Abstract

Regulation of water metabolism is one of the most important homeostatic functions in mammals. The discovery of aquaporin water channels has greatly expanded our understanding of the regulation of water movements across certain biological membranes. Brain edema accompanies most cases of brain injury, and has long been considered as the major impediment to tissue repair after injury. In brain edema, astrocyte foot processes, where the water channel aquaporin-4 (AQP4) is localized, always swell first, followed by astrocyte proliferation and migration. Proliferation of astrocytes occurs in a limited period, 3.5 to 4 days after injury; migration occurs just after proliferation. Synapses that are not damaged during injury are then recognized and enveloped by migrating astrocytes. Astrocytes play critical roles for the formation of functional synapses and the blood-brain-barrier (BBB). Astrocytes also appear to be important for generation of new neurons in the adult brain. Proliferating astrocytes in the area of injury re-express neuronal stem cell markers, Musashi-1 and nestin, suggesting that they may differentiate into neurons. We examine the molecular mechanisms underlying astrocyte behavior during brain edema and tissue repair: swelling, proliferation, migration, and establishment of synapses and BBB. We also discuss if astrocytes generate new neurons in the area of injury. (Presented at the 1222nd Meeting July 24, 2001.)

The last half century has seen rapid progress in medical knowledge and technology. It was also the time of advance in civil society in terms of expansion of civil rights. The medical profession has kept up with these changes in the field of diagnosis and treatment. Yet it has been slow in adjusting to the change in social structure. I would like to focus on a few issues of the physician's interaction to the society on informed consent and right to die movement. <Informed consent> In America, up until 1970, the doctor-patient relationship was based on what doctor thought was best for the patient — what we now call "Paternalism." In recent years, society has become increasingly aware of human rights and individual autonomy. With this awareness of the patient's human rights, paternalism which prevailed in the past in the doctor-patient relationship has been shifting toward the emphasis of the patient's right — patient's autonomy. Autonomy is a form of personal liberty of action where the individual determines his or her own course of action in accordance with a plan chosen by himself/herself. Along with this, the concept of informed consent has been taking its place not only in the legal system but also the informed care system. Voluntary informed consent has become an important element in the patient's rights. This requires that certain information be shared with patients. Adequacy of information for informed consent may be difficult to ascertain. At this time, it appears that an acceptable standard of adequacy of information for informed consent would be a combination of a reasonable personal standard, supplemented by an individual personal inquiry. While a sufficient quantity of information is needed for informed consent, adequate comprehension of information by patients is also necessary for a valid informed consent. Ethically and legally, it is also important to note a voluntary degree of consent free of coercion or undue influence. Further, respect for autonomy means the shared decision making in one's own health care. This shared information and shared decision making — informed consent — would humanize the doctor-patient relationship in these socialized health care environments and ultimately achieve better health care. <Right to die> With advance in medical knowledge and technology in recent years, the objective of medicine has been to prolong life, fight to the death, for the sake of extending life for its own sake. In the last decade, we have seen the shift back to focus on the quality of life and the the care at the end of life. As one physician termed it, "prolonging a meaningful life and humanizing the process of dying." Recent emphasis on the patient's right in shared decision making extended into the right to refuse treatment. This right to refuse treatment in life threatening contexts present rather complexp roblems in spite of the general endorsement of the patient's right to autonomous choice. The right is considered not only in routine medical treatment but also in terminal care at the end of life. The issue is raised relating to physician assisted death in the terminal ill suffering patient. Historicaly, the case of Dr. Postma in 1973 ignited the movement of "Right to die" and started the Nethelands down a path to becoming the only nation in the world where euthanasia, while technically illegal, could be practiced openly. The court found Dr. Postma guilty for injecting a lethal dose of morphine into her terminally ill and suffering mother. The court also laid down guidelines for the medical profession in physician assistance in dying which were widely accepted in medical circle and which the courts accepted. In 1984, the Royal Dutch Medical Society set out "Rule of Careful Conduct" to guide doctors in physician assisted dying. In America, the state of Oregon became an only state to pass the "death with dignity" act in 1994 legally sanctioning physician assisted dying with well defined restrictions. This became effective in 1997. The right to die — physician assisted dying is an unquestionably controversial issue. People who face end of life care deserve the compassion of society. We should improve palliative care, its access and quality as a civilized society. The policy for end of life care should include the consideration for physician assistance in the dying process for the select group of terminaly ill suffering patients. Compassion of society should respond to the changing dying process resulting from the advance in medical technology with its own limitations. (Presented at the 1245th Meeting, February 8, 2002.)

The term carpal instability is commonly used, but carpal stability has not been defined. Much of the mechanically complexwrist's versatility is due to the intercalated three bone proximal carpal row. Landsmeer described the collapse tendency associated with intercalated segments. The factors which provide stability are the compressive forces exerted across the joint acting on the morphology of the joint surfaces, the oblique alignment of the scaphoid, the obliquely aligned dorsal and palmar ligamentous complexs, the intrinsic perilunate ligaments, the transiting transcarpal tendons and the negative intraarticular pressure. The proximal carpal row translates ulnarly along the sloped radial articular surface while the distal row slides radially on the wedge shaped lunate. Activity produces differential tension in the ligaments attached to the triquetrum which in turn inherently effects an extension stance of the triquetrum to compensate for the inherent flexion tendency of the scaphoid. The bowstringing of the flexor carpi radialis also counteracts scaphoid flexion. Disruptions in any of these factors may upset the delicate mechanical balance of the joint. (Presented at the 1246th Meeting, February 8, 2002.)

The molecular basis of lymphoid organogenesis has recently been elucidated using gene-targeted mice. Mice deficient in lymphotoxin-α (LTα) lack lymph nodes and Peyer's patches. The action of LTα in lymphoid organogenesis is mediated mostly by the membrane form of LT by lymphotoxin-β receptor (LTβR). Additionally, 108 follicular dendritic cell (FDC) clusters or germinal centers fail to develop in the spleen of LTα-deficient mice. Mice deficient in either TNFR-I or LTβR also fail to develop splenic FDC clusters and germinal centers, indicating that signaling through both TNFR-I and LTβR is required for the development of these structures. The mechanisms underlying the defective lymphoid organogenesis in LTα-deficient mice, together with a natural mutant strain, alymphoplasia (aly) mice, which manifest a quite similar phenotype to LTα-deficient mice and are discovered as a mutant strain of NF-κB-inducing kinase (NIK), were investigated by generating aggregation chimeras. These studies demonstrate that LTα and NIK together control lymphoid organogenesis with a close mechanistic relationship in their biochemical pathways through governing distinct cellular compartments; the former acting as a circulating ligand and the latter as a LTβR-signaling molecule expressed by the stroma of the lymphoid organs. Following receptor ligation, LTβR activates NF-κB, a multifunctional transcription factor involved in many immune and inflammatory responses. Mice deficient for IκB-kinase α (IKKα) are defective in NF-κB activation through LTβR, but not through TNF receptor. Defective LTβR signaling in IKKα-deficient mice resulted in the lack of Peyer's patches. These results demonstrate that both NIK and IKKα are essential for the induction of NF-κB through LTβR, whereas the NIK-IKKα pathway is dispensable in TNFR-I signaling. (Presented at the 1247th Meeting, February 8, 2002.)

Decreased barrier and altered transport function of intestinal epithelial cells are commonly associated with gut mucosal inflammation, particularly inflammatory bowel diseases (IBD). The resulting development of diarrhea has generally been attributed to stimulated anion secretion, a concept based on in vitro observations that many immune and inflammatory modulators produced by inflammatory cells in inflamed gut mucosa stimulate active anion secretion. However, recent observations suggest that epithelial transport and barrier functions are not stimulated, but reduced, in the inflamed intestinal mucosa. To better understand the basis of these effects, we examined how interferongamma (IFN-γ) inhibits epithelial barrier and ion transport functions, using intestinal T84 cells. Shortand long-term effects of IFN-γ on T84 barrier function, Na-K-ATPase activity, and ion transport and tight junctional proteins were determined. These studies showed that IFN-γ acutely decreases cellular Na,K-ATPase activity, followed later (>24 hr) by specific decreases in expression of Na/K/2Cl, alpha subunit of Na,K-ATPase, occludin, and ZO-1. Because ouabain and monensin cause nearly identical changes, we examined whether cell swelling and/or increases in cell Na resulting from inhibited Na pump activity might serve as signaling events mediating the chronic effects of IFN-γ. Incubation in low-Na media significantly blunted the chronic effects of IFN-γ. Hypotonicinduced cell swelling, in contrast, had effects similar to IFN-γ, but did not alter the expression of the Na pump α subunit. Thus, IFN-γ inhibition of Na,K-ATPase activity acutely causes increases in Nai and cell volume which are distinct signaling events that ultimately result in a leaky and dysfunctional epithelium associated with chronic inflammation. (Presented at the 1249th Meeting, March 4, 2002.)

The use of dopaminergic ventromedial (VM) human foetal brain tissue as implants to neurosurgically treat Parkinson's disease has been in progress since the 1980s. A major limitation in the use of VM tissue is the amount of tissue available from each human embryo. Usually tissue from about 7 embryos are required to treat each patient unilaterally. To overcome this we have developed various strategies. One is to convert embryonic cerebral cortexin human embryos into dopaminergic tissue which is stable, and which will secrete dopamine in vivo once implanted. The cerebral cortex is about 500 times larger than the VM and can therefore provide a lot more tissue for transplantation. This can be achieved by genetic manipulation of the embryonic cerebral cortextissue, involving the lipo-transfection of multiple copies of the human tyrosine hydroxylase gene into both neurones and glial cells. In another approach we have biochemically manipulated the development of the cerebral cortexto direct the neurotransmitter phenotype towards the dopaminergic type, and away from other phenotypes. This tissue too is stable and will synthesise and secrete dopamine when transplanted. Our third approach has been to manipulate pluripotential neural cells which are yet to develop into neurons and glial cells. These cells can be expanded in number many-fold before treatment to direct their development into stable dopaminergic neurones in large numbers (70%), which synthesise and release dopamine. When used as transplants in animal models of Parkinson's disease, these various types of artificially induced dopaminergic tissue are very effective at reducing the Parkinsonian syndrome. (Presented at the 1253rd Meeting, March 7, 2002.)

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