A game machine includes a first display, a second display and a game changer. A plurality of spinning reels, each reel having a plurality of symbols of a combination game are displayed on the first display. A role playing game in which a character as an object of operation for a player acts in a virtual field and aims at a predetermined target is displayed on the second display. The game changer changes a first game to a second game advantageous to the player on the first display, depending on whether or not the character as the operation object has achieved the predetermined target.

The invention relates to a game machine and a method for controlling the game machine. Particularly, the invention relates to a game machine which enables a beginner who has not mastered a special technique, such as a pinpoint stopping technique, to increase the number of acquirable game tokens by a technique for operating a game, as well as to a method for controlling the game machine.
An example of a related game machine will be described below with reference to a slot machine installed in an amusement arcade or a casino. A related slot machine has a predetermined number of spinning reels (e.g., three spinning reels) having various symbols printed thereon. The spinning reels, which are rotated by corresponding reel drive motors (e.g., stepping motors), are stopped at timings at which a player presses stop buttons corresponding to the respective spinning reels. When three symbols form a certain winning combination along at least one of the valid lines (i.e., winning lines) in the state of stopping the spinning reels, game tokens (tokens for payoff) corresponding to the winning combination are paid out or the right to play a bonus game is awarded to the player. A slot machine equipped with a liquid-crystal display has recently been available. When symbols that would form a small winning combination have been determined in advance through internal random selection or when symbols that would form a big bonus winning combination have been determined in advance through internal random selection, the result of determination is notified to the player by liquid-crystal presentation of story-like nature provided by the liquid-crystal display.
The related game machine provides liquid-crystal presentation of story-like nature by way of a liquid-crystal display. However, the presentation is a mere display of liquid-crystal screens from a predetermined story or a mere report of symbols that would form a small winning combination and have been determined in advance through internal random selection by a plurality of types of liquid-crystal presentations.

Game machine and method for controlling the game machine


It is provided a ceramic multilayer substrate obtained by co-sintering a low dielectric constant layer made of an insulating material of a low dielectric constant and a high dielectric constant layer of a dielectric material of a high dielectric constant. The low dielectric constant layer includes a ceramic component of xBaO-yTiO2-zZnO (“x”, “y” and “z” represent molar ratios, respectively, and satisfy the relationship: x+y+z=1; 0.09≦x≦0.20; 0.49≦y≦0.61; 0.19≦z≦0.42) and 1.0 to 5.0 weight parts of a glass component comprising boron oxide with respect to 100 weight parts of the ceramic component. The high dielectric layer is made of a barium titanate based dielectric material with CuO and Bi2O3 added thereto.

In recent years, it is designed to attain miniaturization and density growth of electronic equipment, by integrating a passive part, such as a capacitor or inductor, conventionally mounted on a ceramic substrate surface into a ceramic multilayer substrate. Such a ceramic multilayer substrate is produced by forming a green sheet from a slurry of a dielectric porcelain composition and an organic solvent by doctor blade method followed by drying, printing a wiring conductor on the top surface of the sheet, forming a laminated body by laminating such green sheets of the same dielectric porcelain composition as described above, and co-firing it.
Such a ceramic multilayer substrate uses Ag or Cu with small specific resistance as the wiring conductor for performing high-performance signal processing at a high speed. Therefore, various ceramic materials have been developed for co-firing with Ag and Cu at temperatures lower than 962° C., the melting point of Ag, and 1084° C., the melting point of Cu.
In the above-mentioned ceramic multilayer substrate, a one having a dielectric constant of 10 or less is suitably used for suppressing stray capacitance or coupling capacitance between wires. While, when a capacitor is formed within the ceramic multilayer substrate, it is desirable for the ceramics constituting the capacitor to have a high dielectric constant.
The barium titanate-based dielectric porcelain composition generally has a high dielectric constant, and can form a high-capacity capacitor within the ceramic multilayer substrate. However, since it needs a sintering temperature as high as 1150 to 1200° C. or higher, Ag and Cu cannot be used as the wiring conductor to be co-fired. Therefore, it is necessary for the barium titanate-based dielectric porcelain composition to be sinterable at a temperature of 1000° C. or lower, while having practical dielectric constant and dielectric loss.
Various prior literatures are known for the barium titanate-based dielectric porcelain composition. Japanese Patent Publication No. S54-53300A describes addition of copper oxide and bismuth oxide into non-lead composition system.
Further, Japanese Patent Publication Nos. 2006-93484A and H05-325641A describe non-lead barium titanate based dielectric materials sinterable at a low temperature.
Further, according to "Japanese Journal of Applied Physics", Vol. 45, No. 9B, 2006, pp 7360 to 7364, "Dielectric properties and Microstructures of Low-temperature-Sintered BaTiO3-Based Ceramics with CuBiO4 sintering Aid", it is disclosed the addition of CuBi2O4 as a sintering aid to barium titanate dielectric material without the addition of a glass. It is thus confirmed that the barium titanate dielectric material can be sintered at 920° C. to provide good temperature dependence of specific dielectric constant. Specifically, it is disclosed that a specific dielectric constant of about 1900 and a dielectric loss of about 0.6 percent were obtained.
Further, many kinds of low dielectric ceramics were known in the field of ceramic multilayer substrate (Japanese Patent Publication Nos. H09-301768A, 2000-264722A and 2000-264723A).


Methods and systems for generating data transformations to improve ROM yield and programming time. A bit flip register can be configured in association with the ROM and a binary string can be read into the bit flip register on reset. Subsequently, data output from the ROM can be selectively complemented utilizing a content of the bit flip register and the content of the bit flip register can be programmed into the ROM in order to reduce programming time for each ROM. A defective cell can be tolerated by selectively flipping a column with respect to the defective cell to improve yield. A built-in self-test (BIST) engine that generates addresses up to and including content of an address limiting register can be employed to limit the ROM access to a programmed part during testing in order to tolerate defects in any unused location.

ROM is a storage medium class used in computers and other electronic devices. Data stored in ROM cannot be modified or may be modified only slowly or with difficulty, so it is often employed in the distribution of firmware. Strictly, ROM refers to memory that is hard-wired such as diode matrix and the later mask ROM. Although discrete circuits can be altered (in principle), ICs cannot and are useless if the data are bad. Despite the simplicity, speed and economies of scale of mask ROM, field-programmability often make reprogrammable memories more flexible and inexpensive.
The majority of prior art ROM programming techniques increase ROM programming time and decrease ROM yield. For example, consider the case of 8×6 bit eFuse with all bits set to 0 initially. An image consisting of 1/0 s may be programmed into the eFuse. The image to be burnt varies from die to die. An example image to be burnt into the eFuse is shown in the block diagram 100 depicted in FIG. 1. During eFuse programming, one bit at a time is programmed. Programming includes a number of steps such as, for example, addressing a bit location to be programmed to 1, one bit at a time. A long high voltage pulse can be applied at a special pin (VDDQ). For TSMC 45 nm eFuses, the pulse width is 12 us; this pulse width may increase from, for example, 10 us in 65 nm to 12 us in 45 nm. For the example shown in FIG. 1, 18 1 s have to be programmed. Programming time will be approximately 12*18 us=216 us. The larger the number of bits to be programmed, the larger the programming time. Increasing the number of programming cycles adversely affects the eFuse reliability.
Furthermore, a fault-free ROM, prior to programming, may have all bits to be 0 (or 1, depending on the technology). Next, for each bit location that needs to be set to 1, it is programmed to 1 by blowing the fuse. However, due to a defect, some bits may be set to 1 and it cannot have that bit be set to 0. For example, consider the example 16×6 bit ROM shown in diagram 150 in FIG. 2. Initially, all bits in the ROM are set to 0 and only 8 of the 16 words are utilized. Therefore, if a defect is present in any of the bits in location 9 through 16, those defects are "harmless" so far as the native mode usage of this instance of the ROM is concerned. Prior art approaches however, discard such ROM to tolerate the defects thereby reducing ROM yield.
Based on the foregoing, it is believed that a need exists for improved methods and systems for enhancing ROM yield and programming time utilizing data transformation, as described in greater detail herein.

Data transformations to improve ROM yield and programming time

Avago Technologies General IP (Singapore) Pte. Ltd.


A geared motor for driving an electric wheelchair, which can realize features such as light weight, compact size, low noise, and low vibration at the same time, as well as high performance at low cost. In a driving device of an electric wheelchair for driving a wheel shaft by the power of a motor, the motor is disposed in such a manner that a motor shaft thereof is orthogonal to the wheel shaft. A hypoid speed reduction mechanism having a hypoid pinion and a hypoid gear intervenes between the motor shaft and the wheel shaft.

1. Field of the Invention
The present invention relates to a geared motor used in a driving device for an electric wheelchair.
2. Description of the Related Art
In recent years, a wheelchair is widely used by elderly people who find it difficult to walk, people who move around in a hospital, and people with a mobility impairment, when navigating flat roads, sidewalks, and flat floor in doors.
In many cases, people who use the wheelchair are difficult to manually maneuver its wheels. It is not always possible that there is an attendant with them. Against this backdrop, the so-called electric wheelchair, in which wheel shafts are driven by the power of motors, has been recently proposed in large numbers (refer to, for example, Japanese Patent Laid-Open Publication No. 2000-70304).
FIG. 4 shows an electric wheelchair disclosed in Japanese Patent Laid-Open Publication No. 2000-70304.
A wheelchair 1 comprises a frame 2, safety wheels 4 attached in front of the frame 2 (left side in FIG. 4), driving wheels 5 attached in the rear of the frame 2 (right side in FIG. 4), and an operation control panel 6 attached above and anterior to the frame 2. In this wheelchair 1, a battery 7 and a motor (not illustrated) drive a wheel shaft 12 of the driving wheel 5. The motor is disposed in such a manner that its motor shaft (not illustrated) is in parallel with the wheel shaft 12, and the power of the motor is transmitted to the wheel shaft 12 via a not-illustrated mechanism with parallel gears.
Especially in consideration of use in a hospital and a home, a driving device for the electric wheelchair is required to have low noise. Also, vibration must be as small as possible, in addition to light weight and compact size.
A conventional driving device for the electric wheelchair, however, does not always agree with such requirements.


In an automatic transmission control system and method, an electronic control unit is programmed to output a command to establish another gear stage different from the gear stage at the time of occurrence of fault-induced disengagement by combination of engagements of the friction elements other than the friction elements to be engaged at the time of occurrence of fault-induced disengagement, and simultaneously output a plurality of commands to establish a plurality of gear stages corresponding to combination of engagements of the friction elements to be engaged and disengaged, respectively, at the gear stage at the time of occurrence of fault-induced disengagement, when the gear stage at the time of occurrence of the fault-induced disengagement is a predetermined gear stage and the friction element undergoing the fault-induced disengagement is not determined.

The present invention relates to automatic transmission control method and system having a fail-safe function. Specifically, the present invention relates to automatic transmission control method and system capable of performing fail-safe operation upon occurrence of failure in a hydraulic control device for friction elements of an automatic transmission such as a hydraulic control valve.
Conventional automatic transmission control systems are adapted to detect occurrence of electric failure in solenoids, sensors and the like in a hydraulic control circuit and perform fail-safe control depending on the electric failure detected. However, failure of automatic transmissions includes not only the electric failure but also mechanical failure of a hydraulic control valve for controlling a hydraulic pressure that is supplied to friction elements. For instance, the mechanical failure would be caused due to sticking of a valve body of the hydraulic control valve or lodging of a foreign object into the hydraulic control valve.
If the friction element to be engaged is caused to be in a disengagement state due to the mechanical failure of the hydraulic control valve, a gear stage different from instructed one will be established or a neutral stage will be established contrary to the instruction, namely, so-called neutral-fail will be caused, to thereby make it impossible to restart a vehicle after the stop. Occurrence of the operating failure of the hydraulic control valve can be readily detected. However, in contrast to the case of the electric failure, it is difficult to determine the friction element to which the operating failure relates.
Japanese Patent Application First Publication No. 2003-269602 discloses an automatic transmission control system in which when failure such as the neutral-fail is detected, a vehicle is temporarily stopped, and then an engagement command will be generated for engaging friction elements so as to establish a third speed in a low-speed range for the sake of vehicle emergency traveling in the low-speed range. In the automatic transmission control system of this conventional art, if the neutral condition is continued even after the engagement command is generated, then another engagement command will be output for engaging friction elements so as to establish a fifth speed in a high-speed range for the sake of vehicle emergency traveling in the high-speed range. In the conventional art, it is intended to enable the vehicle to restart by temporarily selecting any one of the gear stages even though it is not possible to determine the friction element to which the failure relates.

Automatic transmission control method and system having fail-safe function


A portable computer housing including an enclosure with a support wall and a strike zone including a first protrusion in the support wall. A support member is attached to the enclosure. The support member includes a base wall positioned in close proximity to the support wall of the enclosure. A second protrusion is formed in the base wall of the support member. The second protrusion is offset from the base wall by a first distance with at least a portion of the second protrusion being received within the first protrusion. A recess in the second protrusion is offset from the base wall by a second distance. The second distance is less than the first distance. The potential for impact-related failure of components in the portable computer is greatly reduced. Also, the configuration of the strike zone reduces the magnitude of the shock from an impact and eliminates a portion of the high frequency content that is known to damage components such as the hard drive.

The disclosures herein relate generally to computer systems and more particularly to an apparatus and method for reducing impact-induced shock and vibration in a portable computer.
Electronic devices such as portable computers, personal digital assistants and portable telephones typically have relatively expensive impact-sensitive components that must be protected from harmful mechanical vibration and shock. In many types of portable electronic devices, impact to the enclosure of the device can result in harmful mechanical vibration and shock. The shock and vibration can adversely affect the performance of many components in a portable computer, including the hard drive, flat panel display and other shock-sensitive components. If the impact is great enough, one or more of the heads in the hard drive may experience an impact-induced head crash. An impact-induced head crash occurs when the actuator arm collides against the surface of an adjacent disk. A head crash may damage the head or the disk, resulting in reduced performance and reliability. The damage may result in immediate failure or undetected damage leading to a shortened operating life.
Although impact loadings occur when an electronic device is accidentally dropped, they are also possible when the electronic device is intentionally placed on a support surface. An impact loading sometimes referred to as a xe2x80x98flat slapxe2x80x99 impact often occurs in portable computers when the bottom surface of the enclosure engages a hard flat surface such as the surface of a table. This type of impact occurs even though most portable computers are generally equipped with resilient feet on their bottom surface for offsetting the bottom surface of the enclosure from the support surface. Warping of the bottom surface of the enclosure and the inertia of the heavy internal components of a portable computer contribute to flat slap impact that can damage internal components.
The hard drive of a portable computer is especially susceptible to damage from shocks associated with impact loadings. To reduce the potential for damage to the hard drives in portable computers, attempts have been made at providing damping devices that protect against loads being applied directly to the case of a hard drive. For example, U.S. Pat. Nos. 5,760,998 and 5,703,734 disclose hard drives that incorporate resilient members protruding from the exterior of the drive case to protect against impact loadings from flat drops of the hard drive. U.S. Pat. No. 5,535,092 discloses a hard drive that incorporates resilient members protruding from the corners of the drive case to protect against the case being dropped on a corner. Furthermore, other components in a hard drive may be mounted on resilient bushings to aid in reducing the transmission of shock and vibration to adjacent components of the hard drive and computer.
A feature commonly referred to as a strike zone has also been used to reduce the adverse effects of flat slap impacts in portable computers. The strike zone is a raised protrusion formed in a metal support member and sometimes in an adjacent portion of the plastic enclosure of the portable computer. The intent of the strike zone is to define an energy dissipating point of contact on the bottom of the portable computer. Typically, a peripheral device such as a hard drive is attached to the support member adjacent to the strike zone. The strike zone is intended to absorb and dissipate shock and vibration from an impact for reducing the peak amplitude of the resulting shock and vibration.
Although various attempts have been made to use strike zones to reduce the loadings applied to the internal components in a portable computer, only limited success has been achieved. Accordingly, there is a need for an improved strike zone configuration that provides greater reduction of impact related shock and vibration in a portable computer without any appreciable increase in manufacturing cost.
One embodiment, accordingly, provides a portable computer including a strike zone having a recessed region for providing improved dissipation of shock and vibration associated with impact loadings. To this end, one embodiment provides an apparatus for dissipating impact energy in a computer system. The apparatus includes a support member including a base wall and a protrusion in the base wall of the support member. The protrusion is offset from the base wall by a first distance. A recess in the protrusion is offset from the base wall by a second distance. The second distance is less than the first distance.
A principal advantage of this embodiment is that the potential for impact related failures of components in a portable computer is greatly reduced.

Apparatus and method for reducing impact-induced shock and vibration in a portable computer


The invention relates to a method and to an apparatus for continuously removing metabolically produced carbon dioxide from respired air, such as the air found in life support systems or cabin circulating systems, using two sets of hollow fibers disposed in a flowing, carbon dioxide-selective liquid membrane. The carbon dioxide-containing respired air flows through the first set of hollow fibers and the second set of hollow fibers serves to carry away the permeate stream.

The present invention relates to a method and an apparatus for removing carbon dioxide, useful for life support systems and cabin circulation systems.
The continuous removal of metabolically produced carbon dioxide in life support systems and cabin circulation systems is necessary in order to make quality breathable air available as required by humans. Because of physiological requirements, the carbon dioxide content of breathable air must not exceeded 0.5%. Residual oxygen content at such carbon dioxide concentrations is adequate for the respiration function; however, prolonged exposure to higher carbon dioxide concentrations leads to physiological disorders with, in some cases, a dramatic decrease in reactivity. Currently, the biochemical mode of action is largely not understood and cannot be explained solely by an oxygen deficiency.
Typical areas of application, where removal of carbon dioxide from the breathing air is essential, are primary systems with completely closed air circulation, such as in manned space flight systems and submarines used for military or civilian purposes. Furthermore, applications in the areas of civilian air travel and high-speed railroad systems (conventional and linear motor systems) can be identified, which envision cabin air circulation that is sealed to the extent of about 85%, in order to save energy for heating, cooling and preparing air.
In each case, such sealed systems require continuous removal of metabolically produced carbon dioxide.
Currently, completely closed circulation systems such as in the MIR space station and submarines, remove carbon dioxide with solid absorbers. An example of a solid absorber is the use of lithium hydroxide cartridges, in which the carbon dioxide is removed by the irreversible formation of lithium carbonate from the hydroxide. After the loading limit has been reached, the absorber must be exchanged. At the present time, lithium hydroxide systems cannot be regenerated.
Regenerating systems based on materials which selectively absorb carbon dioxide are known in the area of chemical process technology and are state of the art, for example pressure change adsorption, with zeolite absorbing materials as well as liquid phase absorption using organic nitrogen bases, such as ethanolamine, with thermal or pressure-change regeneration. The typical area of application of such processes is in large stationary installations. These technically established processes can not easily be transferred to mobile systems. Additionally, by their very nature, such systems are discontinuous processes and require extensive chemical engineering effort in order to develop a quasi-continuous process. Continuous gas removal processes which can be operated with justifiable process technology effort, require the use of membrane-supported methods.
It is necessary to distinguish between membrane-supported absorption/desorption (for example, as disclosed in TerMeulen et al., WO 94/01204) and a true gas permeation membrane separation process. The present invention relates to a true gas permeation membrane separation.
Classical membranes used in gas permeation are solution-diffusion membranes, with a dense, active separating layer of polymer materials. Materials and performance data disclosing permeability and selectivity of such membranes for the separation of carbon dioxide from air are disclosed in Jehle et al., "Concentration and Subsequent Methanation of Carbon Dioxide for Space and Environmental Applications", Carbon Dioxide Chemistry, Env. Issues, The Royal Soc. of Chem., Stockholm 1994, pages 261-269. As can be seen from this disclosure, the presently known polymer membranes cannot be used for mobile applications, which are of primary interest here, because of the anticipated volume and weight of the module.
An improvement, specifically in carbon dioxide transport properties, for gas permeation processes is possible through the use of liquid membrane systems with so-called "carrier effects". Such carrier liquid membranes are characterized by a substance which preferentially binds the material to be transported in a selective and reversible manner. This substance is added to a solvent, which for membrane systems is often water. As such, it is possible to increase the transport rate by several orders of magnitude in comparison to the material transport rate naturally existing for a particular solvent. The latter is determined by the physical solubility of a substance in a solvent as well as by the corresponding diffusion coefficient.
FIG. 1 diagrammatically shows the basic concept of a carrier-borne transport process in a liquid membrane. The essential distinguishing feature is the fact that the carrier molecule, as well as the carrier/carbon dioxide complex, are free to move in the solvent. However, directed carbon dioxide transport through the liquid membrane can only occur if the carrier/carbon dioxide complex can dissociate into the starting components on the permeate side of the boundary phase. This process is thermodynamically controlled according to the following equilibrium: ##STR1##
K.sub.c is the reaction constant for the process. The equilibrium can be controlled exclusively by the partial pressure of the carbon dioxide. In each case, a resulting carbon dioxide flow through the membrane by carrier transport requires that the partial pressure of the carbon dioxide be lower in the gas space on the permeate side than in the gas space on the feed side. Therefore, high carbon dioxide concentrations favor formation of the carrier/carbon dioxide complex and low carbon dioxide concentrations favor the decomposition of the carrier/carbon dioxide complex.
The following measures are important for continuous gas permeation membrane processes:
i) Vacuum operation on the permeate side. The vacuum, produced by the vacuum pump, must be adapted so that at all times, the partial pressure of the carbon dioxide is lower on the permeate side than on the feed side. PA1 ii) Flushing gas operation on the permeate side. The pressure level of the flushing gas is not important. Only the ratio of the volume flow of flushing gas to the volume flow of permeate gas under steady state operation is important. For the transport of carbon dioxide through the membrane, it is necessary that, as a result of the dilution effect of the flushing gas with respect to the carbon dioxide, the partial pressure of the carbon dioxide on the permeate side is less than the partial pressure of the carbon dioxide on the feed side.
It will be apparent that measures i) and ii) can also be used in combination (with no pressure level limitation for ii)).
FIG. 1 furthermore shows the basic, necessary arrangement of a liquid membrane, in this case, a liquid membrane based on water. The membrane liquid is between microporous, hydrophobic membranes, which usually consist of polymer materials, such as polytetrafluoroethylene (PTFE), polypropylene or polyvinylidenefluoride (PVDF).
At first, the gas exchange takes place without interference; liquid is prevented from emerging by the hydrophobic nature of the materials. If the liquid membrane is at rest, the system involves an immobilized liquid membrane. Methods for removing carbon dioxide with such membranes are disclosed in U.S. Pat. No. 4,750,918. Such methods involve continuously removing metabolically produced carbon dioxide from air, such as the air found in life support systems and cabin circulation systems, wherein the air containing metabolically produced carbon dioxide is passed through a first set of hollow fibers, which are embedded in a carbon dioxide-selective liquid membrane and the carbon dioxide-rich permeate is drawn off through a second set of hollow fibers, which are also disposed in the membrane. Solutions, consisting of potassium carbonate/potassium hydrogen carbonate with organic nitrogen bases such as monoethanolamine (MEA) and diethanolamine (DEA), are taught as selective carriers. The selective and reversible nature of the carbon dioxide bonding by organic nitrogen bases is established from gas-scrubbing methods (such as the activated MDEA method of BASF AG in Ludwigshafen, Germany).
A different possibility for constructing immobilized liquid membranes is to impregnate porous carrier structures (membranes) with an active removing liquid as disclosed in EP 0 309 259 B1.
The immobilized liquid membrane variations are clearly limited with respect to their commercial use for the removal of carbon dioxide with water-supported liquid membranes.
A problem not solved by such systems is that a constant loss of solvent (water) is noted due to the vacuum and/or flushing gas operation required on the permeate side of the system.
While moderate water losses from the liquid membrane do not interfere with the carrier transport mechanism, the water loss is much more serious with respect to the ability of the hydrophobic membranes to retain the removing liquid. Such processes involving membrane systems do not exhibit long-term stability unless water is supplied continuously.
A further disadvantage of such systems with immobilized liquid membranes is the fact that the separation capacity required for use in life support systems or cabin circulation systems leads to a relatively large exchange surface and thus to a large overall size of the separation system.
In addition to immobilized liquid membrane systems, flowing liquid membrane systems based on plate and frame modules for removing carbon dioxide are disclosed, for example in, Teramoto et al., Kakakukogaku Rombunshu 16, 6 (1990), Eido T., et al. Japanese Published Application No. HEI 2-246989 (1990), and Jehle, W., et al., SAE Technical Paper 941339 (1994). Teramoto and Jehle use experimental laboratory equipment to determine the relevant transport resistances. Solutions of potassium carbonate/potassium hydrogen carbonate with organic nitrogen bases (MEA, DEA) are used as selective membranes.
In the case of such plate and frame modules, there are significant problems with sealing the individual plates. This problem has yet to be solved for units with a larger number of plates, as required to be economically useful.
It is an object of the present invention to provide a method with high operating efficiency and good separating power for the removal of carbon dioxide from air in closed systems such as in life support and cabin circulation systems. This objective is accomplished by a method for continuously removing metabolically produced carbon dioxide from respired air, such as the air found in life support systems and cabin circulation systems, in which the carbon dioxide-containing respired air is passed through a first set of hollow fibers, which are embedded in a carbon dioxide-selective liquid membrane and the carbon dioxide-rich permeate is drawn off through a second set of hollow fibers, which are also disposed in the membrane, and in which the liquid membrane is circulated.
According to the present invention, two sets of hollow fibers are disposed in a circulating liquid membrane, which is selective for carbon dioxide. Carbon dioxide-containing respired air flows through a first set of hollow fibers and the carbon dioxide-rich permeate stream is discharged through a second set of hollow fibers.
Improved removal is achieved by virtue of the fact that a flowing liquid membrane is used. The carbon dioxide transport properties can be influenced further by varying the liquid flow conditions. Additionally, leakage problems, such as those known with the use of plate and frame modules, do not exist.
In a preferred embodiment, in order to facilitate the transport of material, each hollow fiber from the first set can be disposed adjacent to a hollow fiber from the second set.
In a preferred embodiment, a liquid membrane is used, which is based on aqueous, organic nitrogen bases. It may furthermore contain additions of potassium carbonate and/or potassium hydrogen carbonate. In another preferred embodiment, the liquid membrane is an aqueous solution of diethanolamine (DEA) at a concentration ranging from 0.1 to 2 moles/liter.
The concentration ratio of the individual components of the liquid membrane is preferably kept constant. In order to achieve this, individual losses are determined by a measurement and control mechanism, and appropriate amounts are added continuously.
A vacuum operation, a flushing gas operation or a combination of the two can be provided on the permeate side.
In a preferred embodiment, both sets of hollow fibers consist of identical, microporous, polymer material of a hydrophobic nature, for example, polytetrafluoroethylene, polyethylene or polypropylene.
According to the present invention, a technically usable method which exhibits long-term stability and high selectivity is created.
Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings.

Method and apparatus for removing carbon dioxide


A radio-frequency (RF) generator is provided that produces a controlled overshoot. One embodiment includes a RF power amplifier and a direct-current (DC) power supply that includes a primary DC power supply, an auxiliary DC power supply, a half-bridge circuit, and a control circuit. The half-bridge circuit, in a first switching state, electrically connects, in series, the auxiliary DC power supply with the primary DC power supply and, in a second switching state, electrically disconnects the auxiliary DC power supply from the primary DC power supply. The control circuit places the half-bridge circuit in the first switching state for a first period of time and places the half-bridge circuit in the second switching state for a second period of time to produce a controlled overshoot in the power produced by the RF generator throughout the first period of time.

Field
The present disclosure relates generally to radio-frequency (RF) generators and, more specifically, to apparatuses and techniques for improving the performance of RF generators that employ balanced power amplifiers to supply power to a plasma processing chamber.
Background
Balanced amplifiers, as described for instance by K. Kurokawa, "Design theory of balanced transistor amplifiers," Bell System Technical Journal, Oct. 1965, are often used in power supply systems for plasma processing chambers. Unlike traditional single amplifiers, balanced amplifiers provide more desirable pulse shapes when using pulsed power to sustain a plasma. Balanced amplifiers also provide better plasma stability and further produce forward power independent of load impedance. In other words, for a given control input to the power amplifier, forward power does not change as a result of load impedance changes (e.g., due to changes in the plasma density or other plasma characteristics).
Yet, balanced amplifiers also create and amplify problems associated with traditional single amplifiers. For instance, when there is a load mismatch (e.g., during ignition or reignition of the plasma, where impedance changes drastically), power dissipation becomes unevenly distributed between the two amplifiers making up the balanced amplifier, which can damage the one dissipating more power. The traditional solution to this problem is to reduce the balanced amplifier's power profile (e.g., reduce load power at high load reflection coefficient magnitude) such that the amplifier dissipating more power is not damaged. In plasma ignition applications, this is a major drawback since plasma ignition normally requires an amplifier delivering substantial power into a non-matched load.
There is, therefore, a need in the art for an improved RF generator to supply power to a plasma processing chamber.

Apparatus for controlled overshoot in a RF generator


A driving circuit for a LCD (Liquid Crystal Display) panel is provided which is capable of performing overdriving operations in all shades of gray and of obviating the necessity of predetermining a driving pattern based on experimental results. The driving circuit for the LCD panel includes an operational amplifier to a non-inverted input terminal of which a voltage to charge a pixel for current gray level display is applied and to an inverted input of which a voltage for charging a corresponding pixel occurred one field before, a NAND circuit to detect an output state of operational amplifiers, a P-channel MOSFET (Metal Oxide Semiconductor Field Effect Transistor) to switch operational states from one state in which the operational amplifier operates as a comparator to perform overdriving operations using source voltages to one state in which a pixel to be charged using a gray level voltage.

1. Field of the Invention
The present invention relates to a driving circuit and a driving method for driving an LCD (Liquid Crystal Display) panel.
The present application claims priority of Japanese Patent Application No. 2005-341783 filed on Nov. 28, 2005, which is hereby incorporated by reference.
2. Description of the Related Art
In recent years, as technology of a display device has progressed, a liquid crystal television set using an LCD panel for screen displaying has become commercially practical. FIG. 7 is a diagram showing an example of configurations of a conventional liquid crystal television set using an overdriving operation circuit, as disclosed in prior art Patent Document 1 (Japanese Patent Application Laid-open No. Hei4-365094). In the liquid crystal television set shown in FIG. 7, synchronizing signals extracted through a television (TV) linear circuit 52 from signals received via an image receiving channel and selected by a tuner 51 are output to a synchronizing control circuit 53 and video signals including Y/C (luminance/color) signals are output to an analog to digital (A/D) converting circuit 54. The A/D converting circuit 54 converts input video signals into digital signals.
Video data output from the A/D converting circuit 54 and to be displayed in a current field is compared in a ROM (Read Only Memory) 56 with image data stored in an image memory 55 and obtained one field before and then a signal representing a result from the comparison is output to a segment electrode driving circuit 58. A common electrode driving circuit 57 generates a signal to commonly control each common electrode of a liquid crystal panel 59 in accordance with a synchronizing control signal fed from the synchronizing control circuit 53. In the liquid crystal panel 59, by the above operations, an image is displayed to provide a preset pattern in a manner based on horizontal/vertical synchronizing signals separated by the synchronizing control circuit 53 from signals received through the image receiving channel and in accordance with control signals to commonly control each common electrode fed from the common electrode driving circuit 57 and in a manner driven by using an overdriving voltage based on data in the first frame and by using a voltage of a pixel electrode based on data in the second frame.
According to technology disclosed in prior art Patent Document 1 (Japanese Patent Application Laid-open No. Hei4-365094), it is reported that, by performing overdriving operations to achieve a sharp rise or sharp fall in optical transmittance of an LCD and to improve a response speed of a liquid crystal panel, it is made possible to speedily track an image which changes rapidly.
Also, a liquid crystal display device including a liquid crystal panel having a liquid crystal layer and an electrode to supply a voltage to the liquid crystal layer and a driving circuit to apply a driving voltage to the liquid crystal panel is disclosed in prior art Patent Document 2 (Japanese Patent Application Laid-open No. 2003-172915) in which, when the liquid crystal panel shows an extreme value in a voltage-transmittance characteristic curve at a voltage exceeding a maximum gray level voltage, the driving circuit supplies, in accordance with a combination of an input image signal existed one vertical period before and an input image signal existing during a current vertical period, a driving voltage obtained by overshooting a gray level voltage corresponding to an input image signal occurring during a predetermined current vertical period is applied to the liquid crystal panel and, as a result, a response speed is improved.
Another liquid crystal display device to display an image by using a liquid crystal panel is disclosed in prior art Patent Document 3 (Japanese Patent Application Laid-open No. 2004-287139) in which a first storing means to store a previous image signal occurred one vertical display period before and a second storing means to store a previous image occurred two vertical display periods before, an enhancement converting means to obtain an enhancement converting signal for compensating for changes in optical response characteristics of the liquid crystal display panel from a previous image signal occurred one vertical display period before stored in the first storing means and from an image occurred two previous vertical display periods before stored in the second storing means and an image signal in a current vertical display period are provided and, therefore, when gray-level transition occurs in an input image signal, it is made possible to compensate for changes in optical response characteristics of a liquid crystal display pattern and to make a liquid crystal reach a transmittance (target gray-level luminance) determined by an input image signal without fail after the elapse of one vertical display period, thus enabling a desired gray-level luminance to be displayed all the time and high-quality image display to be achieved.
However, in the conventional driving circuit for the liquid crystal television set shown in FIG. 7, the LCD is driven by performing an overdriving operation using gray level voltages between the minimum gray level voltage and the maximum gray level voltage and, therefore, a wide variety of intermediate shades of gray can be selected, which provides big advantages, however, when a gray level voltage near the maximum gray-level voltage is selected, since a voltage to be used for overdriving is almost equal to a voltage of a pixel electrode, almost no effect can be expected that, by improving a response speed of a liquid crystal panel, an image changing rapidly can be speedily tracked.

Driving circuit and driving method for liquid crystal display panel


Method of selecting oocyte donor candidates for oocyte donation. A number of triple CGG repeats on each allele of the isolated FMR1 gene is measured by using an assay, and an oocyte donor is selected for oocyte donation only if both alleles of the isolated FMR1 gene have more than 26 CGG repeats.

1. Field of the Invention
The present invention relates generally to methods for selecting oocyte donors by evaluating CGG repeats on the fragile X mental retardation 1 (FMR1) gene. Particularly, the present invention provides methods for selecting oocyte donor candidates for oocyte donation and/or excluding oocyte donor candidates from oocyte donation based on a candidates' FMR1 genotype.
2. Description of the Related Art
The following acronyms are used throughout this specification:
AIRE: Autoimmune Regulator
CGG: Cytosine-Guanine-Guanine
DHEA: Dehydroepiandrosterone
FMR1: Fragile X Mental Retardation 1
FMRP: Fragile X Mental Retardation Protein
FOR: Functional Ovarian Reserve
FXS: Fragile X Syndrome
GnRH: Gonadotropin Releasing Hormone
GnRH-a: Gonadotropin Releasing Hormone Agonist
OPOI: Occult Primary Ovarian Insufficiency
OR: Odds Ratio
POA: Premature Ovarian Aging
POF: Premature Ovarian Failure
POI: Primary Ovarian Insufficiency
POS: Premature Ovarian Senescence
TOR: Total Ovarian Reserve
These acronyms also appear after the first use of each full term.
The FMR1 gene (gene location Xq27.3) is commonly studied or analyzed because of its association with Fragile X Syndrome (FXS). FXS is the most common cause of familial mental retardation and autism (see, Bagni C., Tassone F., Neri G., Hagerman R., Fragile X Syndrome: Causes, Diagnosis, Mechanisms, and Therapeutics, The Journal of Clinical Investigation, December 2012, 4314-22, hereinafter referred to as "Bagni"). FXS occurs when the FMR1 gene is inactivated and does not produce Fragile X Mental Retardation Protein (FMRP). FMRP is important for proper neurological development and is involved in RNA translation. This inactivation is usually caused by too many Cytosine-Guanine-Guanine (CGG) trinucleotide repeats on the FMR1 gene. FMR1 genes are usually classified by the number of CGG repeats on the gene. The usual classification in current medical practice recognizes four ranges of CGG repeats on the FMR1 gene: a normal (or common) range of CGGn<45, an intermediate range of CGGn˜45-54, a premutation range of CGGn˜55-200 and a full mutation range of CGGn>200. FXS usually occurs in persons with an FMR1 gene in the full mutation range. A gene in the premutation range can expand to the full mutation range in the next generation of offspring (see, Willemsen R., Levenga J., Oostra B. A., CGG Repeat in the FMR1 Gene: Size Matters, Clinical Genetics, September 2011; 214-25, hereinafter referred to as "Willemsen"). Because of such expansion, FXS risk screening focuses on women with FMR1 genes in the premutation range, who are at risk for having children with FXS. FXS risk screening is the primary purpose of FMR1 testing in current medical practice.
Y. H. Fu found a peak in the population distribution of CGG repeats in the range CGGn=29-30 (see, Fu Y. H., Kuhl D. P., Pizzuti A., et al., Variation of the CGG Repeat at the Fragile X Site Results in Genetic Instability: Resolution of the Sherman Paradox, Cell, December 1991; 1047-58, hereinafter referred to as "Fu"). The inventors herein investigated a connection between the FMR1 gene and ovarian function based on the distribution peak at CGGn=29-30. Ovarian effects of the FMR1 gene are supported by a known association between FMR1 genotypes in the premutation range (CGGn˜55-200) and Primary Ovarian Insufficiency (POI), also known as Premature Ovarian Failure (POF) (see, Gleicher N., Weghofer A., Barad D. H., Defining Ovarian Reserve to Better Understand Ovarian Aging. Reproductive Biology and Endocrinology, February 2011, 23, hereinafter referred to as "Gleicher I"). A recent study of a mouse FMR1 homologue also supports the association of the FMR1 gene with ovarian aging (see, Hoffman G. E., Le W. W., Entezam A., et al. Ovarian Abnormalities in a Mouse Model of Fragile X Primary Ovarian Insufficiency. The Journal of Histochemistry and Cytochemistry, June 2012, 439-56).
The inventors defined new ranges of CGG repeats on the FMR1 gene relevant to ovarian health: a normal (norm) range of CGGn=26-34, a low range of CGGn<26 and a high range of CGGn>34. Further refinement of these ranges defined norm (both alleles in normal range), heterozygous (het, one allele in and the other outside normal range) and homozygous (hom, both alleles outside normal range) genotypes. Het and hom genotypes were further subdivided into high or low. For example, a female with a het-high genotype has one FMR1 allele with more than 34 CGG repeats and one FMR1 allele with 26-34 CGG repeats. Cross-sectional studies demonstrate associations between the various genotypes described above and specific ovarian aging patterns (see, Gleicher N., Weghofer A., Barad D. H., Ovarian reserve Determinations Suggest New Function of FMR1 (Fragile X Gene) in Regulating Ovarian Ageing. Reproductive Biomedicine Online, June 2010, 768-75, hereinafter referred to as "Gleicher II"; Gleicher N., Weghofer A., Lee I. H., Barad D. H., FMR1 Genotype With Autoimmunity-Associated Polycystic Ovary-Like Phenotype and Decreased Pregnancy Chance. PloS One, December 2010, e15303, hereinafter referred to as "Gleicher III"; Gleicher N., Weghofer A., Lee I. H., Barad D. H., Association of FMR1 Genotypes With in Vitro Fertilization (IVF) Outcomes Based on Ethnicity/Race, PloS One, April 2011, e18781, hereinafter referred to as "Gleicher IV"; and Gleicher N., Weghofer A., Kim A., Barad D. H., The Impact in Older Women of Ovarian FMR1 Genotypes and Sub-Genotypes on Ovarian Reserve, PloS One, March 2012, e33638, hereinafter referred to as "Gleicher V"). These associations are more fully disclosed herein. Genotype/phenotype interactions are usually studied in homozygous subjects, but these studies have so far only studied norm and het women because all three hom sub-genotypes, combined (high/high, high/low and low/low), occur in less than 10 percent of women, not enough to provide a significant population size for study (see, Gleicher II, Gleicher III, Gleicher IV and Gleicher V). These new range and genotype definitions allow the use of the FMR1 gene to assess ovarian health.
Human females are typically tested to determine ovarian health and to assess their fertility only if they are experiencing infertility, at risk for infertility based on age and/or are indicated to have ovarian aging by showing signs of ovarian aging. These tests are for Anti-Müllerian Hormone (AMH) and/or Follicle Stimulating Hormone (FSH) levels. The tests are performed once and the human female's level of AMH and/or FSH is compared against the normal range for human females of her age. If AMH is lower than the normal range or FSH is higher than normal the normal range, the human female is considered to have Premature Ovarian Aging (POA), also known as Occult Premature Ovarian Insufficiency (OPOI). These AMH/FSH tests, however, are generally not performed in young human females, defined herein to mean human females who have not experienced infertility and are not otherwise indicated to have ovarian aging.
Because testing for ovarian health is presently performed only when the human female already experienced infertility and/or is indicated for ovarian aging by showing symptoms of infertility, such as menstrual irregularities, the diagnosis of POA or POF is usually only obtained when the POA is at advanced clinical stages, after POF has occurred or when the human female is about 38 years or older. As a result, there is an absence of prospective risk assessments in adolescent and young adult females even though approximately 10% of human females will suffer from premature ovarian aging. At advanced clinical stage or advanced age, even advanced fertility treatments for POA demonstrate limited success, and egg donation remains the only realistic choice for women with POF (see, Gleicher I). Late diagnosis, of course, assumes further significance in older, often single, women because POA further compounds the negative effects of advanced age. As a result, late diagnosis of POA leads to limited success in treatment.
Earlier diagnosis of premature ovarian aging presents many benefits for women, most notably, earlier and potentially more effective treatment options (see, Cil A. P., Bang H., Oktay K., Age-Specific Probability of Live Birth With Oocyte Preservation: An Individual Patient Data Meta-Analysis, Fertility and Sterility, August 2013, 492-9). Identification of human females likely to be affected by POA when their ovarian reserve is still relatively normal offers a choice between childbirth at a younger age than they otherwise planned or fertility preservation by assisted reproductive technologies. All methods of fertility preservation are more efficient at younger than at older ages and, therefore, less costly and more cost-effective. The reduced cost is especially important given ever-increasing medical costs and the present high cost of infertility testing and treatment, which, in many cases, is not covered by health insurance.
Fertility preservation for young women is relatively recent and resulted from a need by women who became infertile after undergoing cancer treatment but who still desired to have children. Fertility preservation emerged to provide young cancer survivors a reproductive future (see, Waimev K. E., Duncan F. E., Su H. I., Smith K., Wallach H., Jona K., Coutifaris C., Gracia C. R., Shea L. D., Brannigan R. E., Chang R. J., Zelinski M. B., Stouffer R. L., Taylor R. I., Woodruff T. K., Future Directions in Oncofertility and Fertility Preservation: A Report From the 2011 Oncofertility Consortium Conference, Journal of Adolescent and Young Adult Oncology, March 2013, 25-30). Aside from fertility preservation for cancer patients, women are delaying childbirth for various social and personal reasons and use fertility preservation to have children later in life (see, Donnez J., Introduction: Fertility Preservation, from Cancer to Benign Disease to Social Reasons: The Challenge of the Present Decade, Fertility and Sterility, May 2013, 1467-1468; and Cobo A., Garcia-Velasco J. A., Domingo J., Remohl J., Pellicer A., Is Vitrification of Oocytes Useful for Fertility Preservation for Age-Related Fertility Decline and in Cancer Patients? Fertility and Sterility, May 2013, 1485-1495). Fertility preservation in response to causes of infertility other than cancer or voluntary delay, such as endometriosis, is also entering medical practice (see, Bedoschi G., Turan V., Oktay K., Fertility Preservation Options in Women with Endometriosis, Minerva Ginecologica, April 2013, 99-103). However, fertility preservation in response to other causes of infertility, such as premature ovarian aging, has not yet received attention because premature ovarian aging was not predictable by the existing knowledge in the art.
Ovarian aging is the combination of declines in oocyte quality and oocyte number. Ovulation, the maturation and release of oocytes, begins at menarche, the onset of menstrual cyclicity. Menarche is the start of a complex process of steady follicle recruitment that organizes recruited follicles into maturing monthly cohorts, groups of follicles in the same stage of development. In natural ovulation cycles, follicular cohorts mature over 2-4 months, resulting in ovulation of a single dominant follicle in each cohort. Other follicles in each cohort undergo degeneration and apoptosis (see, FIG. 1), resulting in unifollicular ovulation. The ovary's ability to organize cohesive monthly cohorts of follicles of similar sizes and maturity is a characteristic of young age and normal ovarian function. The ability to organize and carry out monthly unifollicular ovulation diminishes with advancing female age and/or in association with POA (and possibly early stages of POF). Older females and patients with POA have more inhomogeneous follicle sizes and oocyte maturity distribution than females who are young and not experiencing POA. This difference is shown in IVF studies for those two populations (see, Gleicher I).
As FIG. 1 shows, the current medical understanding holds that females are born with a limited pool of follicles, also known as the total ovarian reserve (TOR), that depletes throughout life until menopause. TOR peaks in intrauterine life at approximately 7 million follicles/oocytes with significant depletion before birth. Females have less than 1 million follicles/oocytes at birth and by menarche approximately only 400,000 remain in the female. The speed of ovarian depletion slows between menarche and menopause, when only a few hundred to one thousand follicles/oocytes remain in the ovaries (see, Gleicher I).
A patient's TOR is primarily the large pool of unrecruited, primordial follicles "resting" at a very primitive stage. A patient's recruited follicles (also called "growing" follicles) are a much smaller part of TOR known as the Functional Ovarian Reserve (FOR). After weeks to months of maturation, the recruited follicles reach maturity in either natural or ovarian stimulation cycles. A patient's TOR and FOR deplete over time and reflect the patient's ovarian age.
The speed of follicle recruitment is statistically correlated to the number of remaining primordial follicles. Therefore, the size of the pool of growing follicles (representing FOR) also correlates with speed of recruitment (see, Gleicher V; Gleicher I; and Nelson S. M., Anderson R. A., Broekmans F. J., Raine-Fenning N., Fleming R., La Marca A., Anti-Müllerian Hormone: Clairvoyance or Crystal Clear? Human Reproduction, March 2012, 631-636, hereinafter referred to as "Nelson I"). AMH is produced in the granulosa cells of these small growing follicles and inhibits follicle recruitment and growth (see, Gleicher I; Ledger W. L., Clinical Utility of Measurement of Anti-Müllerian Hormone in Reproductive Endocrinology. Journal of Clinical Endocrinology & Metabolism, December 2010, 5144-5154, hereinafter referred to as "Ledger"; and Gleicher N., Weghofer A., Barad D. H., The Role of Androgens in Follicle Maturation and Ovulation Induction: Friend or Foe of Infertility Treatment? Reproductive Biology and Endocrinology, August 2011, 116). Because of this connection between AMH and the small growing follicles, a human female's AMH levels reflect the size of her pool of small growing follicles. Age-specific AMH levels, which reflect age-specific follicle pool size, are known in the art (see, Barad D. H., Weghofer A., Gleicher N., Utility of Age-Specific Serum Anti-Müllerian Hormone Concentrations, Reproductive Biomedicine Online, March 2011, 284-291, hereinafter referred to as "Barad"; and Kelsey T. W., Wright P., Nelson S. M., Anderson R. A., Wallace W. H. B., A Validated Model of Serum Anti-Müllerian Hormone from Conception to Menopause, PLoS One 2011, e22024, hereinafter referred to as "Kelsey").
Additionally, the gene that controls the AMH type II receptor (AMHR2) is also associated with follicle recruitment, further connecting AMH to follicle recruitment (see, Voorhuis M., Broekmans F. J., Fauser B. C., Onland-Moret N. C., van der Schouw Y. T., Genes Involved in Initial Follicle Recruitment May be Associated With Age at Menopause, Journal of Clinical Endocrinology & Metabolism, March 2011, 473-479). Because of the connection of AMH to follicular recruitment and growth, AMH levels are widely considered to best reflect TOR (see, Ledger; Nelson I). Because TOR is the primary component of ovarian age, low AMH levels are indicative of ovarian aging and AMH levels below normal for a particular age are indicative of POA.
Because of the association of AMH with FOR and TOR, an AMH test with levels below age-specific normal levels can indicate POA. As discussed above, POA affects approximately 10% of all women, and can have different causes, including, but not limited to, the factors set forth in Table 1:
TABLE 1KNOWN CAUSES OF PREMATURE OVARIAN AGINGLow number of follicles/oocytes at birth/menarcheKnown genetic causesExcessive follicle recruitmentAnti-ovarian autoimmunity   Autoimmune oophoritis   Anti-ovarian autoimmunity   Autoimmune polyglandular syndromes   Turner syndromeSpace occupying lesions   Endometriosis   Ovarian tumorsIatrogenic interventions   Surgery   Chemotherapy   Radiation therapy   Bone marrow transplantation   Anti-viral therapies
As Table 1 shows, aside from iatrogenic (caused by medical treatment) follicle/oocyte losses and ovarian tissue loss from space-occupying lesions, POA has other causes, such as excessively rapid recruitment of follicles, low follicle numbers at birth and/or menarche, genetic disorders and anti-ovarian autoimmunity. Both low follicle numbers at birth and excessively rapid recruitment are under strong genetic control. The other major causes of POA, as discussed below, are also under genetic control.
Approximately one-third of POA cases are caused by anti-ovarian autoimmunity (see, Gleicher N., Weghofer A., Oktay K., Barad D., Do Etiologies of Premature Ovarian Aging (POA) Mimic Those of Premature Ovarian Failure (POF)? Human Reproduction, October 2009, 2395-2400). Anti-ovarian autoimmunity is well-known in humans with Addison's disease who develop autoimmune (lymphocytic) oophoritis, autoimmune polyglandular syndromes (APS), and Turner's syndrome. (see, Hoek A., Schoemaker J., Drexhage H. A., Premature Ovarian Failure and Ovarian Autoimmunity, Endocrinology Review, February 1997, 107-134, referred to hereinafter as "Hoek"). Hoek also reveals that ovaries are often subject to an autoimmune attack that is statistically associated with thyroid autoimmunity, anti-adrenal autoimmunity and other, often non-organ-specific, autoimmune responses. The X chromosome's role as an autoimmune chromosome also explains the association of autoimmunity and Turner syndrome (see, Bianchi I., Lleo A., Gershwin M. E., Invernizzi P., The X Chromosome and Immune Associated Genes, Journal of Autoimmunity, May 2012, 187-192; Bukalov V. K., Gutin L., Cheng C. M., Zhou J., Sheth P., Shah K., Arepalli S., Vanderhoof V., Nelson L. M., Bondy C. A., Autoimmune Disorders in Women with Turner Syndrome and Women with Karyotypically Normal Primary Ovarian Insufficiency, Journal of Autoimmunity, June 2012, 315-322; and Lleo A., Moroni L., Caliari L., Invernizzi P., Autoimmunity and Turner's Syndrome, Autoimmune Review, May 2012, 538-543). Therefore, autoimmune attacks on the ovaries are known in the art, but their precise mechanisms are not well understood.
Autoimmune-associated POA is most understood in combination with autoimmune polyendocrine syndrome type 1 (APS-1), also known as polyendocrinopathy candidiasis ectodermal dystrophy or Whitaker syndrome. It is caused by a mutation in the Autoimmune Regulator (AIRE) gene (see, Michels). This gene is of crucial importance in the thymus, where it regulates the process that prevents T cells from attacking a human's own cells. AIRE mutations that interfere with normal AIRE activity are associated with attacks against a human's own cells. The connection between AIRE and POA is supported by animal models. AIRE gene knockout mice experience early follicle depletion by age 20 weeks and complete follicle depletion (POF/POI) in 50-60% of animals. Therefore, AIRE appears crucial for preventing POA, and mutations in the gene de-inhibit follicle maturation, leading to the rapid depletion discussed above. Because of AIRE's strong association with autoimmunity, impaired fertility in the AIRE knockout mouse model can be attributed to immune-mediated loss of TOR. Such immune-mediated loss of TOR is caused by autoimmune attacks on the ovaries, thereby destroying the oocyte reserve. The AIRE gene is the first gene associated with autoimmune-induced POA (see, Michels; and Cushman R. A., Evidence That the Autoimmune Regulator Gene Influences Thymic Production of Ovarian Antigens and Prevents Autoimmune-Mediated Premature Reproductive Senescence, Biology of Reproduction, April 2012, 109).
Genes involved in follicle recruitment, such as AIRE, appear to limit over-recruitment of primordial follicles, which can rapidly deplete unrecruited follicles. When genes that affect follicle recruitment in either rodents or humans are mutated, blocked or knocked out, primordial follicles are over-recruited and deplete rapidly. Genes involved in follicle recruitment also influence a female's age at menopause. These genes appear to reduce the rate of follicular recruitment. Slower recruitment preserves more follicles/oocytes, leading to better remaining TOR at later ages.
Because of the link between autoimmunity and ovarian aging, any autoimmunity in females must be considered a risk factor for POA. Moreover, because autoimmunity is highly familial, a patient's family history of autoimmunity is also a risk factor. This includes a familial history of repeated pregnancy loss, often the consequence of abnormal immune system activation.
In addition to familial autoimmunity, other genetic influences on ovarian aging are well-demonstrated. Age at menopause is correlated between mothers and daughters and between pairs of sisters (see, van Asselt K. M., Kok H. S., Pearson P. L., Dubas J. S., Peeters P. H., Te Velde E. R., van Noord P. A., Heritability of Menopausal Age in Mothers and Daughters, Fertility and Sterility, November 2004, 1348-1351; and Morris D. H., Jones M. E., Schoemaker M. J., Ashworth A., Swerdlow A. J., Familial Concordance for Age at Natural Menopause; Results From the Breakthrough Generations Study, Menopause, September 2011, 956-961). Additionally, age at menarche, which is also genetically influenced, relates to risk for POA (see, Weghofer A., Kim A., Barad D. H., Gleicher N., Age at Menarche: A Predictor of Diminished Ovarian Function, Fertility and Sterility, October 2013, 1039-1043). Therefore, whether a human female's mother or sister(s) entered menopause early and/or a human female's own young age at menarche are also risk factors for POA.
IVF is the creation of an embryo outside a human female's body from an oocyte harvested from a human female. The created embryo is then implanted in a human female, referred to as the IVF patient. The oocyte may be harvested from the IVF patient, in which case it is called an autologous oocyte, or it may be harvested from another human female, in which case the IVF patient is the recipient and the human female the oocyte was harvested from is the donor. Oocyte donors are selected from a pool of oocyte donor candidates who apply to donate oocytes. Donor selection is based on interviews and medical testing of candidates. Genetic testing to exclude genetic defects in embryos produced by IVF, including FMR1 testing to exclude FXS, is performed in oocyte donors after they are selected.
Related Studies
A longitudinal study studied the association of low (CGGn<26) alleles of the FMR1 gene, carried by approximately one-quarter of all females, with POA and female infertility. This study is summarized in the article entitled FMR1 Gene Mutations Already at Young Ages Are Predictive Of Later Premature Ovarian Senescence and Infertility (Kushnir V. A., Yao Y., Himaya E., Barad D. H., Weghofer A., Lee H. J., Wu Y. G., Shohat-Tal A., Lazzaroni-Tealdi E., Gleicher N., FMR1 Gene Mutations Already at Young Ages Are Predictive Of Later Premature Ovarian Senescence and Infertility, 2013, hereinafter referred to as the "longitudinal study" and included as Appendix A). Females carrying such alleles can now be identified at young ages as at risk for imminent POA and infertility. Such women can then undergo specific treatment and/or testing regimens, based on their FOR, until a diagnosis of POA is either confirmed by additional hormonal testing or until testing indicates that there is no clinical basis for a diagnosis of POA. Women whose deviation from normal levels of FOR is confirmed can be counseled at young ages when fertility preservation is more efficient, effective and less costly as compared with older women. This provides such women options of advancing pregnancies or of pursuing fertility preservation by oocyte and/or ovary freezing at younger ages than currently performed. Accordingly, fertility outcomes are improved.
By analyzing the FMR1 genes of young human females, young human females can be identified as at risk of POA and/or infertility and a hormone testing regimen based on the young human females' FMR1 genotypes can be performed. If the testing indicates that the young human female has POA, the young human female can then be treated. The treatment for POA may be any treatment or treatments for a human female who has experienced infertility or is at risk for infertility based on age, even though the human female does not currently exhibit such infertility. Examples of such treatment are disclosed in Gleicher II, Gleicher III, Gleicher IV and Gleicher V and other references mentioned herein and include, without restriction, oocyte cryopreservation, hormonal treatment, and/or gene therapy.
Approximately 10 percent of all females are affected by POA (see, Gleicher I). Many of those affected will seek infertility treatment. Early diagnosis of impending POA would allow such women to either change their reproductive life schedule and/or take fertility-preserving steps, like oocyte cryopreservation (see, Donnez J., Introduction: Fertility Preservation, From Cancer to Benign Disease to Social Reasons: the Challenge of the Present Decade, Fertility and Sterility, May 2013, 1467-8). Both of these options are more patient-friendly, effective and economical than the current practice of treating POA after POA progresses to an advanced stage.
The data in the longitudinal study allowed for analysis of how the FMR1 genotype is indicative of imminent ovarian aging in human females who have not experienced infertility and are not otherwise indicated to have POA. The data was correlated to progression of ovarian aging over a significant span of a human female's life and enabled highly accurate prediction of the expected onset of ovarian aging. Such accurate prediction allows treatment when ovarian aging is in its early stages or even before it begins to affect a human female's reproductive ability.
In addition to the prediction of imminent ovarian aging, the longitudinal data obtained during the study allows for prediction of female infertility. A female is considered infertile after trying and failing to become pregnant for at least a year. Many women who experience infertility have POA. As such, early predictions based on the longitudinal data of the study enabled the development of treatment and/or testing regimens of human females for infertility before they are infertile.
More particularly, the longitudinal study investigated functional ovarian reserve (FOR), as reflected by AMH levels, relative to FMR1 genotypes/sub-genotypes in 233 consecutive oocyte donor candidates, who underwent 233 baseline and 122 repeat AMH measurements (355 total measurements), and 354 consecutive infertility patients under 38 (mean age 35.5±3.5 years), who underwent 354 baseline AMH measurements. The 354 infertile women served as a cross-sectional comparison group to assess effects of FMR1 mutations on later occurring female infertility. Sixty-six donors had multiple longitudinal assessments over approximately 4 years, typically at substantially uniform intervals (e.g., yearly). Donor candidates with presumed increased reproductive risks based on medical, family and genetic histories were excluded.
FMR1 genotypes and sub-genotypes are defined in Gleicher II, Gleicher III, Gleicher IV and Gleicher V. By defining a normal CGGn=26-34 range, all CGGn below and above that range are considered abnormal. A female with both FMR1 alleles in normal range, therefore, is norm, a female with one within and one outside normal range is het and a female with both alleles outside norm range is hom. Whether an allele is above (high) or below (low) normal range further sub-divides het and hom genotypes (het-norm/high, het-norm/low, hom-high/high, hom-high/low, hom-low/low) into sub-genotypes. Table 2 provides the definitions of the terms for FMR1 alleles and genotypes used herein.
TABLE 2CGG Repeat Counts and FMR1 GenotypesGenotype/One AlleleOther AlleleSub-genotype(CGG 26 ≦ n ≦ 34 = norm)HighHighHom-high/highHighNormHet-norm/high(CGG n > 34 = high)HighLowHom-high/lowNormNormNorm(CGG n < 26 = low)NormLowHet-norm/lowLowLowHom-low/low
The longitudinal study had two purposes. The first purpose was to assess potential impacts of FMR1 genotypes/sub-genotypes on POA, also called Occult Primary Ovarian Insufficiency (OPOI) (see, Gleicher I). To avoid contamination by the effects of physiologic ovarian aging, only infertile women under age 38 years were included in the study. The second purpose was to determine whether differences in distribution of FMR1 genotypes/sub-genotypes between younger oocyte donors and older infertility patients are influenced by the increasing risk of experiencing infertility with advancing age. The 354 consecutive infertility patients below age 38 years (mean age 33.5±3.5 years) served as an older cross-sectional comparative group to assess whether the speed of decline in FOR, as measured by the size of the decreases in AMH (Δ AMH), differed between FMR1 genotypes and sub-genotypes and whether the prevalence of individual FMR1 genotypes and sub-genotypes differed between donor and infertility patient populations.
The longitudinal study found that donors with both alleles with a low CGG count (CGGn<26) (hom-low/low) demonstrated significantly lower AMH levels than donors with normal CGG counts (both alleles CGGn=26-34, norm). The het-low FMR1 genotype was associated with more rapid declines in AMH levels than the norm genotype or het-high FMR1 genotype. The Δ AMH significantly differed between the young donor subjects and the older infertility subjects and among het-norm/low, norm and het-norm/high populations. The overall distribution of the FMR1 genotypes and sub-genotypes also differed between young donor subjects and older infertility subjects.
The longitudinal study assessed effects on FOR of all FMR1 genotypes and sub-genotypes. In the longitudinal study, the difference in Δ AMH between young human female donors and older infertility patients was determined for the FMR1 genotypes/sub-genotypes. The longitudinal study showed that the hom FMR1 genotypes and het-low sub-genotypes identify young females at risk for POA. POA is a major cause of female infertility that affects approximately 10% of all women, and is only diagnosed at advanced stages, when potential interventions are less effective and more costly than they would be at earlier stages.
FIG. 3 summarizes characteristics of the egg donor subjects (human females who have not experienced infertility and are not otherwise indicated to have POA, as defined above) and known infertility patients. The mean age of women at the time of the baseline measurements was 24.4±3.3 years for the egg donors and 33.5±3.5 years for the infertility patients. The age of human females within the donor and infertility patient groups did not vary significantly for different FMR1 genotypes and sub-genotypes. Mean AMH at the baseline measurement was 4.3±2.6 for the donor human females and 1.9±2.1 ng/mL for the infertile patients. Mean body mass indices (BMI) at the baseline measurement were 21.4±2.4 for the donor human females and 24.4±5.5 kg/m2 for the infertile patients.
Baseline AMH values are the values in the initial AMH testing for each subject, performed after her FMR1 gene was isolated and the number of CGG repeats on both alleles of the FMR1 gene were determined. The FMR1 and AMH tests were performed by routine commercial assays, as described in Gleicher II, Gleicher III, Gleicher IV and Gleicher V. The age of each donor/infertile patient was recorded with her first AMH collection. AMH values were logarithmically transformed to provide a normal distribution and to obtain a new variable, logAMH. FIG. 3 shows a histogram for AMH for all 355 donor samples. Repeat AMH tests were performed if a donor was matched with an IVF candidate more than six months after the initial AMH test. Values from these repeat tests were statistically adjusted, including adjustments for age. This provided baseline values for all subjects of the longitudinal study and repeat AMH values for many subjects.
In FIG. 3, the p-value for Age, AMH and BMI is based on two independent sample t-tests of the distribution of means of donors and infertility patients. The p-value for FMR1 n % is based on a chi-square test related to the distribution of FMR1 sub-genotypes of donors vs. infertility patients. The p-values of the correlations show that the FMR1 sub-genotypes and AMH are strongly correlated.
Donors and infertile patients differed significantly in age, AMH and BMI values (all P<0.001; see, FIG. 3). Low mean AMH and high mean FSH values in the infertile patient group reflect an infertility patient population with very poor fertility characteristics based on those hormone levels. Full (CGGn>200) and premutation range alleles (CGGn˜55-200) were almost absent in both subject groups with 1 case in each group. The high alleles (CGGn>34) in the FMR1 data, therefore, primarily represent CGG values in the ranges CGGn<45 or CGGn˜45-54, and the correlations are not due to FXS, which appears in persons with full mutation range FMR1 genotypes.
The relationship between AMH and FMR1 genotypes/sub-genotypes was examined while accounting for the age variations among the subjects. Repeated AMH measurements, age and FMR1 genotype/sub-genotype were collected from the 233 donor candidates. A generalized estimating equation (GEE) model, using the norm FMR1 genotype as a reference level, was used to study the effect of FMR1 genotypes/sub-genotypes on AMH while accounting for correlations within subjects. A linear mixed-effect (LME) model was used to confirm the results provided by GEE. The results of the GEE and LME models are reported in FIGS. 5-7.
Short-term (approximately 4 years) time-related AMH changes were investigated using a LME model based on repeated AMH measurements in donors. Long-term (approximately 10 years) time-related AMH changes were studied by comparing baseline AMH values between donor candidates and infertility patients. The AMH baseline decline Δ AMH was calculated. Baseline AMH in donors with the norm genotype was higher than in donors with the hom-low/low sub-genotype (P=0.001), but did not differ from other FMR1 sub-genotypes (See, FIG. 3). A statistical comparison of repeated measurements of donor AMH between norm and all other FMR1 sub-genotype using a GEE model revealed a difference between norm and hom-high/high (p<0.001) and hom-low/low (p=0.006) (see, FIG. 5). This conclusion was further confirmed by an LME model.
The correlation between FMR1 genotype/sub-genotype and change in AMH level over time is statistically significant (P=0.046) (see, FIG. 7). Based on this correlation, a human female's future decline in AMH levels can be predicted based on her FMR1 genotype. FIG. 8 shows predicted AMH levels over a 4 year observation period and shows that AMH declines more rapidly in donors with at least one low (CGGn<26) allele than in donors with only norm and high alleles. Specifically, FIG. 8 presents the greater predicted decline of AMH over time for women with low vs. norm and high FMR1 genotypes (P=0.046).
This decline in AMH in young human females with at least one low allele indicates that additional testing and treatment for POA and risk of infertility is more useful and productive in such young human females than in other young human females. Early commencement of infertility treatment improves the likelihood of successful conception and pregnancy and is not otherwise performed without early detection of POA.
Young hom-high/high and hom-low/low donors start with lower AMH levels than young norm FMR1 donors. AMH levels decline in all FMR1 genotypes/sub-genotypes between younger oocyte donors and older infertility patients. The decline varies among FMR1 genotypes/sub-genotypes, demonstrating that ovarian aging speed varies based on FMR1 genotypes/sub-genotypes. The statistical comparison of donor AMH baseline between normal alleles and the other FMR1 sub-genotypes, using ANCOVA, showed *P=0.001. The mean and standard deviation of ΔAMH for each FMR1 genotypes/sub-genotypes are summarized in FIG. 9. The ΔAMH for each FMR1 genotype allows prediction of the change over time of a human female's AMH levels based on her FMR1 genotype.
Because of the small total number of subjects with hom FMR1 genotypes, hom-high/high, hom-high/low and hom-low/low were combined. ANCOVA was used to compare the distribution between genotypes and remaining het sub-genotypes. The results show a statistically significant difference in the decline in ΔAMH between human females with the het-norm/low sub-genotype and the norm genotype (P=0.045) or the het-norm/high genotype (P=0.042) (see, FIG. 10). The data is presented as a mean and a standard error of mean. The absence of a statistically significant difference between het-norm/low and hom FMR1 sub-genotypes is likely due to the small number of hom sub-genotypes. This is further supported by individual AMH values in the hom-high/low donor group, where AMH levels were either high or low, resulting in a mean value for all hom-high/low subjects in between these two extremes even though individual human females with the hom-high/low FMR1 genotype did not exhibit such in-between levels. The resulting mean is probably not representative of gene activity.
FIG. 11 shows the ΔAMH and the statistical significance of all pairwise comparisons of ΔAMH between the FMR1 genotypes. Decline in FOR, as measured by ΔAMH, is associated with FMR1 low genotypes/sub-genotypes in younger oocyte donors and older infertility patients. More rapid declines in FOR lead to more female infertility and, therefore, either to more or less observed infertility treatments. Fewer infertility treatments will be observed if patients with a particular FMR1 genotype dropped out of treatment before inclusion in this study (see, Gleicher N., Weghofer A., Kim A., Barad D. H., Comparison of Ovarian FMR1 Genotypes and Sub-Genotypes in Oocyte Donors and Infertile Women, Journal of Assisted Reproduction and Genetics, June 2012, 529-32). The relative absence of infertility patients with the FMR1 low genotypes associated with poor ovarian reserve and poor IVF outcomes in the infertility patients indicates their early dropout from infertility treatments. This is because such patients are unlikely to achieve successful pregnancy, and are likely to receive discouraging results early in infertility treatment. This would be especially prevalent in a highly adversely selected patient population, such as the population of the longitudinal study (see, FIG. 2). That is, a young human female with a low number of CGG repeats on one or both alleles of the FMR1 gene would be expected to benefit from treatment for infertility, but would be expected to abandon such treatments when they were unsuccessful, and a young human female with a normal number of CGG repeats on both alleles of the FMR1 gene would not be expected to seek treatment for infertility.
The data from the longitudinal study supports the increased drop-out rate of infertility patients with particular FMR1 genotypes. The largest drop-out rates were seen in hom-high/high (4.3% to 0.6%), hom-low/low (3.4% to 2.8%), hom-high/low (3.9% to 1.4%) and het-norm/low (21.5% to 18.6%) FMR1 genotypes/sub-genotypes, which are also associated with abnormally low FOR in young oocyte donors. By contrast, women with norm FMR1 genotypes (54.5% to 59.0%) and het-norm/high (12.5% to 17.5%) sub-genotypes increased in prevalence among infertility patients. The het-norm/high is associated with comparatively good preservation of FOR into older ages (see, Gleicher V). These changes in the overall distribution of FMR1 genotypes and sub-genotypes were statistically significant (P=0.005), suggesting that women with unfavorable FOR at young ages drop out of infertility treatments earlier than women with normal FOR for their age. This further demonstrates the importance of providing treatment for infertility and/or POA at young ages and before infertility is experienced.
A low (CGGn<26) allele, as in a het-norm/low patient, appears to reduce pregnancy chances by approximately half in comparison to patients with the norm genotype (see, Gleicher III). Young women, however, have high FOR that masks the reduced FOR in young women with FMR1-low genotypes. Therefore, infertility does not become clinically apparent until older age, and even detection of the reduced FOR is difficult in young women (Gleicher N., Weghofer A., Barad D. H., Intermediate and Normal Sized CGG Repeat on the FMR1 Gene Does not Negatively Affect Donor Ovarian Response, Human Reproduction, July 2012, 2241-2; author reply 2-3, hereinafter referred to as "Gleicher VI"; Gleicher N., Kim A., Barad D. H., et al. FMR1-Dependent Variability of Ovarian Aging Patterns is Already Apparent in Young Oocyte Donors, Reproductive Biology and Endocrinology, August 2013, 80, hereinafter referred to as "Gleicher VII"; and Lledo B., Guerrero J., Ortiz J. A., et al. Intermediate and Normal Sized CGG Repeat on the FMR1 Gene Does not Negatively Affect Donor Ovarian Response. Human Reproduction, February 2012, 609-14, hereinafter referred to as "Lledo").
The results of the longitudinal study confirm the importance of the FMR1 gene in female reproductive aging. The most important conclusion is that analyzing the FMR1 gene at a young age allows a determination of risk of POA and infertility, and the targeted treatment of young human females. The longitudinal study demonstrates that, in young human females, significant differences in AMH levels are apparent only in association with the hom-low (CGGn<26) FMR1 genotype. Over 4 years of longitudinal follow-up, donors with the hom-high (CGGn<26) FMR1 genotype demonstrated significantly reduced FOR in comparison to norm donors. Single het-low donors demonstrated significantly greater ΔAMH compared to norm donors (see, FIG. 10).
FIGS. 5 and 9 show the data of longitudinal versions of earlier cross-sectional studies (see, Gleicher VI; Gleicher VII; and Lledo). FIGS. 5 and 9 show that young human females who are oocyte donors with norm and het FMR1 genotypes demonstrate similar FOR. Only young human females with the hom-low/low sub-genotype have significantly lower baseline FOR than young human females with the norm FMR1 genotype (FIG. 11). Only a few years later, all hom sub-genotypes (except hom-high/low) and women with even a single low (CGGn<26) allele are adversely affected in comparison to either norm or high (CGGn>34) allele-carrying women (see, FIGS. 11 and 12).
These findings also confirm that women with het-norm/low sub-genotypes rapidly recruit follicles at young ages, leading to quick depletion of FOR and early ovarian aging (see, Gleicher III). AMH is considered the best tool to assess FOR (see, Nelson II). Actively recruiting het-low women demonstrate relatively high AMH values at young ages (FIG. 11). The two low alleles in hom-low/low females produce a more severely affected ovarian phenotype characterized by significantly depleted FOR. Women with the hom-low/low genotype have FOR loss as severe at young ages as the FOR loss seen at middle-age in women with het-low genotypes, as described in the cross sectional studies discussed in Gleicher III. Accordingly, women with the hom-low FMR1 genotype are more likely than women with het-low genotypes to experience infertility.
FIGS. 10 and 11 confirm previously noted longitudinal observations of rapid declines in AMH in het-norm/low women. Het-norm/low women experience a much larger ΔAMH than norm and het-norm/high women. Hom-low/low women's AMH levels decline less than those of het-norm/low females, but start from a very low baseline at young ages. Het-norm/low females actively recruit oocytes at very young ages and continue to do so into middle-age (see, Gleicher III).
The longitudinal study also indicates a difference in the ΔAMH between het-norm/low and het-norm/high, demonstrating a profound divergence in ovarian aging phenotypes after young donor ages. While het-low sub-genotypes continue to rapidly deplete FOR, het-high sub-genotypes slow their depletion. As a result, women with het-norm/high sub-genotypes have unexpectedly good FOR at very advanced ages (see, Gleicher V).
As previously noted, the statistical similarity in ΔAMH between het-norm/low and hom women is attributable to small patient numbers. Moreover, patients with the hom-high/low sub-genotype further distort the data because they are evenly split between high and low FOR. FOR is determined in patients with the hom-high/low sub-genotype by which allele undergoes X chromosome-inactivation and, likely, how methylated the active X chromosome is. This sub-genotype, therefore, requires careful additional longitudinal AMH evaluations before the risk for POA can be determined.
The longitudinal study further found that analysis of FMR1 genotypes/sub-genotypes in young human females allows the detection of risk of POA and appropriate treatment. Women found to be at risk for POA based on their FMR1 genotype can be carefully followed with AMH and/or other tests of ORe, including FSH and/or androgens, recently associated with low ovarian reserve. This allows for earlier diagnosis and treatment if the tests indicate that such treatment is necessary (see, Gleicher N., Kim A., Weghofer A., et al., Hypoandrogenism in Association with Diminished Functional Ovarian Reserve, Human Reproduction, April 2013, 1084-91).
Finally, the longitudinal study indicated that, in a very adversely selected patient population, such as the infertile women of the longitudinal study, women with disproportionally quick ovarian aging FMR1 genotypes/sub-genotypes drop out of infertility treatment early. This further demonstrates the importance of early diagnosis of POA to allow for timely interventions by either enhanced conception planning and/or fertility preservation by oocyte freezing or other evolving technologies.
The longitudinal study supports the proposition that slower follicle recruitment preserves more follicles/oocytes, leading to better remaining TOR at later ages. As demonstrated by the study, low FMR1 gene alleles are associated with early depletion of ovarian reserve and resulting POA/OPOI. That is, in the study, for the young oocyte donors, homozygous (hom) donors with two low alleles demonstrated significantly reduced FOR by their early 20's. Young heterozygous (het) donors with only one low allele demonstrated significantly accelerated loss of FOR in comparison with donors who only had high and/or norm alleles. By contrast, high alleles appear to preserve FOR into advanced female ages (see, Gleicher V). Analysis of FMR1 genotype in young human females is predictive of imminent ovarian aging patterns.
In high-risk patients, the availability of age-specific normal AMH values allows for longitudinal monitoring of TOR. If patients deviate from normal AMH levels at their ages, such longitudinal monitoring allows the diagnosis of POA at significantly younger ages than was previously possible. It is currently unknown what percentage of females between the ages of 16-21 would be found to be at increased risk of POA by such a screening process, and how many amongst those would develop POA. Considering an approximate 10% prevalence of POA in the general population, the number of patients at risk is expected to be large.
All of the publications mentioned above, as well as those mentioned below, are incorporated by reference herein.

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Screening of oocyte donor candidates based on the FMR1 gene