of its employment, a mode that was not contemplated in the French patent but is the subject of the present invention, namely closed surgery. The practice and techniques of closed surgery, such as laparoscopy and thoracoscopy, have made tremendous progress over the past five years and many surgical procedures on internal organs are now carried out in this mode. Whereas in conventional, open, surgery, a relatively large incision is made in the abdominal wall or chest, closed surgery is characterized by insertion of very thin tools through otherwise intact walls--usually with the aid of small tubular ports, called trocars, which also serve to seal the openings during operation. Some of these tools serve for viewing and usually include a video system so that the entire operation is viewed and monitored on a video screen. The main advantages of closed surgery are (a) the much reduced trauma, resulting in fewer complications and much faster recuperation, which, in turn, shortens hospitalization and costs, (b) reduced risk of infection and (c) considerable reduction of scars.
Closed surgery of the digestive tube is also being practiced. However, because the only practical instrument now available for anastomosis is the rigid type described hereabove, which has to be operated under open conditions, the surgery ends up being, in part, of the open type (such as laparoscopically assisted surgery) and thus foregoes some of the advantages listed above. Basically, a flexible stapler, as described hereabove and contrary to a conventional, rigid, stapler, lends itself to completely closed surgery (such as laparospcopy and thoracoscopy), since the instrument is insertable either through the natural openings or through a suitable opening in the intact wall and can reach almost any location. However, such use of a flexible stapler has not yet been attempted nor, to the best of the inventor's knowledge, even been suggested. Moreover, there are certain aspects of this type of surgery that render direct utilization of the instrument, as disclosed in the French patent, difficult or impractical. For example, the preliminary circular sewing of the butt ends over the instrument's head or anvil, difficult even during open surgery, is close to impossible. Under certain circumstances it is preferable to place the active part of the instrument in the affected area prior to excision; it is then difficult to sense its position within the intestines. Also, there is a need for endoscopy during the operation and it may be difficult to insert or manipulate both the endoscope and the flexible stapler simultaneously in the same tube. A similar difficulty holds for internal ultrasonic examination.
Since, as stated, use of a flexible stapler in closed surgery has not yet been attempted and since, moreover, such an instrument is not yet available, there has been no clinical experience with anastomosis in the digestive tube under conditions of closed surgery and certainly no experience using such an instrument. Thus, no suitable procedures have so far been developed, which fact keeps the clinicians and patients from benefiting from the tremendous potential advantages of the technology and also hinders potential acceptance by clinicians of the instruments when they become available.
There is thus a recognized need for, and it would be highly advantageous to have, an improved stapler for anastomosis in the digestive tube that will overcome the shortcomings of presently known instruments and will, moreover, enable such operation under conditions of closed surgery. There is, furthermore, a need for practical methods and procedures for utilizing such an instrument under conditions of closed surgery.

Flexible annular stapler for closed surgery of hollow organs


A light detection and ranging system includes a mirror unit rotating around a scan axis. The mirror unit includes a receiving portion and a transmitting portion offset by an angle about the scan axis relative to a surface plane of the receiving portion. Respective centroids of the receiving and transmitting portions are positioned at a common point on the scan axis while the receiving and transmitting portions rotate around the scan axis. A transmitter transmits a light pulse toward the mirror unit. The transmitting portion is positioned to reflect the light pulse toward a target. A receiver is positioned to reflect the light pulse reflected from the target toward the receiver. The angle offset compensates for a change between a cone of illumination of the transmitting portion and a field-of-view of the receiving portion resulting from the rotation of the mirror unit.

The present invention relates to a scanning optical ranging system. It finds particular application in conjunction with a light detection and ranging (LIDAR) system and will be described with particular reference thereto. It will be appreciated, however, that the invention is also amenable to other applications.
A light detection and ranging (LIDAR) system transmits a pulse of light (e.g., from a laser), which is reflected from a target. An optical receiver detects the reflected light, and the range to the target is computed from the delay time between the transmission of the light pulse and the detection of the reflected light. The receiver field-of-view and the transmitted light beam are usually matched and co-aligned to ensure maximum light collection efficiency. If the LIDAR contains a fast optical scanner (such as a rapidly moving mirror), it is possible for the field-of-view of the receiver to lose alignment with respect to the projected light beam. Such alignment loss is caused by a change in the pointing direction that occurs during the time required for the light pulse to travel to the target, reflect, and then travel back to the receiver. The extent of this misalignment is a "lag angle," which depends on the speed of the scanner and the range of the target. For a scanning LIDAR that is "diffraction-limited" (i.e., the light beam divergence is limited only by the wavelength and the diameter of the beam at the exit aperture of the LIDAR), the scanner angular speed ω1/2 (measured in radians/second) for which the lag angle is half of the transmitted light beam divergence is:
            ω              1        /        2              =                  θ        .            =                        0.5          ·          λ          ·          c                          2          ·          D          ·          R                      ,
where λ is the wavelength of the transmitted light (in meters),                c is the speed of light (˜3×108 meters/second),        D is the transmitted light beam diameter at the exit aperture of the LIDAR (in meters), and        R is the range to the target (in meters).
If the receiver field-of-view is initially aligned to a transmitted light cone of illumination, the received signal is reduced by the lag angle. The effect becomes worse at longer ranges and as the scanner speed increases.
If the LIDAR system is not diffraction-limited and the transmitted beam divergence is instead Δ, then the formula above becomes:
      ω          1      /      2        =            θ      .        =                            0.5          ·          Δ          ·          c                          2          ·          R                    .      For example, if the divergence of the transmitted light beam is 2 milliradians (mrad) and the range of a target is 3 km, the angular speed at which the lag angle is half of the transmitter beam width is 50 radians/second, or 480 revolutions/minute (rpm). In this case if the receiver field-of-view is matched to the transmitted light beam divergence, the lag angle is still sufficiently small for the optical receiver to detect some reduced amount of scattered light from the target, but for scanner speeds greater than 960 rpm, the lag angle effect causes the receiver field-of-view to completely miss or obscure the signal from 3 km and beyond. The condition for this complete obscuration is:
      ω    obscure    =            θ      .        =                            Δ          ·          c                          2          ·          R                    .
All LIDAR systems, whether they are scanning or staring, must often contend with another issue—large signal dynamic range. Signal dynamic range is the ratio of the maximum detectable light signal intensity (i.e., detector saturation) to the minimum detectable light signal intensity. The detected signal decreases rapidly with increasing target distance. Therefore, the received signals from targets at closer ranges may over-saturate the detector, while those from targets at longer ranges may be barely detectable. A design technique known as "geometric compression" can reduce the signal dynamic range by controlling the fixed overlap of the transmitter and receiver optical fields-of-view, the separation of the receiver and transmitter optics, and the shadowing of the receiver by the transmitter optics to attenuate the close-range signal. The time delay of the received light signal with respect to the transmitted light pulse does not enter into this compression calculation since these design parameters are static. Geometric compression can benefit both scanning and staring LIDAR systems.
The present invention provides a new and improved apparatus and method which addresses the above-referenced problems.


A composition is described which is useful for treating neurological and mental disorders which are associated with and/or related pathogenetically to deficient serotonin neurotransmission and impaired pineal melatonin functions in humans the composition being administered in combination with a sufficient amount of an AC pulsed magnetic field alone or in conjunction with a DC magnetic field and a sufficient amount of random noise to the brain of a human in need of such treatment which composition comprises an effective amount of a composition which increases serotonin transmission to the human to be treated. A method of treating neurological and mental disorders which are associated with and/or related pathogenetically to deficient serotonin neurotransmission and impaired pineal melatonin functions in humans is described which comprises administering to a human in need thereof an effective amount of a composition which increases serotonin transmission to the human to be treated followed by the application to the brain of the human of a sufficient amount of AC pulsed magnetic field alone, or in combination with a DC magnetic field and low frequency random noise, of proper intensity, frequency, waveform, wave symmetry and phase shift of the wave to treat the disorder.

The present invention relates to a method of treating neurological and mental disorders which are associated with and/or related pathogenetically to deficient serotonin neurotransmission and impaired pineal melatonin functions in humans.
The pineal gland serves as a magnetoreceptor organ in the brain of humans and other mammals and its stimulation with an AC pulsed magnetic field has shown beneficial effects in the treatment of neurological and mental disorders which are associated with or related pathogenetically to impairment of pineal melatonin functions including multiple sclerosis, Parkinson's disease, juvenile Parkinsonism, progressive supranuclear palsy. Huntington's chorea, Shy-Drager syndrome, essential tremor, AIDS dementia complex, motor neuron disease, traumatic spinal cord injuries, ischemic stroke, diabetic neuropathy, dystonia, myoclonus, tardive dyskinesia, Tourette's syndrome, epilepsy, narcolepsy, Restless-legs syndrome, akathisia, chronic pain syndromes, migraine, Alzheimer's disease, depression (including seasonal affective disorder and premenstrual depression), autism, Attention Deficit hyperactivity disorder, schizophrenia, alcohol and substance abuse, obsessive-compulsive disorder, anxiety and panic disorder, posttraumatic stress disorder, trichotillomania, impulsive and aggressive behavior, chronic insomnia, sleep paralysis, and bulimia.
For many years physiologists considered the pineal gland, lodged deep within the brain, a vestigial organ which is merely an anatomical remnant of a primary sensory system. To the clinician the pineal gland, by virtue of its midline position and calcification, was of interest as a radiological landmark to identify intracranial space occupying processes. The pineal gland attracted scientific attention in 1963, when its primary secretion, melatonin, was first recognized as a hormone. Wurtman and Axelrod (1965) "The pineal gland." Scientific American, 231, 50-60) considered the pineal gland a "neuroendocrine transducer," an organ which converts neural signals from the external environment such as photic, acoustic, thermic, and magnetic cues into neuroendocrine output which acts on the nervous system largely via the secretion of its principal hormone melatonin. The pineal gland is unique among endocrine organs for a number of reasons: (1) it is one of the few unpaired endocrine organs: (2) on a weight basis, it receives one of the richest blood supplies of any organ; (3) it lies outside the blood brain barrier, but has direct access to the cerebrospinal fluid (CSF) via the third ventricle; (4) it produces and/or contains high concentrations of a number of different indoleamines and low molecular weight peptides of probable endocrine importance; and (5) it is responsive to changes in magnetic field strength and to external electrical stimuli (Foley et al., (1986) "Pineal indoles: significance and measurement." Neuroscience & Biobehavioral Reviews, 10, 273-293).
Over the post several years scientists have come to suspect that melatonin could be a "master hormone" involved in the control of circadion rhythms (biological cycles that recur at approximately 24-hour intervals), and protecting against some of the common diseases of aging through its free radical scavenging effects (Daniels et al., (1996) "Free radical scavenging effects of melatonin and serotonin: possible mechanism." NeuroReport, 7, 1593-1596). Melatonin is now recognized to exert an important influence on a host of biological functions including synchronization of biological rhythms, stabilization of neuronal activity, regulation of sexual maturation and reproduction, immunomodulation, temperature control, sleep, mood, pain control, cognitive functions, and motor behavior (Ehrlich and Apuzzo (1985) "The pineal gland: anatomy, physiology, and clinical significance." Journal of Neurosurgery, 63, 321-341; Miles and Philbrick (1988) "Melatonin and Psychiatry." Biological Psychiatry, 23, 405-425; Romijn (1978). "The pineal, a tranquillizing organ?" Life Sciences, 23, 2257-2274; Lakin et al., (1981) "Involvement of the pineal gland and melatonin in murine analgesia." Life Sciences, 29, 2543-2551; Kavaliers et al., (1983) "Ageing, opoid analgesia and the pineal gland." Life Sciences, 32, 2279-2287; Cotzias et al., (1971) "Melatonin and abnormal movement induced by L-dopa in mice." Science, 173, 450-452; Reiter (1991) "Pineal melatonin: cell biology of its synthesis and of its physiological interactions." Endocrine Reviews, 12, 151-180; Brzezinski (1997) "Melatonin in humans," New England Journal of Medicine, 336, 186-195).
Many of the biological effects of melatonin result from its action on serotonergic neurons indicating that the neurotransmitter serotonin is an important mediator of melatonin's biological actions and that deficient serotonin neurotransmission may disrupt melatonin's biological functions (Anton-Tay et al., (1968) "Brain serotonin concentration: elevation following intraperitoneal administration of melatonin." Science, 162, 277-278; Gaffori and Van Ree (1985) "Serotonin and antidepressant drugs antagonize melatonin-induced behavioral changes after injection into the nucleus accumbens of rats."Neuropharmacology, 24, 237-244: Namboodiri et al., (1983) "5-hydroxytryptophan elevates serum melatonin." Science, 221, 659-661; Aldegunde et al., (1985) "Effects of pinealectomy on regional brain serotonin metabolism." . International Journal of Neuroscience, 26, 9-13; Sugden and Morris (1979) "Changes in regional brain levels of tryptophan, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, dopamine and noradrenaline after pinealectomy in the rat." Journal of Neurochemistry, 32, 1593-1594; Olcese (1985) "Enhancement of melatonin's antigonadal action by daily injections of the serotonin uptake inhibitor fluoxetine in male hamsters." Journal of Neural Transmission, 64, 151-161; Smythe and Lazarus (1974) "Growth hormone responses to melatonin in man." Science, 184, 1373; Koulu and Lamrmintausta (1979) "Effect of melatonin on L-tryptophan and apomorphine-stimulated growth hormone secretion in man." Journal of Clinical Endocrinology & Metabolism, 49, 70-72; Dugovic et al., (1989) Melatonin modulates the sensitivity of 5-hydroxytryptophan-2-receptor mediated sleep wakefullness in the rat. Neuroscience Letters, 104, 320-325; Miguez et al., (1996) "Changes in serotonin level and turnover in discrete hypothalamic nuclei after pinealectomy and melatonin administration to rats." Neurochemistry International, 29, 651-658).
Melatonin production has been shown to change across the lifespan, peaking in childhood and gradually decreasing after puberty. The gradual decline in the secretory activity of the pineal gland after puberty has been linked with the process of aging as melatonin is thought to counteract the deleterious effects of oxygen free radicals--unstable molecules thought to play an important part in atherosclerosis and other diseases associated with aging (Nair et al., (1986) "Plasma melatonin--an index of brain aging in humans?" Biological Psychiatry, 21, 141-150; Sack et al., (1986) "Human melatonin production decreases with age." Journal of Pineal Research, 3, 379-388; Armstrong and Redman (1991) "Melatonin: a chronoblotic with antiaging properties?" Medical Hyotheses, 34, 300-309).
Impaired pineal melatonin function has been implicated in the pathophysiology of numerous systemic, neurological and mental disorders including cancer, autoimmune disorders (i.e., rheumatoid arthritis, systemic lupus), AIDS, diabetes mellitus, hyper-cholesterolemia, mental depression including seasonal affective disorder (SAD), schizophrenia, autism, panic disorder, obsessive compulsive disorder, trichotillomania, substance abuse including alcoholism, posttraumatic stress disorder, impulsive and aggressive behavior, chronic insomnia, sleep paralysis, bulimia, Parkinson's disease, juvenile Parkinsonism, Shy-Drager syndrome, progressive supranuclear palsy (PSP), Huntington's chorea, AIDS dementia, Alzheimer's disease, Korsakoffs dementia, tardive dyskinesia, chronic pain syndromes, diabetic neuropathy, epilepsy, narcolepsy, migraine, multiple sclerosis, ischemic stroke, motor neuron disease, traumatic spinal cord injuries and macular degeneration. These diseases are associated either with deficient melatonin production and/or disruption of melatonin circodian rhythmicity associated with deficient or dysregulated serotonin neurotransmission as disclosed in Anton-Tay et al., (1971) "On the effects of melatonin upon human brain. Its possible therapeutic implications." Life Sciences, 10, 841-850; Smith et al., (1978) "Decrease in human serum melatonin concentrations with age." Journal of Neural Transmission, 13 (Suppl), 396; Pavel et al., (1980) "Vasotocin, melatonin and norcolepsy: possible involvement of the pineal gland in its pathophysiological mechanism." Peptides, 1, 281-284; Martin et al., (1984) "Decreased 6-hydroxymelatonin excretion in Korsakoff's psychosis." Neurology, 34, 966-968; Fanget et al., (1989) "Nocturnal plasma melatonin levelsin schizophrenic patients" Biological Psychiatry, 25, 499-501; Skene et al., (1990) "Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer's disease." Brain Research, 528, 170-174; Souetre et al., (1989) "Abnormal melatonin response to 5-methoxypsoralen in dementia." American Journal of Psychiatry, 146, 1037-1040; Renfrew et al., (1987) "Circadian rhythms in Alzheimer's disease." Neurosciences Abstracts, 1, 322; Armstrong and Redman (1991) "Melatonin: a chronobiotic with antiaging properties?" Medical Hypotheses, 34, 300-309; Nair et al.. (1986) "Plasma melatonin--an index of brain aging in humans?" Biological Psychiatry, 21, 141-150: Tohgi et al., (1992) "Concentrations of serotonin and its related substances in the cerebrospinal fluid in patients with Alzheimer-type dementia." Neuroscience Letters, 141, 9-12: Ferti et al., (1991) "Circadian secretion pattern of melatonin in Parkinson's disease." Journal of Neural transmission, 3, 41-47: Ferti et al., (1993) "Circadian secretion pattern of melatonin in de novo Parkinsonian patients: evidence for phase-shifting properties of l-dopa." Journal of Neural Transmission (P-D Sect), 5, 227-234: Sandyk (1992) "The pineal gland and the clinical course of multiple sclerosis." International Journal of Neuroscience, 62, 65-74; Sandyk (1992) "The pineal gland and multiple sclerosis." (Editorial) International Journal of Neuroscience, 63, 206-215: Toglia, J. U. (1986) "is migraine due to a deficiency of pineal melatonin"? Italian Journal of Neurological Sciences, 7, 319-32; Sandyk and Kay (1990) "Pineal melatonin in schizophrenia: a Review and hypothesis." Schizophrenia Bulletin, 16, 653-662; Sandyk et al., (1990) "Pineal gland calcification and tordive dyskinesia." Lancet, 335, 1528; Robinson et al., (1991) "Serum melatonin levels in schizophrenic and schizoaffective hospitalized patients." Acta Psychiotrica Scandinavica, 84, 221-224; Miles and Philbrick (1988) "Melatonin and Psychiatry." Biological Psychiatry, 23, 405-425; Nir et al., (1969) "Changes in the electrical activity of the brain following pinealectomy." Neuroendocrinology, 4, 122-127; Philo (1982) "Catecholamines and pinealectomy-induced convulsions in the gerbil (Merinos unguiculatus)." Progress in Clinical Biological Research, 92, 233-241; Reiter et al., (1973) "Nature and time course of seizures associated with surgical removal of the pineal gland from parathyroldectomized rats." Experimental Neurology, 38, 386-397; McIntyre et al., (1990) "Plasma concentrations of melatonin in panic disorder." American Journal of Psychiatry, 147, 462-464; Moteleone et al. (1994) "Circadian rhythms of melatonin, cortisol and prolactin in patients with obsessive compulsive disorder." Acta Psychiatrica Scandinavica, 89, 411-415; Catapano et al., (1992) "Melatonin and cortisol secretion in patients with primary obsessive compulsive disorder." Psychiatry Research, 44, 217-225; Sandyk and Kay (1991) "Concordance of Tourette's syndrome and bipolar disorder: possible role of the pineal gland." International Journal of Neuroscience, 58, 235-240; Sandyk and Kay (1991) "Pineal melatonin secretion during puberty: possible relevance to Giles de la Tourette's syndrome." International Journal of Neuroscience, 58, 232-235; Molina-Carballo et al., (1994) "Day-night variations in melatonin secretion by the pineal gland during febrie and epileptic convulsions in children." Psychiatry Research, 52, 273-283; Waldhauser et al., (1993) "Clinical aspects of the melatonin action: impact of development, aging and puberty, involvement of melatonin in psychiatric disease and importance of neuroimmunoendocrine interactions." Experientia, 49, 671-681; Brambilla et al., (1988) "Melatonin circadion rhythm in anorexia nervosa and obesity." Psychiatry Research, 23, 267-276; Pierpaoli and Regelson (1995) "The melatonin miracle." (pp. 175-177). New York: Pocket Book; Relter (1995) "Melatonin." (pp. 60-72). New York: Bantam Books; Norden (1995) "Beyond prozac." (pp. 8-10). New York: Regan Books; McEntee and Crook (1991) "Serotonin, memory, and the aging brain." Psychopharmacology, 103, 143-149; Lawlor (1990) "Serotonin and Alzheimer's disease." Psychiatric Annals, 20, 567-570; Comings (1990) "Serotonin and human behavior" In D. E. Comings (Ed.), Tourette syndrome and human behavior (pp. 429-444). Duarte: Hope Press; Erlich and Apuzzo (1985) "The pineal gland: anatomy, physiology, and clinical significance." Journal of Neurosurgery, 63, 321-341; Sandyk and Fisher (1988) "Serotonin in involuntary movement disorders." International Journal of Neuroscience, 42, 185-205; Fuller (1992) "Clinical applications of 5-HT uptake inhibitors." In P B Bradley et al. (Eds.), Advances in the Biosciences: serotonin, CNS receptors and brain function, vol. 85 (pp. 255-270); Weingartner et al., (1983) "Effects of serotonin on memory impairments produced by ethanol." Science, 221, 472-473; Amit et al., (1984) "Zimeildine: a review of its effects on ethanol consumption." Neuroscience & Biobehavioral Reviews, 8, 35-54; Meara (1996) "Serotonin and the extrapyramidal system--a neurological perspective." Human Psychopharmacology. 11, S95-S102; Hubble et al., (1989) "Essential tremor." Clinical Neuropharmacology, 12, 453-482; Kulmann et al., (1995) "Lack of light/dark rhythm of the pineal hormone melatonin in autistic children." First International Congress of Clinical Neuroimmunomodulation, Monza, Italy; Young et al, (1982) "Clinical neurochemistry of autism and associated disorders." Journal of Autism and Developmental Disorders, 12, 147-165; Johonsson and Roos (1974) "5-hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluid of patients with neurological disorders." European Neurology, 11, 37-45; Barbeau (1969) "L-dopa and Juvenile Huntington's disease." Lancet, 2, 1066; Klawans (1970) "A pharmacologic analysis of Huntington's chorea." European Neurology, 4, 148-163; Brody et al., (1970) "Depressed monoamine catabolite levels in cerebrospinal fluid of patients with parkinsonian dementia of Guam" New England Journal of Medicine, 232, 947-950; Vaughan et al., (1979) "Melatonin, pituitary function and stress in humans." Psychoneuroendocrinoloy, 4, 351-362; Tetsuo et al., (1981) "Urinary b-hydroxymelatonin excretion in patients with orthostatic hypotension." Journal of Clinical Endocrinology and Metabolism, 53, 607-610; Snyder and llams (1982) "Serotoninergic agents in the treatment of isolated sleep paralysis." American Journal of Psychiatry, 139, 1202-1203; Anden et al., (1965) "5-hydroxyindole-acetic acid in rabbit spinal cord normally and after transection." Acta Physiologica Scandinavica, 64, 193-196; Brun et al., (1971) "Studies of the monoamine metabolism in the central nervous system in one patient with Jakob Creutzfeldt disease." Acta Neurologica Scandinavica, 47, 642-645; Kneisley et al., (1978) "Cervical spinal cord lesions disrupt the rhythm in human melatonin excretion." Journal of Neural Transmission, 13 (suppl), 311-323; Li et al., (1989) "Rhythms of serum melatonin in patients with spinal lesions at the cervical, thoracic or lumbar region." Clinical Endocrinology, 30, 47-56; Wetterberg (1978) "Melatonin in humans, Physiological and clinical studies." Journal of Neural Transmission, 13 (suppl) 289-310; Rojdmar et al., (1993) "Inhibition of melatonin secretion by ethanol in man." Metabolism, 42, 1047-1051; Pang et al., (1990) "Acute cerebral haemorrhage: changes in nocturnal surge of plasma melatonin in humans." Journal of Pineal Research, 9, 193-208; Manev et al., (1996) "Increased brain damage after stroke or excitotoxic seizures in melatonin-deficient rats." FASEB Journal, 10, 1546-1551). Moreover, recent studies have indicated that pineal melatonin exerts an important neuroprotective effect as melatonin deficient animals demonstrate increased vulnerability to cerebral damage after sustaining a focal ischemic/stroke or epileptic-like seizures (Giusti et al., 1995) "Melatonin protects primary cultures of cerebellar granule neurons from kainate but not from N-methyl-D- aspartate excitoxicity." Experimental Neurology, 131, 39-46; Manev et al., (1996) "Increased brain damage after stroke or excitotoxic seizures in melatonin-deficient rats." FASEB Journal, 10, 1546-1551). These studies suggest that melatonin deficiency reflects a pathophysiological mechanism in neurodegenerative diseases.
The pineal gland is a neural structure that is functionally related to the visual system. Indeed, the circadian production of melatonin is determined by the photoperiodic environment to which animals are exposed. Bright light suppresses pineal melatonin synthesis and secretion while ambient darkness stimulates the production and secretion of the hormone. The effects of the environmental illumination on the pineal gland are mediated via a well-delineated retino-hypothalamic-pineal circuit. The rhythms of melatonin secretion are generated by the paired suprachlasmatic nuclei (SCN) of the hypothalamus which serve as the body's biological clock. Serotonin concentrations are higher in the pineal than in any other organ or in any brain region. They exhibit a striking diurnal rhythm, remaining at a maximum level (in the rat) during the daylight hours and falling by more than 80% soon after the onset of darkness, as serotonin is converted to melatonin.
Melatonin is a unique indole derivative. It acts both as a neurotransmitter and neurohormone. Melatonin is lipid soluble and rapidly crosses the blood brain barrier and other tissues. Once released from the pineal gland, which is highly vascularized, it enters both the general circulation and the cerebrospinal fluid (CSF). Melatonin acts on the central and peripheral nervous system as well as on peripheral endocrine target tissues. Laboratory studies have indicated that the primary effects of melatonin is on the neuroendocrine system where it has been shown to influence the activity of the hypothalamic-pituitary-gonadal-thyrold-adrenal axis. In addition, melatonin has been shown to be involved in the regulation of the activity of monoaminergic neurotransmitters such as dopamine, norepinephrine, gamma-aminobutyric acid (GABA) and serotonin as well as the opioid peptides (Ehrich and Apuzzo (1985) "The pineal gland: anatomy, physiology, and clinical significance. Journal of Neurosurgery, 63, 321-341 Anton-Tay (1974) "Melatonin: effects on brain function." Advances in Biochemical Psychopharmacology, 11, 315-324; Datta and King (1980) "Melatonin:effects on brain and behavior." Neuroscience & Biobehavioral Reviews, 4, 451-458; Rosenstein and Cardinall (1986) "Melatonin increases in vivo GABA accumulation in rat hypothalamus, cerebellum, cerebral cortex and pineal gland." Brain Research, 398, 403-406; Zisapel et al., (1982) "Inhibition of dopamine release by melatonin: regional distribution in the rat brain." Brain Research, 246, 161-163). At a cellular level, melatonin acts to produce antioxidants as by increasing CGMP. It also provides guanine nucleotides for DNA and partakes in DNA repair mechanisms and in maintenance of membranes and other intracellular components (Grad and Rozencwaig (1993) "The role of melatonin and serotonin in aging: update." Psychoneuroendocrinology, 18, 283-295.
In addition to the ambient light/dark cycle, the activity of the pineal gland and hence the rate of melatonin secretion is influenced also by the earth's geomagnetic field which is in the order of 30,000-60,000 nanotesia (0.3-0.6 Gauss). The earth's magnetic field is primarily a nontime-varying (DC) field with angle of incidence to the earth's surface increasing with increasing latitude. For comparison, anthropogenic magnetic fields are primarily time varying at 50 or 60 Hz and harmonic of these frequencies. Typical magnetic fields measured in residental settings range from 0.1 microtesia to 3 microtesia at 60 Hz frequency. The geomagnetic field has been a part of the environment throughout the evolution of animals and is used by certain species in their adaptive strategies. Organisms are capable of perceiving its intensity, polarity, and direction (Gould (1984) "magnetic field sensitivity in animals." Annual Review of Physiology, 46, 585-598). It is thought that the circadian rhythmicity of the earth's magnetic field may have an additional "Zeltgeber" (time cue) function in the organization of biological rhythms (Cremer-Bartels et al., (1984) "Magnetic field of the earth as additional zeitgeber for endogenous rhythms?" Naturwissenschaften, 71, 567-574; Wever (1968) "Einfluss Schwacher Elektro-magnetischer Felder auf die Circadlane Perlodik des Menschen." Naturwissenschaften, 55, 29-32; Bartsch et al., (1994) "Seasonality of pineal melatonin production in the rat: possible synchronization by the geomagnetic field." Chronobiology International, 11, 21-26).
Since the activity of the pineal gland is sensitive to the influences of the geomagnetic field it has been suggested that it functions as a magnetoreceptor as well (Semm et al., (1980) "Effects of an earth-strength magnetic field on electrical activity of pineal cells." Nature, 288 607-608; Semm (1983) "Neurobiological investigations on the magnetic sensitivity of the pineal gland in rodents and pigeons." Comparative Biochemistry and Physiology, 76A, 683-689; Olcese et al., (1988) "Geomagnetic field detection in rodents." Life Sciences, 42, 605-613; Demaine and Semm (1985) "The avian pineal gland as an independent magnetic sensor." Neuroscience Letters, 62, 119-122; Rudolph et al., (1988) "Static magnetic fields decrease nocturnal pineal cAMP in the rat." Brain Research, 446, 159-160). Based on histological studies and electrophysiological single unit recordings from the pineal gland of rodents and pigeons, it has been estimated that 20%-30% of pineal cells respond to magnetic field Stimulation (Semm (1983) "Neurobiological investigations on the magnetic sensitivity of the pineal gland in rodents and pigeons." Comparative Biochemistry and Physiology. 76A, 683-689). Electrophysiological studies by Reuss et al., (1983) "Different types of magnetically sensitive cells in the rat pineal gland" Neuroscience Letters, 40 23-26) have demonstrated the presence of different types of magnetically sensitive cells in the pineal gland of the rat.
Furthermore, short-term exposure of experimental animals to DC external magnetic fields of various intensities and frequencies has been shown to inhibit temporarily the secretion of melatonin while more chronic exposure may even induce ultrastructural morphological changes in the pineal gland (Bardasano et al., (1985) "Ultrastructure of the pineal cells of the homing pigeon Columba livia and magnetic fields (first trials)." Journal Fuer Hirnforschung, 26, 471-475; Semm et al., (1980) "Effects of an earth-strength magnetic field on electrical activity of pineal cells. Nature, 288 607-608; Welker et al., (1983) "Effects of an artificial magnetic field on serotonin N-acetyltransferase activity and melatonin content of the rat pineal gland." Experimental Brain Research 50, 426-432; Wilson et al., (1981) "Neuroendocrine mediated effects of electromagnetic field exposure:possible role of the pineal gland." Life Sciences, 45, 1319-1332; Reiter (1993) "Static and extremely low frequency electromagnetic fields exposure: reported effects on the circadian production of melatonin." Journal of Cellular Biochemistry, 51, 394-403). Exposure of animals to magnetic fields also has resulted in increased pineal and cerebral serotonin levels (Reiter and Richardson (1992) "Magnetic fields effects on pineal indoleamine metabolism and possible biological consequences." FASEB Journal, 6, 2283-2287).
The human pineal gland, likewise, is believed to be sensitive to changes in the environmental magnetic fields. Howard et al., (1965) "Psychiatric ward behaviour and geophysical parameters." Nature, 205, 1050-1052) made the seminal observation of a relationship between increased geomagnetic activity and the rate of admission of patients to psychiatric facilities. Rajaram and Mitra (1981) "Correlation between convulsive seizure and geomagnetic activity." Neuroscience Letters, 24, 187-191) and Venkatraman (1976) "Epilepsy and solar activity. An hypothesis." Neurology (India), 24, 1-5) reported an association between changes in the geomagnetic field due to magnetic storms and frequency of seizures in epileptic patients. Semm (1992) "Pineal function in mammals and birds is altered by earth-strength magnetic fields." In Moore-Ede, Campbell, and Relter (Eds.), Electromagnetic Fields and Circadian Rhythmicity, (pp. 53-62), Boston: Birhauser) observed in normal subjects placed in the center of a Helmholtz coil system that inversion of the horizontal component of the ambient magnetic field for 30 minutes at midnight resulted in a significant (70%) depression of plasma melatonin concentrations.
Melatonin is a "master hormone" involved in the regulation of a host of biological functions related to the control of neuroendocrine functions, immunomodulation, analgesia, motor behavior, mood, sleep, cognition, and neurotransmitter synthesis and release including serotonin synthesis (Datta and King (1980) Melatonin: effects on brain and behavior." Neuroscience & Biobehavioral Reviews, 4, 451-458; Ehrlich and Apuzzo (1985) "The Pineal Gland: anatomy, physiology, and clinical significance" Journal of Neurosurgery, 63, 321-341; Frazer and Brown (1987) "Melatonin: a link between the environment and behavior." Integrative Psychiatry, 5, 3-26; Bradbury et al., (1985) "Melatonin action in the midbrain can regulate forebrain dopamine function both behaviourally and biochemically." "In Brown and Wainwright (Eds.), The Pineal Gland: Endocrine Aspects (pp. 327-332) New York: Pergamon Press; Aldegunde et al., (1985) "Effects of pinealectomy on regional brain serotonin metabolism." International Journal of Neuroscience, 26, 9-13; Miguez et al., (1991) "Differential effects of pinealectomy on amygdala and hippocampus serotonin metabolism". Journal of Pineal Research, 10, 100-103; Miguez et al., (1991) "Long-term pinealectomy alters hypothalamic serotonin metabolism in the rat." Journal of Pineal Research 11, 75-79; Miguez et al., (1996) "Changes in serotonin level and turnover in discrete hypothalamic nuclei after pinealectomy and melatonin administration to rats." Neurochemistry International, 29, 651-658). Consequently, it is believed that intermittent transcranial applications of AC pulsed magnetic fields of extremely low intensity may be used therapeutically by boosting the activity of the pineal gland with resultant increased melatonin and serotonin production.
I and others working in this area believe that AC pulsed applications of magnetic fields in the picotesia range intensity administered transcranially are beneficial in the treatment of several neurological and mental disorders including epilepsy, Parkinson's disease, juvenile Parkinsonism, Alzhelmer's disease, dystonia, tardive dyskinesia, Tourette's syndrome, migraine, and multiple sclerosis (Anninos et. al., (1991) "Magnetic stimulation in the treatment of partial seizures." International Journal of Neuroscience, 60, 141-171; Sandyk and Anninos (1992) "Attenuation of epilepsy with application of external magnetic fields: a case report."International Journal of Neuroscience, 66, 75-85; Sandyk (1992) "The influence of the pineal gland on migraine and cluster headaches and the effects of treatment with picotesia magnetic fields." International Journal of Neuroscience, 67, 145-171; Sandyk (1992) "Weak magnetic fields as a novel therapeutic modality in Parkinson's disease." International Journal of Neuroscience, 66, 1-15; Sandyk (1992) "Successful treatment of multiple sclerosis with magnetic fields." International Journal of Neuroscience, 66, 237-250; Sandyk and Iacono (1993) "Resolution of longstanding symptoms of multiple sclerosis by application of picotesia range magnetic fields." International Journal of Neuroscience, 70, 255-269; Sandyk and Iacono (1993) "Reversal of visual neglect in Parkinson's disease by treatment with picotesia range magnetic fields." International Journal of Neuroscience, 73, 93-107); Sandyk (1994) "Alzheimer's disease: Improvement of visual memory and visuoconstructive performance by treatment with picotesia range magnetic fields." International Journal of Neuroscience, 76, 185-225; Sandyk (1994) "A drug naive Parkinsonian patient succesfully treated with electromagnetic fields." International Journal of Neuroscience, 79, 99-110; Sandyk (1995) "Improvement of right hemispheric function in a child with Gilles de la Tourette's syndrome by weak electromagnetic fields." International Journal of Neuroscience, 81, 199-213. Sandyk (1994) "Reversal of visuospatial hemi-inattention in patients with chonic progressive multiple sclerosis by treatment with weak magnetic fields" International Journal of Neuroscience, 79, 169-184; Sandyk (1995) "Long term beneficial effects of weak electromagnetic fields in multiple sclerosis." International Journal of Neuroscience, 83, 45-57; Sandyk (1996) "Treatment with electromagnetic fields alters the clinical course of chronic progressive multiple sclerosis, a case report." International Journal of Neuroscience, 88, 75-82; Sandyk (1996) "Freezing of gait in Parkinson's disease is improved by treatment with weak electromagnetic fields." International Journal of Neuroscience, 85, 111-124; Sandyk (1997) "Progressive cognitive improvement in multiple sclerosis from treatment with electromagnetic fields." International Journal of Neuroscience, 89, 39-51).
However, I believe that the therapeutic efficacy of externally applied magnetic fields, administered as described in the prior art, without the use of the composition, is limited by several factors:
First, the pineal gland tends to undergo calcification with progression of age and particularly in association with various systemic and neurological disorders (Trentini et al., (1987) "Pineal calcification in different physiopathological conditions in humans," in Trentini et al., Fundamentals and clinics in Pineal research, (pp. 291-304), New York: Raven Press, Welsh (1985) "Pineal calcification: Structural and functional aspects." Pineal Research Reviews, 3 41-68; Zimmerman and Bilaniuk (1982) "Age-related incidence of Pineal calcification detected by computed tomography." Neuroradiology 142, 659-662; Sandyk et al., (1990) Pineal gland calcification and tardive dyskinesia" Lancet. 335, 1528; Sandyk et al., (1991) "pineal calcification and anticonvulsont responsiveness to artificial magnetic stimulation in epileptic patients." For instance, in the case of epileptic patients it has been found that patients who demonstrated calcification of the pineal gland on computed tomography (CT) scan responded less favourably to magnetic treatment in terms of seizure control than those subjects who showed no calcification of the pineal gland (Sandyk et al., (1991) "Pineal calcification and anticonvulsant responsiveness to artificial magnetic stimulation in epileptic patients." International Journal of Neuroscience, 60, 173-175).
Second, the secretory activity of the pineal gland, as reflected by nocturnal melatonin plasma levels, diminishes with age. In addition, aging is associated with diminished capacity of the pineal gland to initiate the production of melatonin after sunset (Nair et al., (1986) "Plasma melatonin--an index of brain aging in humans?" Biological Psychiatry, 21, 141-150; Sack et al., (1986) "Human melatonin production decreases with age," Journal of Pineal Research, 3, 379-388). The decline in the secretory activity of the pineal gland with aging reflects in part the limited regenerative abilities of the pineal cells due to their neuronal derivation.
Finally, melatonin secretion is significantly decreased or its circadian rhythmicity is disrupted in various neurological and mental disorders inducing multiple sclerosis, Parkinson's disease, juvenile Parkinsonism, progressive supranuclear palsy, Shy-Drager syndrome, Alzheimer's disease, motor neuron disease, ischemic stroke, traumotric spinal cord injuries, Korsakoff's dementia, depression, eating disorders, alcoholism, obsessive compulsive disorder, trichotillomania, posttraumatic stress disorder, impulsive and aggressive behavior, chronic insomnia, sleep paralysis, builmia, and schizophrenia (Martin et al., (1984) "Decreased 6-hydroxymelatonin excretion in Korsakoff's psychosis." Neurology, 34, 966-968; Skene et al., (1990) "Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzhelmer's disease." Brain Research, 528, 170-174; Nair et al., (1986) "Plasma melatonin rhythm in normal aging and Alzheimer's disease." Journal of Neural Transmission, 21 (suppl), 494; Sandyk and Awerbuch (1992) "Nocturnal melatonin secretion in multiple sclerosis patients with affective disorders," International Journal of Neuroscience, 68, 227-240; Miles and Philbrick (1988) "Melatonin and psychiatry." Biological Psychiatry, 23, 405-425; Fertl et al., (1993) "Circadian secretion pattern of melatonin in de novo Parkinsonian patients: evidence for phase-shifting properties of l-dopa." Journal of Neural Transmission {P-D Sect}, 5, 227-234; Ehrlich and Apuzzo (1985) "The pineal gland: anatomy, physiology, and clinical significance." Journal of Neurosurgery, 63, 321-341; Pang et al., (1990) "Acute cerebral hemorrhage changes the nocturnal surge of plasma melatonin in humans." Journal of Pineal Research, 9, 193-208; Li et al., (1989) "Rhythms of serum melatonin in patients with spinal lesions at the cervical, thoracic or lumbar region." Clinical Endocrinology 30, 47-56; Vaughan et al., (1979) "Melatonin, pituitary function and stress in humans." Psychoneuroendocrinology, 4, 351-362; Tetsuo et al., (1981) "Urinary b-hydroxy melatonin excretion in patients with orthostatic hypotension." Journal of Clinical Endocrinology and Metabolism, 53, 607-610).
In addition, several of the biological effects of melatonin are enhanced by serotonin neurons indicating that serotonin is an important mediator of the melatonin's biological signal (Olcese (1985) "Enhancement of melatonin's antigonadal action by daily injection of the serotonin uptake inhibitor fluoxetine in male hamsters." Journal of Neural Transmission, 64, 151-161; Miguez et al. (1996) "Changes in serotonin level and turnover in discrete hypothalamic nuclei after pinealectomy and melatonin administration to rats." Neurochemistry International, 29, 651-658).
It is believed that reduction in the activity of the pineal gland in these neurological and mental disorders may be related to various factors including, among others, decrease in pineal receptor sensitivity and/or density, decline in the availability of nutritional co-factors for serotonin and subsequent melatonin synthesis, decline in the capacity of pineal cells to synthesize serotonin from tryptophan, decrease sympathetic nervous system activity which provides a stimulus for melatonin synthesis, and progressive loss of neurons in the suprachlasmatic nucleus of the hypothalamus which activate the pineal gland.
Thus, a definite need exists in therapy today for an effective treatment for patients with neurological and mental disorders which are associated with and/or related pathogenetically to deficient serotonin neurotransmission and impaired pineal melatonin functions.

Methods useful for the treatment of neurological and mental disorders related to deficient serotonin neurotransmission and impaired pineal melatonin functions


Methods for performing seal validation with a chemical pre-treatment are provided. One such method includes establishing an Arrhenius relationship between a material property response of a material exposed to a test fluid based on experimental results of testing a plurality of material samples made of the material across multiple temperatures. The method also includes determining, based on the Arrhenius relationship, a pre-treatment time and a pre-treatment temperature that approximates a seal end-of-life condition. The method further includes pre-treating a seal by exposing the seal to the test fluid at the determined pre-treatment temperature for the determined pre-treatment time, the seal having at least in part a same material composition as the plurality of material samples, and after pre-treating the seal, performing one or more validation tests on the pre-treated seal.

In order to find and produce new oil and gas reserves, exploration continues to lead to greater depths within the ocean. As a result, Christmas tree and wellhead equipment must operate at greater depths and therefore must be capable of withstanding greater external hydrostatic head pressures. In addition, downhole equipment lowered through the well is often exposed to various chemicals during well completion and production operations. As such, seals (e.g., non-metallic seals) designed for use within these types of equipment must be properly tested and validated prior to use in a particular environment (e.g., a subsea or subterranean environment). Several existing methods for validating seals for use in these extreme environments do not address the long-term behavior of the seals used in permanent installations. Although some standards for validating seals provide an accurate estimate of total seal life and long-term behavior, the testing procedures are time-consuming and expensive. It is now recognized that a need exists for a low-cost seal validation method for evaluating the end-of-life behavior of seals for use in equipment installations.

Seal validation with chemical pre-treatment


A disposable absorbent pants type undergarment is provided on front and rear waist regions with a plurality of elastic members extending circumferentially parallel to one another and spaced apart one from another along a longitudinal axis of the undergarment so that, between each pair of adjacent elastic members provided on one of the front and rear waist regions, each elastic member provided on the other of the front and rear waist regions is interposed.

The present invention relates generally to disposable absorbent pants type undergarments in the form of a disposable diaper, training pants, incontinence pants or the like.
Conventional disposable pants type diapers are generally provided along an edge of a waist-opening thereof with circumferentially extending elastic members. Specifically, Japanese Patent Publication Application No. Hei 7-44945 discloses a disposable diaper provided with a first group of elastic members extending circumferentially parallel one to another along edges of a waist-opening defined by front and rear waist regions thereof. In addition, on the front and rear waist regions between the first group and a crotch region thereof, there is provided a second group of elastic members extending circumferentially parallel to one another. In this known diaper, opposite side edges of the front and rear waist regions are joined together, respectively, to form the pants type diaper. Consequently the elastic members of the front and rear waist regions substantially overlap at the flat side edges thereof and are bonded together such that the respective circumferential lines of elasticity are continuous.
Locations of each side edge at which the elastic members of the front and rear waist regions overlap are substantially thicker than the remaining locations of the side edge and present the correspondingly high rigidity. As a result, the locations at which the elastic members of the front and rear waist regions overlap form protuberances which are relatively stiff and deteriorate touch of the diaper.

Disposable absorbent pants type undergarment with improved heat sealed edges