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Background. Although thymomas are characterized histologically by a benign appearance, they have the potential for aggressive local invasion, and occasionally they metastasize. Case report. We describe a 47-year-old woman who recently presented to our clinic with asymptomatic spinal cord compressiondue to an intra-abdominal metastasis of a thymoma arising as the first site of metasfasis 21 years after the primary tumour was resected. Conclusions. For the patient presented here, radiotherapy and surgery were chosen over systemic therapy as the primary treatment modalities at the time of recurrence for two reasons. First, the patient had a single, isolated metastasis that occurred after a 2-decade disease-free interval; thus, preoperative radiotherapy followed by resection was potentially curative. Second, it was thought, on the basis of the retroperitoneal location of the recurrent tumour immediately below the diaphragm, that it possibly was not a haematogenously disseminated metastasis but a local pleural and lymphatic migration. Izhodišča. Čeprav so timomi histološko benigni tumorji, je lokalno njihova rašča lahko zelo agresivna, redko pa tudi metastazirajo. Prikaz primera. Opisujemo primer 47-letne bolnice, ki je bila pred 21 leti radikalno operiranazaradi timoma in nato postoperativno obsevana. K nam je bila napotenazaradi solitarne intraabdomimalne metastaze, ki je povzročala asimptomatsko utesnitev hrbtenjače. Bolnico smo zdravili s preoperativnim radikalnim obsevanjem, ki smo ga načrtovali s pomočjo magnetne resonance in računalniške tomografije, nato pa operirali. Operacija je bila narejena prav tako radikalno, brez zajetih robov. Po zdravljenju nismo opazili nevroloških motenj. Zaključki. Za lokalno zdravljenje z obsevanjem in operacijo smo se odločili, ker je poteklo kar 21 let od zdravljenja prvotnega tumorja in ker smo dopuščali možnost, da se je počasi rastoči tumor širil limfogeno preko plevralnega prostora v retroperitonealni, podobno kot mezoteliom.

Vascular dementia is the second cause of dementia after Alzheimer's disease. It is a broad term which includes dementia due to: single or multiple infarcts related to large vessel disease, subcortical ischemic pathology linked to small vessel disease, hemorrhages, and hypoperfusion. Furthermore, vascular and Alzheimer lesions often coexist leading to a mixed dementia. The diagnosis should be considered in the presence of dementia, clinical or neuroradiological signs of cerebrovascular disease and a plausible link between the two. Newly identified preventive strategies and encouraging results of recent trials using cholinesterase inhibitors or memantine suggest therapeutic potential.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) in which demyelination and axonal loss result in permanent neurologic disability. We examined the neuroprotective property of the immunosuppressant FK506 (tacrolimus), FK1706 (a nonimmunosuppressant FK506 derivative) and cyclosporin A (CsA) in a chronic relapsing experimental autoimmune encephalomyelitis (EAE) model of MS. Female SJL/J mice were immunized by subcutaneous (s.c.) injection with proteolipid protein 139-151 peptide in complete Freund's adjuvant. At the onset of paralysis, 12-14 days after immunization, mice received daily s.c. injections of FK506 (0.2, 1, and 5 mg/kg), FK1706 (5 mg/kg), CsA (2, 10, and 50 mg/kg), saline or vehicle (30% dimethylsulfoxide) for 30 days. FK506 (at a dose of 5 mg/kg) reduced the severity of the initial disease and suppressed relapses. FK1706 did not significantly alter the clinical course and CsA (at a dose of 50 mg/kg) lessened the severity of the initial episode of EAE but did not alter relapses. In the thoracic spinal cord, FK506 (5 mg/kg), FK1706 (5 mg/kg), and CsA (50 mg/kg) significantly (P < 0.001) reduced the extent of damage in the dorsal, lateral, and ventral white matter by a mean of up to 95, 68, and 30%, respectively. A nonimmunosuppressant dose of FK506 (0.2 mg/kg) also significantly (P < 0.001) reduced the extent of damage in the spinal cord by a mean of up to 45%. Other dosages of these compounds were ineffective. FK506 markedly protects against demyelination and axonal loss in this MS model through immunosuppression and neuroprotection.

We assessed the effects of FK506 administration on regeneration after a 6-mm gap repair with a collagen guide seeded with allogeneic Schwann cells (SCs) in the mouse sciatic nerve. SCs were isolated from predegenerated adult sciatic nerves and expanded in culture using a defined medium, before being seeded in the collagen guide embedded in Matrigel. Functional reinnervation was evaluated by noninvasive methods to determine recovery of motor, sensory, and autonomic functions in the hindpaw over 4 months postoperation. Histological analysis of the regenerated nerves was performed at the end of the study. Using simple collagen guides for tubulization repair, treatment with an immunosuppressant dose of FK506 (5 mg/kg/day) resulted in significant improvement of the onset and the degree of reinnervation. While the introduction of allogeneic SCs did not improve regeneration versus a collagen guide filled only with Matrigel, treatment with FK506 allowed for successful regeneration in all the mice and for significant improvement in the levels of functional recovery. Compared with the untreated group, there was greater survival of transplanted pre-labeled SCs in the FK506-treated animals. Morphologically, the best nerve regeneration (in terms of nerve caliber and numbers of myelinated axons) was obtained with SC-seeded guides from FK506-treated animals. Thus, FK506 should be considered as adjunct therapy for various types of tubulization repair.

An immunosuppressant drug that also possesses neuroregenerative properties, FK506 enhances the rate of axonal regeneration and improves recovery after nerve lesions. Nevertheless, prolonged immunosuppression may not be justified to assure the success of nerve regeneration. In this study, we compare the effects of continuous and discontinuous FK506 treatment on regeneration and reinnervation after sciatic nerve resection repaired with autologous or allogenic grafts in the mouse. For each type of repair, one group received FK506 (5 mg/kg) for 4 months, whereas a second group was treated with FK506 at 5 mg/kg for 5 weeks followed by 3 mg/kg for 4 weeks; a control group received saline only. Functional reinnervation was assessed by noninvasive methods to determine recovery of motor, sensory, and autonomic functions in the hind paw over 4 months after operation. Morphological analysis of the regenerated nerves was performed at the termination of the study. Autografts and allografts treated with sustained FK506 (5 mg/kg) reached high levels of reinnervation and followed a course of recovery faster than controls. The numbers of myelinated fibers also were similar. Allografts without immunosuppression demonstrated a slower rate of regeneration, exhibiting lower final levels of recovery compared with other groups and containing fewer numbers of regenerating myelinated fibers. Withdrawal of immunosuppressant therapy resulted in a decline in the degree of reinnervation in all functions tested during the third month, with stabilization between the third and fourth months. The number of regenerated myelinated fibers in the group was significantly lower than in autografts. Thus, continuous or discontinuous FK506 administration slightly accelerated the rate of reinnervation in autografts. In allograft repair, FK506 significantly enhanced both the rate and degree of regeneration and recovery, but its withdrawal resulted in graft rejection, a marked deterioration in function, and loss of regenerating fibers. Muscle Nerve 29: 812–822, 2004

Objective The present review analyzes long-term survival, recurrence sites, and toxicity in women with peritoneal spread of endometrial treated with abdominal radiotherapy, in order to provide therapeutic options as a function of disease spread and histology. Methods Retrospective medical record review was performed of 86 patients receiving abdominal radiotherapy for endometrial carcinomas from 1975 to 1995 at the University of Minnesota. Results FIGO stage distribution was 54 stage IIIA, 2 stage IIIB, 11 stage IIIC, and 19 stage IVB. Disease-free survivals were 55% at 5 years, 46% at 10 years, and 36% at 20 years. Recurrence rates were 16% for stage IIIA with one peritoneal site, 48% for stage IIIA with multiple peritoneal sites or stage IIIB or stage IIIC, and 72% for stage IVB. With univariate analysis, statistical significance was found for stage, gross peritoneal disease, nodal metastases, histology, concurrent chemotherapy, isolated adnexal spread, grade, angiolymphatic invasion, myometrial invasion, and age. Multivariate analysis found only stage, histology, and age to be significant. Most recurrences were pulmonary or peritoneal. Acute toxicity was acceptable. Six percent of patients required surgical intervention for small bowel obstructions. Conclusions Abdominal radiotherapy confers an excellent prognosis for women with stage IIIA cancers with one site of peritoneal involvement. Lack of randomized trials makes definitive treatment recommendations difficult to provide. Results are less optimal with multiple peritoneal sites of involvement, gross peritoneal spread, or papillary serous/clear cell pathology but a substantial number of such women can be cured as well.

Using the n-back task, we recently identified, in young subjects, a positive-negative event related potential component (PN(wm)) in a time-range window between 140 and 280 ms after stimulus onset representing an electrophysiological correlate of working memory load. To evaluate age-related electrophysiological changes in working memory processing, we applied the same neuropsychological paradigm and compared densities of the PN(wm) component in 17 young (mean age: 26) and 17 healthy elderly individuals (mean age: 75). Both age groups displayed a PN(wm) component during the two working memory tasks. For the 1-back task, densities were similar in both young and elderly individuals. In contrast, PN(wm) densities increased with higher memory load (2-back1-back) in the younger but not in the older group. This difference was mainly observed over parietal electrodes suggesting an impaired activation of neural generators within this brain region. The present results are consistent with the hypothesis of decreased brain reserve in the elderly and provide evidence for age-related deficits in the recruitment of posterior cortical neurons with increasing working memory load.

Acrylamide (AC) is a known industrial neurotoxic chemical that has been recently found in carbohydrate-rich foods cooked at high temperatures. Repeated AC administration produces a pronounced neuropathy characterized by flaccid paralysis and ataxia and represents a well-established animal model of progressive axonal loss. AC also elicits prominent morphologic alterations (e.g., eccentrically placed nuclei, infolding of the nuclear membrane, accumulations of dense bodies, and clusters of smooth endoplasmic reticulum (SER) associated with numerous microtubules) in cerebellar Purkinje cells that may contribute to the pronounced ataxia in these animals. Here, we examined the neuroprotective action of FK506 (tacrolimus) in male and female rats given daily intraperitoneal injections of AC (30 mg/kg) for 4 weeks. Daily subcutaneous injections of FK506 (2 mg/kg/day) dramatically reduced the behavioral signs of neuropathy (i.e., paralysis and ataxia), markedly protected against axonal loss (by 82% and 73% in the tibial nerves of male and female rats, respectively), and reduced the pathologic changes in Purkinje cells. In a separate study, subcutaneous injections of FK506 (2 or 10 mg/kg) for 2 weeks markedly increased heat shock protein-70 (Hsp-70) immunostaining in sensory neurons, motor neurons, Purkinje cells, and other regions of the brain (in particular, the amygdala) from nonintoxicated and AC-intoxicated rats compared to controls. In contrast, AC-intoxicated animals not given FK506 demonstrated reduced Hsp-70 staining. Thus, the ability of FK506 to increase Hsp-70 expression may underlie its neuroprotective action. We suggest that compounds capable of eliciting a heat shock response may be useful for the treatment of human neuropathies.

The new SYCAR resin is shown to have the desirable characteristics for a liquid encapsulant. Unlike epoxy-based encapsulants, this resin consists of a silicon-carbon backbone which is highly crosslinked during the cure reaction. The desirable characteristics of this resin include a low level of ionic contamination, low moisture absorption, high glass transition temperature, excellent dispensability, and long shelf life. Package level reliability results indicated that the SYCAR encapsulant outperformed the leading domestic and Japanese encapsulants and met the 144 h of autoclave, 1000 h of bias humidity, and 1000 cycles of thermal shock requirements for mold compounds. >

The development of good clinical systems has been impeded by the complexities of clinical medicine. The authors have described a strategy of clinical system development which exploits the benefits of the object-orientated paradigm notably the ability to represent a complex domain. Moreover, clinicians can easily assimilate OO analysis and then apply these techniques to their own domain. They have created a generic data model which is designed to allow representation of all areas of clinical practice and using this model as a common basis for system development will facilitate communication between disparate systems. >

SLICC (Slightly Larger than IC Carrier) is a chip-scale ball grid array (BGA) package currently under development at Motorola. The SLICC package consists of a solder-bumped integrated circuit (IC) which is flip-chip bonded to an interposer substrate-approximately 8 mils thick-and then underfilled with an encapsulant. Chip I/Os are routed to package I/Os through plated through holes (PTHs) in the interposer substrate. Package I/Os are composed of solder bumps (approx. 22.2 mils in diameter on a 32-mil pitch) attached to the bottom side of the interposer substrate. The most apparent benefit of the SLICC package is its utilization of the area efficiency associated with direct chip attach (DCA) technology, coupled with the assembly, test, and repair simplicity afforded by BGA-type packaging.

The polyketides FK506 (tacrolimus) and FK520 (ascomycin) are potent immunosuppressants that function by inhibiting calcineurin phosphatase through formation of an FKBP12-FK506/520-calcineurin ternary complex. They also have calcineurin-independent neuroregenerative properties in cell culture and animal models of nervous system disorders. Based on the crystal structure of the FKBP12-FK506-calcineurin complex, we deduced that the 13- and 15-methoxy groups of FK506 or FK520 are important for inhibition of calcineurin phosphatase but not for binding to FKBP12. By genetic modification of the FK520 gene cluster, we generated 13- and 15-desmethoxy analogs of FK520 that contain hydrogen, methyl, or ethyl instead of methoxy at one or both of these positions. These analogs bind FKBP12 tightly, have decreased calcineurin phosphatase inhibition and immunosuppressive properties, and enhance neurite outgrowth in cell cultures. A representative compound was also shown to accelerate nerve regeneration and functional recovery in the rat sciatic nerve crush model.

The neuropathological changes associated with normal brain aging and Alzheimer's disease involve specific cortical circuits. Extensive hippocampal alterations are correlated with age-associated memory impairment, while substantial neurofibrillary tangle formation in neocortical association areas of the temporal lobe is a prerequisite for the development of Alzheimer's disease. Several lines of evidence indicate that there is no correlation between senile plaque densities and the degree of dementia in this disorder. The cortical involvement in the ninth and tenth decades of life is different from that observed in younger patients in that parietal and cingulate areas are affected early in the course of Alzheimer's disease, and neocortical senile plaques densities are strongly correlated with the severity of dementia. Moreover, Alzheimer's disease pathology is characterized in these very old patients by high neurofibrillary tangle densities in the anterior CA1 field, but not in the entorhinal cortex and inferior temporal cortex. These patterns of lesion distribution are discussed in respect to the neurochemical, genetic and metabolic factors which may influence the neuronal vulnerability in Alzheimer's disease.

We compared the effects of FK506 administration on regeneration and reinnervation after sciatic nerve resection and repair with an autologous graft or with a silicone tube leaving a 6-mm gap in the mouse. Functional reinnervation was assessed by noninvasive methods to determine recovery of motor, sensory, and sweating functions in the hindpaw over 4 months after operation. Morphometric analysis of the regenerated nerves was performed at the end of follow-up. The nerve graft allowed for faster and higher levels of reinnervation in the four functions tested than silicone tube repair. Treatment with FK506 (for the first 9 weeks only) resulted in a slight, although not significant, improvement of the onset of reinnervation and of the maximal degree of recovery achieved after autografting. The recovery of pain sensibility and of the compound nerve action potentials in the digital nerves, which directly depend on axonal regeneration, showed better progression with FK506 than reinnervation of muscles and sweat glands, which require reestablishment of synaptic contacts with target cells. The myelinated fibers in the regenerated nerve showed a more mature appearance in the FK506-treated rats. However, FK506 showed a marginal effect in situations in which regeneration was limited, as in a silicone tube bridging a 6-mm gap in the mouse sciatic nerve. In conclusion, treatment with FK506 improved the rate of functional recovery after nerve resection and autograft repair.

Atherosclerotic dementia was described in the late 19th century by Binswanger (1894) and Alzheimer (1895) at a time when syphilis was a leading cause of dementia and mental illness. For most of the 20th century, senile dementia was thought to result from decreased cerebral perfusion due to vascular disease. However, in the mid-1970s, Alzheimer's disease (AD) became recognized as the main cause of dementia, and interest in dementia of vascular origin waned. Since then, the concept has broadened and newer criteria have been proposed that have taken advantage of evolving neuroimaging techniques. At the dawn of the 21st century, vascular dementia (VaD) remains an important cause of dementia and a diagnostic challenge (Bowler and Hachinski, 1996; Desmond, 1996; Gold et al., 1999; Chiu et al., 2000). Although preventive strategies are likely to be highly beneficial, effective therapeutic interventions have yet to developed (Hachinski, 1992).

The term frontotemporal dementia has been used to classify several clinical syndromes previously described based on a relatively homogeneous symptomatology. Patients in this diagnostic group present with an insidious and gradual change in personality and social conduct, early deficits of mental manipulation, sequencing and hierarchical organization processes, frontal-type amnesia, contrasting with preserved orientation, visuoconstructive and visuospatial abilities. Frontotemporal dementia may represent more than 20% of degenerative dementias and is currently considered as the third most common cause of dementia after Alzheimer's disease and Lewy body dementia. Biochemical and molecular genetic studies have made it possible to identify at least three biologically homogeneous subgroups of frontotemporal dementias: typical frontotemporal dementia cases with no tau or ubiquitin-positive neuronal and glial inclusions, two tauopathies, namely Pick's disease and frontotemporal dementia with parkinsonism linked to chromosome 17, and one ubiquitin-related disorder, the frontotemporal dementia with motor neuron disease. We provide here a detailed overview of current concepts regarding the clinical characteristics and etiopathogenesis of these conditions.

Neurofibrillary tangles, senile plaques, and neuronal loss are the three major pathologic hallmarks of Alzheimer's disease (AD); however, they are also observed in the course of normal brain aging. In recent years, the classical neuropathological description of these changes has been tentatively replaced by an integrative view, including morphological, biochemical, and molecular characteristics. The first part of this chapter focuses on the description of AD-related lesions and attempts to highlight possible relationships between their structure and hypotheses regarding their etiopathogenesis. Moreover, the time evolution and codependence of these lesions in the aged brain is discussed. The second part of this chapter provides a critical review of diagnostic systems for the neuropathological diagnosis of AD. Comparative analysis of these systems is presented with particular reference to their theoretical framework, validity, and acceptance.

The possible relationship between changes in islet cell mass and in islet neogenesis-associated protein (INGAP)-cell mass induced by sucrose administration to normal hamsters was investigated. Normal hamsters were given sucrose (10% in drinking water) for 5 (S8) or 21 (S24) weeks and compared with control (C) fed hamsters. Serum glucose and insulin levels were measured and quantitative immunocytochemistry of the endocrine pancreas was performed. Serum glucose levels were comparable among the groups, while insulin levels were higher in S hamsters. There was a significant increase in beta-cell mass (P

Several studies have demonstrated a good correlation between clinical severity and Braak’s neuropathological staging in Alzheimer’s disease (AD). However, nonagenarians and centenarians display a different pattern of cortical vulnerability to the neurodegenerative process compared to younger elderly, and it is not known whether correlations between clinical severity and neuropathological stages remain valid in this age group. To address this issue we compared Clinical Dementia Rating scale (CDR) scores and Braak stages in 116 patients over 90 years of age with either no cognitive impairment or very mild to severe AD. There is a strong positive correlation between CDR scores and Braak staging (Spearman coefficient = 0.66; P < 0.01). However, neuropathological staging does not distinguish cases with normal cognition (CDR 0) from those with mild cognitive changes (CDR 0.5). Unlike younger cohorts, Braak stages I and II are frequently associated with questionable dementia in this age group. Braak stage III overlaps with all CDR levels and correlates poorly with cognitive function. Braak stages IV or greater are consistently associated with at least mild dementia. Consistent with our previous neuropathological analyses of nonagenarians and centenarians, the present data suggest that the substantial involvement of the hippocampus which characterizes Braak stage IV is a key step in the development of overt clinical signs of dementia in the oldest-old. Moreover, they indicate that Braak staging represents a broad concept of the evolution of neurofibrillary tangles rather than a precise hierarchical model associated with a stepwise deterioration of cognitive abilities near the upper limit of life.

The authors examined the ability of FK506 to accelerate axonal regeneration of rat spinal cord axons in a peripheral nerve (PN) graft. Predegenerated autografts were produced by transecting the left tibial nerve 1 week prior to spinal cord implantation into the lumbar (L-3-L-4) spinal cord. Rats were given daily injections of either FK506 (5 mg/kg, subcutaneous) or vehicle for 21 days. The PN grafts from FK506-treated rats contained larger sized regenerating axons compared with vehicle-treated controls, and mean axonal areas increased by 25% at 7.5 mm along the PN graft. Fluoro-Gold retrograde labeling confirmed that the regenerating axons originated from the central nervous system. Unexpectedly, the majority (>50%) of neurons in the red nucleus were retrogradely labeled in the FK506-treated animals only. The results indicate that FK506 not only accelerates the elongation of spinal cord axons but also promotes regeneration of rubrospinal neurons.

Opioid addiction therapy includes successful detoxification, rehabilitation, and sometimes methadone maintenance. However, the patient may have physical, mental, and emotional pain while trying to achieve abstinence. A new detoxification technique that incorporates general anesthesia uses a high-dose opioid antagonist to compress detoxification to within 6 h while avoiding the withdrawal.After Institutional Review Board approval and detailed informed consent, 20 patients, American Society of Anesthesiologists status I-II, addicted to various opioids underwent anesthesia-assisted rapid opioid detoxification. After baseline hemodynamics and withdrawal scores were obtained, anesthesia was induced. After testing with 0.4 mg intravenous naloxone, 4 mg nalmefene, was infused over 2 to 3 h. After emergence, severity of withdrawal was scored before and after administration of 0.4 mg intravenous naloxone. After 24 h, patients began outpatient follow-up treatment while taking oral naltrexone.All 20 patients were successfully detoxified with no adverse anesthetic events. After the first post-treatment test dose of 0.4 mg naloxone, 13 of 20 patients had no signs of withdrawal and hemodynamic changes were minimal. Withdrawal scores were always very low and similar before and after detoxification. Three of 17 patients (18%) available for follow-up have remained abstinent from opioids since treatment (or = 18 months). Four other patients are clean after brief relapses.Anesthesia-assisted opioid detoxification is an alternative to conventional detoxification.

We examined whether the nerve regenerative property of FK506 exhibits a 'window-of-opportunity' corresponding to the time of injury for maximal efficacy in the sciatic nerve crush model. FK506 (5 mg/kg, s.c.) was administered over the 18-day period of study according to three dosage regiments: delayed (days 9-17), discontinuous (days 0-8) and continuous (days 0-17) administrations. Quantitation of axonal calibers and the extend of myelination in the soleus nerve at 18 days demonstrated that both delayed and discontinuous administrations were equally effective, arguing against a 'window-of-opportunity' for FK506 nerve regenerative effect. However, both protocols were less effective than continuous administration indicating that the compound needs to be given during the entire regenerative period to elicit maximal efficacy.

The neurotrophic property of the immunosuppressant drug FK506 (tacrolimus) is believed to depend on the 12-kDa FK506-binding protein (FKBP-12). Here, we show that FK506 maintains its neurotrophic activity in primary hippocampal cell cultures from FKBP-12 knockout mice. In human neuroblastoma SH-SY5Y cells, the neurotrophic action of FK506 (10 pM to 10 nM) is completely prevented by the addition of a monoclonal antibody (50-100 nM) to the immunophilin FKBP-52 (also known as FKBP-59 or heat shock protein 56), a component of mature steroid receptor complexes. By itself, the FKBP-52 antibody is also neurotrophic. The neurotrophic activity of dexamethasone (50 nM) is potentiated by FK506, whereas that of beta-estradiol (50 nM) is not altered, suggesting a common mechanisms of action. Geldanamycin (which disrupts mature steroid receptor complexes) is also neurotrophic (0.1-10 nM), whereas it reduces the neurotrophic activity of FK506 and steroid hormones (dexamethasone and beta-estradiol). Conversely, 20 mM molybdate (which prevents the disruption of mature steroid receptor complexes) decreases the neurotrophic activity of FK506, FKBP-52 antibody, dexamethasone, and beta-estradiol. In rats, FK506 (10 mg/kg s.c.) augments the regenerative response of regenerating motor and sensory neurons to nerve injury as shown by its ability to increase the axotomy-induced induction of c-jun expression. A model is proposed to account for the neurotrophic action of both neuroimmunophilin ligands (FK506) and steroid hormones. Components of steroid receptor complexes represent novel targets for the rational design of new neurotrophic drugs.

Objective: To examine the neuroanatomic correlates of visual agnosia in AD. Methods: The authors performed an anterograde clinicopathologic study of 23 patients with clinically and neuropathologically confirmed AD in a 305-bed acute care geriatric hospital and a 165-bed acute care psychiatric hospital. The presence of apperceptive visual agnosia was assessed using the Ghent’s overlapping figure test and the Gottschaldt’s hidden figure test. Associative visual agnosia was examined using the conceptual items of the Columbia Mental Maturity Test. Correlations between neurofibrillary tangle (NFT) and senile plaque (SP) densities and visual agnosia were studied using forward stepwise logistic regression. Results: A statistically significant relation was found between NFT densities in Brodmann’s areas 18, 19, and 37, and associative visual agnosia, whereas NFT densities in the areas studied did not correlate with the presence of apperceptive visual agnosia. Senile plaque counts did not correlate with any of the neuropsychological parameters. Conclusions: These results support the existence of a dichotomy between associative and apperceptive agnosia, and show that only the former is related to the damage of secondary and high-order visual association areas in AD. In addition, the results suggest that SP densities do not represent a valuable pathologic correlate of visual agnosia in this disorder.

FK506, an immunosuppressant drug used to prevent allograft rejection in organ transplantations, accelerates functional recovery and nerve regeneration in the rat sciatic nerve crush model. While the mechanism by which FK506 increases regeneration is unknown, in contrast to immunosuppression, it does not involve calcineurin inhibition. Using the reverse-transcriptase polymerase chain reaction (RT-PCR) technique and a digoxigenin-labeled probe, we show that subcutaneous injections of FK506 (10 mg/kg/day) markedly increases the level of axotomy-induced growth-associated protein (GAP-43) mRNA in dorsal root ganglion (DRG) neurons. Quantitation of DRG neurons revealed that FK506 produced a 33% increase in the numbers of neurons exhibiting intense staining. Increased synthesis of GAP-43 may play a role in FK506's ability to speed nerve regeneration.

We have generated a transgenic mouse model in which female mice develop ductal mammary adenocarcinomas and male mice develop prostatic adenocarcinomas by using a transgene containing the hormone-responsive rat prostatic steroid binding protein 5' flanking region C3(1) fused to the simian virus 40 (SV40) large T antigen. We have identified some genetic alterations during mammary and prostate tumor progression: (i) p53 is functionally inactivated during mammary cancer development without p53 mutations; (ii) Alterations in apoptosis during mammary tumor progression are p53 and bcl-2 independent; (iii) Ha-ras mutations occur early in the development of prostate cancer. This unique animal model offers the opportunity to study multistep tumorigenesis in these organs.

This is the burning issue of the hour. In attempting to resolve it within the context of advanced age, it is important to clarify the meaning of the words involved: Independence and autonomy are far from being synonyms. Independence refers to the ability to perform physical activities of daily living (bathing, eating, preparing meals, shopping, money management), whereas the second word, autonomy, refers more to the ability to make decisions, to reason, to express an appropriate opinion in a given situation. Hazard and inevitability are totally at variance. Hazard implies the likelihood of occurrence of an event harmful to health, or to the length or quality of life. Hazard is more or less predictable, whereas inevitability is the expression of a supernatural power controlling all events. To find out whether "dependency is a hazard or an inevitability", it is necessary to conduct a historical review of the extension in human longevity and in particular of the current "weight" of aging both on individuals and on society at large. In Geneva, the proportion of the over 65-year-olds grew from 5.1 percent in 1880 to 13.4 percent in 1990. During that time, the gain in life expectancy was 52.4 percent for Geneva males of 80 years of age and 93 percent for Geneva females of the same age. This drastic change in age groups was coupled with a noteworthy change in household sizes. In 1860, the number of persons per household was 4.5. In 1990, it was down to 2.2. Conversely, the number of inmates in Geneva's medico-social institutions went up from 649 to 1168 between 1982 and 1992. In this socio-economic and cultural perspective, the concept of "globality of the individual" throughout his lifetime explains: age-related physiological changes; the long-term repercussion of physical, professional or leisure activities; the consequences of the accumulation of such varied risk factors as overweight or its opposite, malnutrition, tobacco or stress. Such frailty caused by aging is an ideal breeding ground for disease. For now, what matters most is the functional consequence of disease. Is the disease acute or chronic? Two out of three deaths result from a chronic disease, which caused loss of function by organs (impairment), loss of function by the subject himself (disability) or loss of function by the individual in society (social handicap or disadvantage). Raising the question "Dependency: a hazard or an inevitability?" boils down to asking oneself about the place of disease in our society and its determinants, and about all aspects of medicine and especially of prevention. When detected, a susceptibility brings into play primary prevention, aimed at averting the onset of the disease. After a disease has set in, measures to prevent recurrence, or secondary prevention, are required. Lastly, prevention of dependency and of loss of autonomy is part of tertiary prevention. Except for violent traumatic accidents, the formulation of the above concepts proves that dependency is essentially "a hazard". Therefore, let us anticipate!

Faculty and students at the University of Washington forge interdisciplinary partnerships with the regional community to restore damaged habitats.

The new immunosuppressant drug FK506 (Tacrolimus) increases the rate of nerve regeneration in vivo (Gold et al., 1994; Gold et al., 1995). In the present study, we have examined the dose-dependence of FK506's ability to enhance nerve regeneration. In the first set of experiments, rats received daily s.c. injections of FK506 (2 mg/kg, 5 mg/kg or 10 mg/kg) for 18 days after a sciatic nerve crush injury. Signs of functional recovery in the hind feet appeared earlier than in saline-treated control rats at all three FK506 dosage; recovery was maximally accelerated in the 5-mg/kg group. Light microscopy at 18 days after nerve crush revealed more regenerating myelinated fibers in FK506-treated rats than in controls; this was most apparent in the 5-mg/kg group. Morphometric analysis of axonal areas in the soleus nerve confirmed that axonal calibers were maximally increased in the 5-mg/kg group. In the second set of experiments, the rate of axonal regeneration was determined by radiolabeling the L5 dorsal root ganglion. Regeneration rate for sensory axons was maximally increased (by 34%) in the 5-mg/kg group. In contrast, cyclosporin A (10 or 50 mg/kg; dosages were selected on the basis of the 1/10 lower potency of cyclosporin A) did not significantly alter the rate of axonal regeneration. Cyclosporin A (50 mg/kg) also failed to increase functional recovery or axonal calibers in the soleus nerve. Because the two drugs share a common mechanism for producing immunosuppression (i.e., calcineurin inhibition), these results indicate that FK506's nerve regenerative property involves a distinct, calcineurin-independent mechanism.

To develop unilateral, chronically elevated intraocular pressure in rats, episcleral veins were injected with hypertonic saline and the intraocular pressure was monitored with a Tono-Pen XL tonometer. Histologic analyses of eyes with differing degrees and durations of intraocular pressure elevation were performed to ascertain the effects of these pressures on the optic nerve. Out of 20 consecutive animals, nine had elevations of intraocular pressure following a single injection, while subsequent injections raised intraocular pressure in seven others. One eye became hypotonous. In the remaining animals, subsequent injections sufficient to raise intraocular pressure were deliberately withheld, to determine the possible direct effects of injections on the optic nerve. Mean sustained pressure elevations ranged from 7 to 28 mm Hg and the retinal vasculature remained perfused in all eyes. Optic nerve cross sections from eyes without intraocular pressure elevation appeared identical to those from uninjected eyes, while nerves from eyes with the greatest intraocular pressure rise demonstrated axonal damage that involved 100% of the neural area. Eyes with either less severe pressure elevations or shorter durations showed partial damage, ranging from 0.5% to 10.4% of the neurla area. In 70% of these nerves, damage was concentrated in the superior temporal region. Within the optic nerve head, often associated with astrocytes, axons contained abnormal accumulations of membrane-bound vesicles and mitochondria. The anterior chamber angles showed sclerosis of the trabecular meshwork with anterior synechiae, but Schlemm's canal, collector channels and aqueous veins appeared patent. Unilateral sclerosis of the trabecular meshwork produces sustained elevation of intraocular pressure in rats with optic nerve damage that in many ways resembles that seen in human glaucoma. Understanding the mechanism of nerve damage in this model may provide new insights into the pathogenesis of human glaucoma.

Non-insulin-dependent diabetes mellitus (NIDDM) and dementia are both characterized by high prevalence in later life (Muller, 1993). Differences in prevalence of NIDDM according to regions and races are well-known. In an industrialized society, with a predominantly white population, the rate of NIDDM increases linearly starting from 35 years old, reaching 15% at the age of 75 (Wilson et al., 1986) and 20% at the age of 80 (Morley and Perry, 1991). As for Alzheimer’s Disease (AD), it follows an exponential curve starting from the age of 50, reaching 30% for the 85 year-old population (Skoog et al., 1993).

A field campaign was carried out during May 1994 at the Izaña station, Tenerife. This campaign was part of the program Environment and Climate sponsored by the European Commission to study the influence of European emissions on the oxidizing capacity of a clean tropospheric environment. Daytime and also nighttime measurements were made, covering the OH as well as the NO3 chemistry. This paper presents the OH measurements taken with a multipass optical absorption spectrometer (MOAS) and discusses the daytime chemistry in a statistical and therefore more preliminary way. All relevant parameters influencing the OH concentration were monitored. From the data the two main contributions to the OH production can clearly be discerned and are given by the primary production following the ozone photolysis and the O(1D)-H2O reaction and by the catalytic reactions of NOx in the recycling process. The latter processes prove to contribute a dominant part to the OH concentration. The measurements of the nonmethane hydrocarbons (NMHC) especially of the biogenics, indicate a considerable influence of the NMHC on the absolute values of the OH concentration at Tenerife. This work has been financially supported by the European Commission (grant EV5V-CT93-0321), by the DFG, and by the Fonds der Chemischen Industrie, which is gratefully acknowledged.

Alterations in apoptosis and associated mechanisms during mammary tumor progression were investigated in transgenic mice expressing the SV40 large T antigen (T(AG)) driven by the rat prostatic steroid-binding protein C3(1) 5'-flanking region. Apoptosis levels, assessed by in situ end labeling, were low in normal mammary epithelial cells, highest in atypical hyperplasias (preneoplastic lesions), and less pronounced in adenocarcinomas. Preneoplastic cells maintain the ability to undergo apoptosis as a mechanism of tumor growth suppression, but this critical control of apoptosis is lost as these lesions progress to carcinomas. These alterations in apoptosis occur during mammary tumor progression in mice containing wild-type p53+/+ genotype as well as in mice with the p53-/- genotype. Thus, apoptosis in this tumor model occurs through a p53-independent mechanism. Because other studies have demonstrated p53-dependent apoptosis in T(AG)-induced choroid plexus tumors of transgenic mice, we propose that the role of p53 in apoptosis may be tissue-specific. In addition, bcl-2 protein was not expressed in any mammary lesions. SV40 T(AG) expression, which correlated with the nuclear p53 protein at all stages of tumor progression, was low in normal mammary epithelial cells, moderately high in atypical hyperplasias, and strongly expressed in adenocarcinomas. No p53 mutations were found at any stage of mammary adenocarcinoma development, suggesting that tumor progression does not require a dominantly acting p53 mutation in this transgenic model. p2l(Waf1/Cip1), a cyclin-dependent kinase inhibitor, was expressed in normal mammary tissue but was not detected in the mammary carcinomas, despite high nuclear accumulation of wild-type p53 protein, suggesting functional loss of p53 due to binding of SV40 T(AG), to p53. These findings suggest that suppression of apoptosis during the transition from atypical hyperplasia to adenocarcinoma appears to be a critical event for mammary cancer development in C3(1)/T(AG) transgenic mice and occurs by p53- and bcl-2-independent pathways.

The present commercial market supports many nonsteroidal endocardial pacing leads of differing construction. In order to compare the performance of these configurations, we studied the long-term pacing properties of three representative lead types by randomized clinical trial in 99 patients undergoing a first elective VVI implant. Thirty-one patients received sintered platinum leads, 36 activated pyrolytic carbon leads, and 32 vitreous carbon leads. All received generators capable of noninvasive threshold testing. Acute sensing parameters were R wave amplitude and ST segment elevation measured from the endocardial electrogram. Noninvasive voltage thresholds were measured at implantation, 2 days, 1, 3, and 6 months, and yearly thereafter for 5 years. There were no significant differences between leads in pacing or sensing capabilities at implantation. All three demonstrated similar increases in thresholds, peaking at 1 month, then falling to a plateau by 6 months and did not vary significantly thereafter. There were no significant differences in thresholds between leads during 5 years of follow-up. The lowest mean threshold at 5 years was 0.93 V at 0.5 ms. This study suggests that: (1) although these lead types all perform well, none offers any particular clinical advantage over another; (2) the degree of early threshold peaking precludes immediate postimplant output reduction, but later thresholds are sufficiently low to enable reductions in pacing output; (3) safe low energy pacing requires greater attention to the lead-generator combinations; (4) data obtained at subsequent annual follow-up provided no additional useful clinical information to that obtained at 1 year; and (5) in the absence of other differences, cost can be the deciding factor in lead selection.