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Before the 1990s the prevailing theory of Alzheimer's pathogenesis was termed the cholinergic hypothesis.12 This was based on the seminal finding that acetylcholine ACh ; and choline-acetyltransferase ChAT ; levels were low in the brains of Alzheimer's patients.13 The basal nucleus of Meynert, which lies beneath the forebrain, is the brain's major source of ACh. ACh is synthesized in large cholinergic neurons, some as large as 1 mm across. Low ACh levels or cholinergic blockade can produce cognitive impairment, and this was accepted as the explanation for the loss of function seen in Alzheimer's. Until quite recently, the only drugs available for treating AD have been based on the cholinergic hypothesis, and are all cholinesterase inhibitors, drugs which inhibit the breakdown of acetylcholine. It is ironic to note that while they do in fact have beneficial effects, their development was based on what is known now to be false: Alzheimer's disease is not attributable to loss of acetylcholine but is, in fact, attributable to loss of cholinergic and other neurons. The cholinergic deficit is an effect of the illness, not a cause. A new line of drug development has emerged from a more amyloid-based consideration of the pathogenesis of Alzheimer's disease. These are the selective NMDA receptor inhibitors, typified by the first commercially available agent in the USA, memantine. The rest of. Author's Disclosures of Potential Conflicts of Interest Although all authors have completed the disclosure declaration, the following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors and ultram. 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Although the payer community cannot directly influence manufacturer pricing, individual payers can affect per-prescription costs by adopting particular ground rules under which they will pay for drug products. Such strategies include limiting the size of retail networks; and promoting the use of mail service, mandatory generic programs, quantity limits, step therapy and therapeutic switching. Generally the deepest discounts payers can attain are through a mail service pharmacy, which can capitalize on economies of scale to lower cost, with the resulting savings being passed on to clients. Consequently, it would behoove the payer to encourage members to have prescriptions that are used to treat chronic disease filled through mail service. About 80 percent of Express Scripts members have a choice of retail or mail order usage. On the retail side of the equation, better discounts can be obtained in exchange for driving higher volume into network stores. Consequently, a payer willing to limit the number of retail pharmacies in its network can obtain deeper discounts from this limited network. The plan sponsor can directly impact the per-prescription cost by controlling or influencing the mix of products reimbursable under the drug plan benefit. In a mandatory generic program, the member is required to pay the difference between the price for a multi-source brand for which a generic is available and the price for the generic equivalent. A mandatory generic program can be implemented requiring the member to pay the difference only if the physician has indicated that a generic can be substituted or regardless of whether the physician had indicated that a generic can be substituted. The percentage of Express Scripts' sample clients that adopted one of these mandatory generic programs grew from 40 percent in 1996 to about 47 percent in 1997 and 1998, and to 55 percent in 1999. In both 1998 and 1999, 69 percent of HMO clients had a mandatory generic program. In contrast, only 32 percent of non-managed care commercial clients had such a program in 1998. This figure grew to 50 percent in 1999. Excessive quantities per prescription can be controlled by implementing quantity limits per copay. This strategy involves targeting products for which prescriptions are prone to include quantities beyond what is suggested for typical use. Depending on how aggressive the client is willing to be, limiting the quantity per prescription can save between $0.10 and $0.20 per member per month. Additionally, managing drug choices within a therapeutic class has become a viable alternative for reducing costs. Compared with the more indirect approach of physician intervention and behavior changes, plans are opting to manage utilization choices at the point of service. Requiring the, for example, triphasil tablets. Futile."150 If at any point it was deemed appropriate to withdraw Sidney's medical support, she could have been "treated with dignity and respect, and provided with `comfort care' measures."151 The American Academy of Pediatrics AAP ; and many other organizations support the role of families in medical 152 decisionmaking. The AAP believes medical decisions "should be jointly made by physicians and parents."153 Furthermore, the AAP believes initial resuscitation followed by later withdrawal of support allows physicians time to gather more complete clinical information and provide counseling to the family.154 F. Severity of Impairments May Not Justify Resuscitation The Fourteenth Court of Appeals stated that some babies may be "born so prematurely and in such poor condition that sustaining their life, even if medically possible, cannot be justified."155 It can be argued that Sidney's medical condition, impairments, and handicaps were, and are, so grave that resuscitation and life-sustaining treatment upon birth were not justified. 1. Sidney's Medical Condition at Birth. At birth, Sidney's 156 body was small enough to fit in Mark's hand. Her eyes were "fused" and her head was only slightly larger than a golf ball.157 She weighed just one and one-half pounds and her lungs were 158 not fully developed. The Millers wanted their severely premature baby to be free from aggressive and invasive medical procedures and to "live or and vioxx. 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