The deprivation syndrome is the driving force of phylogeny, ontogeny and oncogeny.

Energy is the motor of life. Energy ensures the organism's survival and competitive advantage for reproductive success. For almost 3 billion years, unicellular organisms were the only life form on earth. Competition for limited energy resources and raw materials exerted an incessant selective pressure on organisms. In the adverse environment and due to their 'feast and famine' life style, hardiness to a variety of stressors, particularly to nutrient deprivation, was the selection principle. Both resistance and mutagenic adaptation to stressors were established as survival strategies by means of context-specific processes creating stability or variability of DNA sequence. The conservation of transduction pathways and functional homology of effector molecules clearly bear witness that the principles of life established during prokaryotic and eukaryotic unicellular evolution, although later diversified, have been unshakably cast to persist during metazoan phylogenesis. A wealth of evidence suggests that unicellular organisms evolved the phenomena of differentiation and apoptosis, sexual reproduction, and even aging, as responses to environmental challenges. These evolutionary accomplishments were elaborated from the dichotomous resistance/mutagenesis response and sophisticated the capacity of cells to tune their genetic information to changing environmental conditions. Notably, the social deprivation responses, differentiation and apoptosis, evolved as intercellularly coordinated events: a multitude of differentiation processes were elaborated from sporulation, the prototypic stress resistance response, while apoptosis, contrary to current concepts, is no altruistic cell suicide but was programmed as a mutagenic survival response; this response, however, is socially thwarted leading into mutagenic error catastrophe. In the hybrid differentiation-apoptosis process, cytocide and cannibalism of apoptotic cells thus serve the purpose of fueling the survival of the selfish genes in the differentiating cells. However, successful mutagenesis, although repressed, persisted in the asocial stress response of carcinogenesis as a regression to primitive unicellular behavior following failure of intercellular communication. While somatic mutagenesis was largely prevented, Metazoa elaborated germ cell mutagenesis as an evolutionary vehicle. Genetic competence, a primitive, stress-induced mating behavior, evolved into sexual reproduction which harnessed mutagenesis by subjecting highly mutable germ cells to a rigid viability selection. These processes were programmatically fixed as life- and cell-cycle events but retained their deprivation response phenotypes. Thus, the differentiation-apoptosis tandem evolved as the 'clay' to mold the specialized structures and functions of a multicellular organism while sexual reproduction elaborated the principle of quality-checked mutagenesis to create the immense diversity of Metazoa following the Cambrian explosion. Throughout these events, reactive oxygen and nitrogen species, which are regulated by energy homeostasis, shape the genetic information in a regulated but random, uncoded process providing the fitness-related feedback of phenotype to genotype. The interplay of genes and environment establishes a dynamic stimulus-response feedback cycle which, in animate nature, may be the organizing principle to contrive the reciprocal duality of energy and matter.

The Alzheimer's disease activities of daily living international scale (ADL-IS).

BACKGROUND: Activities of daily living (ADL) deficits are integral components of dementia disorders, and ADL measures are among the most robust markers of the course of Alzheimer's disease (AD). Despite this acknowledged importance, no clearly useful ADL instrument for cross-cultural application in pharmacologic trials in the early stages of AD had been available. METHOD: An international effort was launched to develop an ADL scale for pharmacologic trials in early AD. Steps taken from 1990 to the present included: (1) international scientific working group meetings and reviews, (2) reviews of existing measures, (3) collating of existent, nonredundant items, (4) querying experts for new items, (5) interviews with informants and subjects in the USA, France, and Germany, toward the identification of potential new items, (6) identification of an item pool based upon these procedures, (7) creation of a trial instrument, (8) piloting of this instrument, and (9) refinement of the scale based upon statistical analysis of the pilot data. Final item selection was based upon: (1) relevance for > or = 80% of subjects in severity-stratified USA and German samples; (2) absence of gender and national biases; (3) significant (p <.05) discrimination between (a) normal versus mildly impaired and (b) mildly impaired versus moderately to moderately severely impaired subjects; and (4) Global Deterioration Scale (GDS) scores accounting for > or = 12% of variance in the item after controlling for age and gender. RESULTS: An ADL scale consisting of 40 items that correlate with the global and cognitive progress of AD is developed for international usage in pharmacologic trials in incipient, mild, moderate, and moderately severe AD. The scale contains 40 items falling within 13 ADL categories. The 40-item scale is shown to have .81 correlation with GDS staging, .81 with mental status assessment (Mini-Mental State Examination), and .81 with a psychometric test (the SKT) (p values < .001). CONCLUSION: This scale can be used to measure therapeutic response in AD.

A unifying hypothesis of Alzheimer's disease. IV. Causation and sequence of events.

Contrary to common concepts, the brain in Alzheimer's disease (AD) does not follow a suicide but a rescue program. Widely shared features of metabolism in starvation, hibernation and various conditions of energy deprivation, e.g. ischemia, allow the definition of a deprivation syndrome which is a phylogenetically conserved adaptive response to energetic stress. It is characterized by hypometabolism, oxidative stress and adjustments of the glucose-fatty acid cycle. Cumulative evidence suggests that the brain in aging and AD actively adapts to the progressive fuel deprivation. The counterregulatory mechanisms aim to preserve glucose for anabolic needs and promote the oxidative utilization of ketone bodies. The agent mediating the metabolic switch is soluble Abeta which inhibits glucose utilization and stimulates ketone body utilization at various levels. These processes, which are initiated during normal aging, include inhibition of pro-glycolytic neurohormones, cholinergic transmission, and pyruvate dehydrogenase, the key transmitter and effector systems regulating glucose metabolism. Hormonal and effector systems which promote ketone body utilization, such as glucocorticosteroid and galanin activity, GABAergic transmission, nitric oxide, lipid transport, Ca2+ elevation, and ketone body metabolizing enzymes, are enhanced. A multitude of risk factors feed into this pathophysiological cascade at a variety of levels. Taking into account its pleiotropic regulatory actions in the deprivation response, a new name for Abeta is suggested: deprivin. On the other hand, cumulative evidence, taken together compelling, suggests that senile plaques are the dump rather than the driving force of AD. Moreover, the neurotoxic action of fibrillar Abeta is a likely in vitro artifact but does not contribute significantly to the in vivo pathophysiological events. This archaic program, conserved from bacteria to man, aims to ensure the survival of a deprived organism and controls such divergent processes as sporulation, hibernation, aging and aging-related diseases. In contrast to the immature brain, ketone body utilization of the aged brain is no longer sufficient to meet the energetic demands and is later supplemented by lactate, thus recapitulating in reverse order the sequential fuel utilization of the immature brain. The transduction pathways which operate to switch metabolism also convey the programming and balancing of the de-/redifferentiation/apoptosis cell cycle decisions. This encompasses the reiteration of developmental processes such as transcription factor activation, tau hyperphosphorylation, and establishment of growth factor independence by means of Ca2+ set point shift. Thus, the increasing energetic insufficiency results in the progressive centralization of metabolic activity to the neuronal soma, leading to pruning of the axonal/dendritic trees, loss of neuronal polarity, downregulation of neuronal plasticity and, eventually, depending on the Ca2+ -energy-redox homeostasis, degeneration of vulnerable neurons. Finally, it is outlined that genetic (e.g. Down's syndrome, APP and presenilin mutations and apoE4) and environmental risk factors represent progeroid factors which accelerate the aging process and precipitate the manifestation of AD as a progeroid systemic disease. Aging and AD are related to each other by threshold phenomena, corresponding to stage 2, the stage of resistance, and stage 3, exhaustion, of a metabolic stress response.

Informant-rated activities-of-daily-living (ADL) assessments: results of a study of 141 items in the U.S.A., Germany, Russia, and Greece from the International ADL Scale Development Project.

The analyses of an international pilot study presented in this article focused on the development of a cross-nationally valid activities-of-daily-living (ADL) scale sensitive to therapeutic effects in patients with mild memory impairment and mild to moderately severe dementia. The present report, which is part of an ongoing international research project, describes field testing results for 141 informant-rated items. The comparability of samples investigated in research centers in the U.S.A., Germany, Russia, and Greece concerning cognitive decline was evaluated globally as well as psychometrically using the Global Deterioration Scale, the Short Cognitive Performance Test, and the Mini-Mental State Examination. In the participating countries, a composite ADL score discriminated well between different stages of cognitive impairment because of dementia. However, international differences between the applied measures were observed. A practical ADL scale showing therapeutic sensitivity and international utility, will be constructed from the 141 informant-rated items under investigation in this pilot work.

Neurophysiologic changes in lumbar nerve root inflammation in the rat after treatment with cytokine inhibitors. Evidence for a role of interleukin-1.

STUDY DESIGN: The present study was designed to evaluate the effect of cytokine inhibitors in experimental allergic radiculitis. OBJECTIVE: Evaluation of the effect of cytokine inhibitors in experimental allergic radiculitis. SUMMARY OF BACKGROUND DATA: A number of cytokines are known to be involved in hyperalgesia and may play a role in radiculitis. Corticosteroids and other cytokine inhibitors antagonize their effects. METHODS: Experimental allergic radiculitis was induced in rats by injection of bovine myelin from the peripheral nervous system. The sham group subsequently received saline injections; the treatment groups received either prednisolone or interleukin-1 receptor antagonist. Treatment effect was assessed on the basis of motor performance and neurophysiologic parameters. RESULTS: Treatment ameliorated the symptoms of experimental allergic radiculitis. Prednisolone appeared to be somewhat more effective than interleukin-1 receptor antagonist. CONCLUSIONS: Because interleukin-1 receptor antagonist specifically blocks the effects of interleukin-1 at its receptors, the present results imply that interleukin-1 is a causal factor in the model of experimental radiculitis used. Its specificity and apparent lack of side effects make interleukin-1 receptor antagonist an attractive candidate treatment for the human disease.

[Amitriptyline in therapy of chronic tension headache]. / Amitriptylin in der Therapie des chronischen Kopfschmerzes vom Spannungstyp.

In a double-blind, placebo-controlled trial, the effect of 75 mg of a slow-release formulation of amitriptyline on the clinical severity of chronic tension-type headache and on headache-associated neurophysiological parameters (EMG activity, exteroceptive suppression of temporal muscle activity, contingent negative variation (CNV) and experimental pain sensitivity) was investigated. All of the patients treated had a history of headaches of many years standing, and numerous failed attempts at treatment. In the amitriptyline group, a significant reduction in daily headache duration was already found in the third week of treatment, while in the placebo group no significant changes in headache duration were to be seen. In week 6 the amitriptyline group had a significantly shorter daily duration of headache than the placebo group. Treatment did not result in any significant effects on EMG recording of pericranial muscle activity either during relaxation or contraction, on exteroceptive suppression of the temporal muscle and on CNV. The sensitivity to suprathreshold experimental pain, however, was significantly reduced. The data show a statistically relevant reduction of daily headache duration in chronic tension-type headache. However, they also show that amitriptyline can only partly alleviate chronic headaches but cannot cure them.

Interferon-gamma potentiates antibody-mediated demyelination in vivo.

The pathogenetic events leading to demyelination in experimental allergic encephalomyelitis and in human multiple sclerosis are still unclear. The involvement of anti-myelin antibodies and activated macrophages as effector cells has been postulated. We investigated the synergistic action of the monoclonal antibody 8-18C5 against myelin/oligodendrocyte glycoprotein and recombinant interferon-gamma on demyelination after simultaneous injection into the subarachnoid space of Sprague-Dawley rats. After combined injection of anti-myelin/oligodendrocyte glycoprotein antibody and interferon-gamma, electrophysiological and morphological evidence for demyelination was found. Cervical somatosensory evoked potentials and cervical short-latency somatosensory evoked potentials were significantly delayed, and the demyelinated area in the spinal cord was significantly enlarged when compared to control rats injected with either compound alone. Injection of either an irrelevant antibody and interferon-gamma or of peritoneal macrophages without anti-myelin/oligodendrocyte glycoprotein antibody and interferon-gamma did not induce demyelination. Our data suggest that the deleterious effect of interferon-gamma on multiple sclerosis may be not only due to its effect on antigen presentation but also due to potentiation of demyelination.

Macrophages but not Schwann cells express Ia antigen in experimental autoimmune neuritis.

This study was designed to identify which cells express major histocompatibility complex class II (Ia) antigen in experimental autoimmune neuritis and may therefore be antigen presenters. Serial 1-micron-thick cryosections of ventral roots of animals with experimental autoimmune neuritis were labeled with Ox6 antibody against rat Ia, the ED1 antibody to identify monocytes/macrophages and an antiserum against S100, a marker for Schwann cells. Ia-positive cells were predominantly present before overt clinical signs and demyelination (day 12). At later stages when many axons were demyelinated, their number was markedly reduced. Few Ia-positive cells that had extending long processes, which over some distance were in immediate contact with several myelin sheaths, were scattered in normal-appearing nerve roots at these later time points. Most of the Ia-positive cells could be identified as ED1-positive lean monocytes/macrophages, but in contrast most phagocytic macrophages in advanced stages of myelin degradation no longer expressed Ia. Ia-positive structures were invariably negative for S100 at early and late stages of experimental autoimmune neuritis, indicating that Schwann cells did not express identifiable Ia antigen. These findings contrast with reports of expression of major histocompatibility complex class II antigens by Schwann cells in human neuropathies. Furthermore they do not support the notion that aberrant Ia expression by Schwann cells plays a major pathogenic role in experimental autoimmune disease of the peripheral nervous system.

[New aspects of the pathogenesis and therapy of Guillain-Barré syndrome and chronic polyneuritis]. / Neue Aspekte zur Pathogenese und Therapie des Guillain-Barré-Syndroms und der chronischen Polyneuritis.

The Guillain-Barré syndrome and chronic idiopathic polyradiculoneuropathy (CIDP) are examples of immune-mediated neuropathies. In the Guillain-Barré syndrome, antibodies directed to neutral glycolipids of peripheral nerve myelin have been detected that activate the complement system. There is evidence for the presence of circulating activated T lymphocytes. Humoral factors have been implicated in the pathogenesis of CIDP. The animal model experimental autoimmune neuritis lends itself to the elucidation of pathogenic immune mechanisms. The principal treatment is plasmapheresis. Further approaches to the therapy of the Guillain-Barré syndrome and CIDP are discussed.

The role of interferon-gamma in the pathogenesis of experimental autoimmune disease of the peripheral nervous system.

The role of interferon-gamma in the pathogenesis of experimental autoimmune disease of the peripheral nervous system was investigated. Administration of rat recombinant interferon-gamma markedly augmented both myelin-induced and T-cell line-mediated experimental autoimmune neuritis. Conversely, in vivo application of a monoclonal antibody to interferon-gamma suppressed the disease. Clinical and electrophysiological findings were corroborated by semiquantitative morphometric analysis. Mechanisms responsible for the enhancing effects of interferon-gamma include upregulation of major histocompatibility complex class II antigen expression in the nerve lesion, increased cellular influx of T cells and macrophages, and heightened macrophage activity with enhanced release of toxic oxygen species. These observations establish a pivotal role of the cytokine interferon-gamma in the pathogenesis of experimental autoimmune disease of the peripheral nervous system.

T cell activation in Guillain-Barré syndrome and in MS: elevated serum levels of soluble IL-2 receptors.

Guillain-Barré syndrome (GBS), chronic idiopathic demyelinating polyradiculoneuropathy (CIDP), and multiple sclerosis (MS) are disorders with presumed immunopathogenesis. To obtain evidence for T cell activation, we determined serum concentrations of soluble interleukin-2 receptors (sIL-2 R) in 50 patients with GBS, 24 with CIDP, and 54 with MS. Both in GBS and clinically active MS sIL-2 R levels were markedly increased compared with those in patients with other neurologic diseases. Four of 24 CIDP patients had abnormally increased sIL-2 R concentrations. sIL-2 R concentrations decreased with clinical improvement in serial samples taken from GBS patients, but were not otherwise correlated with disease severity. These data establish that T cells are activated in GBS and some patients with CIDP, and corroborate earlier evidence that activated T cells are circulating in the blood of MS patients.

Role of therapeutic plasmapheresis in chronic inflammatory demyelinating polyneuropathy.

Therapeutic plasmapheresis is an effective therapy in the management of CIDP. A varying percentage of patients, approximately 30 to 60%, may benefit from the treatment. The optimal frequency and volume of PE need to be clarified, but, taking into account the heterogeneity of the disease, a too rigid approach should be avoided. According to our experience, neither morphological findings on sural nerve biopsy, nor conduction slowing, conduction block, or the amount of spontaneous activity on needle electromyography in a weak muscle correlated clearly with the later outcome of PE. Possibly our patient number is too small to provide any statistically significant predictor of outcome. In our opinion it is essential to combine plasmapheresis with effective immunosuppression to avoid a rebound with overshooting synthesis of putative pathogenic antibodies or factors. Finally, IA with T-PVA columns has proven effective in single, case-controlled patients with CIDP. It may be a promising supplement to PE avoiding the need and risks of protein replacement.

The blood-nerve barrier in Wallerian degeneration: a sequential long-term study.

The blood-nerve barrier (BNB) for serum proteins was studied after a crush lesion of the murine sciatic nerve or after transsection with persistent Wallerian degeneration. Using single intraperitoneal injections of biotinylated human albumin, transferrin, IgG, and complement components as tracers, the integrity of the BNB during degeneration and regeneration was determined over time. In Wallerian degeneration induced by crush the BNB became increasingly leaky, with a maximum in the distal stump 8 days after crush (i.e., during early regeneration). When regeneration potentials could first be elicited from the small foot muscles and when thinly myelinated nerve fibers were present, the BNB gradually regained its barrier function and was nearly intact on day 30 after crush. After transsection breakdown of the BNB persisted beyond 30 days. The BNB leakage may foster repair by allowing exchange of trophic factors of large molecular size during nerve regeneration.

Recombinant interleukin-1 beta stimulates eicosanoid production in rat primary culture astrocytes.

Astrocytes may play a prominent role in the initiation of immunoinflammatory responses in the central nervous system. They can be induced to synthesize eicosanoids but how immunologically relevant molecules modulate this process is not known. We examined the influence of recombinant interleukin-1 (rIL-1), an immunomodulating monokine on the release of arachidonic acid metabolites. IL-1 (1-30 U) induced a dose-related elaboration predominantly of the cyclo-oxygenation products prostaglandin E and thromboxane B2. Preincubation of rIL-1 with a specific antibody abrogated and heat-inactivation destroyed this activity. Both mepacrine and the isoquinolinesulfonamide H7 blocked the stimulatory effect dose-dependently, indicating involvement of protein kinase C in this novel biologic activity of IL-1. In central nervous system inflammation, IL-1-evoked release from astrocytes of arachidonic acid-derived metabolites may influence the severity of phlogistic responses and modulate local immune reactivity.

Suppression of P2-T cell line-mediated experimental autoimmune neuritis by interleukin-2 receptor targeted monoclonal antibody ART 18.

The monoclonal antibody ART 18 directed to the rat interleukin-2 receptor (IL-2 R) was administered to Lewis rats immediately prior to and/or on consecutive days after adoptive transfer of autoreactive P2-T line lymphocytes. The effects of ART 18 and sham treatment on the development of adoptive transfer--experimental autoimmune neuritis (AT-EAN) were assessed by clinical inspection, serial electrophysiological monitoring, and semiquantitative histomorphological analysis. Early injection of ART 18 suppressed AT-EAN while treatment after appearance of clinical signs did not. Since the IL-2 R is expressed exclusively on proliferating T cells activated by antigen, the in vivo application of an IL-2 R-targeted monoclonal antibody allows for more selective immunosuppression of experimental autoimmune disease of the peripheral nervous system than has previously been achieved.

Electrophysiological investigations in adoptively transferred experimental autoimmune encephalomyelitis in the Lewis rat.

Lewis rats with experimental autoimmune encephalomyelitis transferred adoptively with myelin basic protein-specific T line cells (AT-EAE) were studied clinically, electrophysiologically, and histologically. Injection with 5 x 10(6) line cells induced EAE with a rapidly developing tetraplegia after a latent period of 4 days. Electrophysiological testing revealed a profound slowing of afferent conduction within the dorsal column of the spinal cord, and conduction abnormalities in the spinal roots. Injection with a lower cell dose of 1 x 10(6) T line cells caused only moderate clinical signs paralleled by milder conduction slowing and conduction failure. Light microscopy showed marked inflammation with infiltration of mononuclear cells and some demyelination throughout the spinal cord and roots. Inflammation and demyelination were dose dependent and the caudal parts of the spinal cord were more affected than the cranial parts. The peripheral nerves were free of electrophysiological and morphological alterations. Systemic treatment with 4-aminopyridine accelerated and partially restored conduction in the dorsal columns and roots, while increasing the body temperature had a detrimental effect, suggesting demyelination as a prominent pathophysiological mechanism. These findings show that in AT-EAE in Lewis rats the dysfunction of the central nervous system and of spinal roots is cell dose dependent, that the peripheral nervous system distal to the spinal roots is spared, and suggest that paranodal demyelination is an important pathogenic mechanism.