Comparative study of chronic aluminum-induced neurofilamentous aggregates with intracytoplasmic inclusions of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is characterized neuropathologically by chromatolysis, Bunina bodies, hyaline inclusions, skein-like inclusions and axonal spheroids. Aluminum, a known neurotoxin, is the cause of dialysis encephalopathy and is considered to be a causative agent in high incidence foci of ALS in the western Pacific. We have developed an experimental model of motor neuron degeneration in New Zealand white rabbits using chronic low-dose intracisternal administration of aluminum and compared the clinical and neuropathological changes to those of human ALS. Aluminum-inoculated rabbits developed progressive hyperreflexia, hypertonia, limb splaying, gait impairment, muscle wasting, hindlimb paralysis and impaired tonic immobility responses without overt encephalopathic features over a 14-month period. Examination of spinal cords from these animals demonstrated the frequent occurrence and progressive development of anterior horn cell lesions that included small, round, argentophilic perikaryal inclusions similar to hyaline inclusions seen in human ALS. Other inclusions were more condensed and eosinophilic, while still others had neurofibrillary tangle-like morphologies. Axonal spheroids and neuritic thickenings were also prominent and were identical to those seen in human ALS. We believe that the similar and progressive development of neuropathological changes observed in the chronic aluminum-intoxication model, compared to human ALS, warrants further study to aid in understanding the cellular and molecular mechanisms of human motor neuron disease.     

NT-3, but not BDNF, prevents atrophy and death of axotomized spinal cord projection neurons

Following spinal cord injury, projection neurons are frequently axotomized and many of the cells subsequently die. One goal in spinal injury research is to preserve damaged neurons so that ultimately they are accessible to regeneration-promoting strategies. Here we ask if neurotrophin treatment can prevent atrophy and death of axotomized sensory projection neurons. In adult rats, a hemisection was made in the thoracic spinal cord and axotomized neurons were retrogradely labelled with Fluoro-Gold. Four distinct populations of cells were identified in the lumbar spinal cord, and both numbers and sizes of labelled cells were assessed at different time points postlesion. A progressive and significant degeneration was observed over time with severe atrophy apparent in all cell populations and significant cell loss evident by 4 weeks postlesion. This time point was used to assess neurotrophin effects. Hemisected rats were treated with either neurotrophin 3 (NT-3) or brain-derived neurotrophic factor (BDNF, 12 microg/day for each), or a vehicle solution, delivered continuously to the lesion site via an osmotic minipump. Treatment with NT-3, but not BDNF, completely reversed cell atrophy in three of the four cell populations and also induced a significant increase in the number of surviving cells. In situ hybridization experiments showed trkB and trkC mRNA to be expressed in the majority of ascending spinal projection neurons, suggesting that these cells should be responsive to both BDNF and NT-3. However, only NT-3 treatment was neuroprotective, indicating that BDNF may not have reached the cell bodies of injured neurons. These results demonstrate that NT-3 may be of benefit in preventing the secondary cell loss that occurs following spinal injury.     

Metabolic consequences of alcohol dependency

Alcohol dependency leads to a variety of biochemical adaptations and morphological changes which may be considered as either adaptive or destructive. This ranges from the utilization of ethanol as a metabolic fuel, to overt tissue and cellular damage, and may lead to increases in morbidity and mortality. Virtually every organ system is affected by either acute and chronic ethanol exposure and numerous metabolic pathways are altered. As a consequence of these wide ranging effects, it is extremely difficult to cover every aspect of alcohol toxicity in a single review. Instead, attention is focussed on selected areas, such as nutrition and protein metabolism in the liver and bone (and to a lesser extent, skeletal muscle and the gastrointestinal tract). The aim is to illustrate the numerous ways in which alcohol affects the body.     

Localisation of insulin-like growth factor-I (IGF-I) immunoreactivity in the olivocerebellar system of developing and adult rats

The molecular mechanisms which underlie the development of the olivocerebellar topography are not fully understood. Insulin-like growth factor-I (IGF-I) is a growth factor known to play important roles in neural development and it has been identified within the cerebellum and the inferior olive. To assess the contribution of IGF-I to the development of climbing fibre topography, the distribution of IGF-I-like immunoreactivity (IGF-I IR) was identified in the cerebellar cortex and inferior olive of rats, 0, 3, 5, 7, 10, 15, 21, 28 and 90 days old. In the cerebellar cortex, IGF-I IR was localised solely to Purkinje cells and its distribution was spatially and temporally regulated in a manner which coincides with climbing fibre development. At birth, weak IGF-I IR was detected in a few Purkinje cells in the ventral vermis. More Purkinje cells became positive until at postnatal day 7(P7) all Purkinje cells displayed IGF-I IR. Subsequently, a subpopulation of Purkinje cells lost their reactivity for IGF-I to leave IGF-I-positive cells organised into sagittal bands by P15. IGF-I IR was also seen in all subdivisions of the inferior olive between birth and P10 in a distribution which paralleled the maturation of the inferior olive. The Purkinje cell and inferior olivary IGF-I IR parallels climbing fibre development and thus the results of this study support the hypothesis that IGF-I is involved in the development of climbing fibre topography.     

Influence of two weeks of non-weight bearing on rat soleus motoneurons and muscle fibers

OBJECTIVES: To analyse the ethical implications of informing patients about their do-not-resuscitate status (DNR). DESIGN: Questionnaire. SETTING: Nationwide, 6 months after the publication of guidelines on DNR in 1994. SUBJECTS: A 10% random sample of the members of the Swedish Cardiac Society. 104 physicians and 196 nurses. MAIN OUTCOME MEASURES: To what extent are patients, physicians and nurses involved in decisions about DNR, and how should the ethical conflict involved in informing patients about their DNR status be described and analysed? RESULTS: Of 73% responding, 84% of the physicians and 8% of the nurses had made a DNR decision. The decision was regarded as ethically right and well timed and it was discussed with 33% of the competent patients. Half of the respondents believed that DNR orders should be discussed with the competent patient. but still only one third of the patients are involved. The ethical conflict is analysed using the principles of autonomy and nonmaleficence as value premises. CONCLUSIONS: Many physicians are still reluctant to find out what the patient wants. Being ignorant they risk harming the patient. It is recommended that information about DNR status should be given incrementally and that the attitudes of the old and chronically ill in-hospital patients are studied. Do they want to be informed, and if so, how and when do they want it to be done?     

Chimeric bispecific OC/TR monoclonal antibody mediates lysis of tumor cells expressing the folate-binding protein (MOv18) and displays decreased immunogenicity in patients

The current environment in which medicine is taught and practiced requires that medical schools pay increased attention to the faculty member's roles, rewards, career development, and productivity. Medical schools must make strategic decisions about the allocation of resources that can nurture their faculties and support the activities in academic and community settings in which faculty are involved. From 1993 to 1995 Allegheny University of the Health Sciences (formerly Medical College of Pennsylvania and Hahnemann University) designed a comprehensive system for the professional development of faculty. This system is based upon expanded categories of faculty academic activity and scholarship. New programs were implemented to reorient faculty toward conducting and documenting the expanded array of scholarly activities. The main characteristics of the new system are the establishment of formally defined performance expectations, the vertical alignment of the individual faculty member's objectives with the department's mission and the school's mission, and an increasing emphasis upon faculty interdependence, accountability, and use of sound business practices. The authors describe these and other aspects of the design of the new system in detail and report initial results and lessons learned from the system's implementation, evaluation, and dissemination throughout the university. The long-term success of this comprehensive professional development program will be assessed over time by observing how this institution advances its mission in a well-planned and cost-effective manner that retains talented, productive, and professionally fulfilled faculty.     

Prevalence of diabetes in rural and urban populations in southern Sierra Leone: a preliminary survey

BACKGROUND: Immunodominant epitopes of Bet v 1a had been identified before, using recombinant (r) Bet v 1a-reactive T cell clones generated from peripheral blood mononuclear cells of patients allergic to birch pollen. This study aimed at evaluating the T cell-stimulating capacity of immunodominant Bet v 1a-derived peptides in a polyclonal system corresponding more closely to the situation in patients. METHODS: Short-term T cell lines (TCL) were established in presence of a protein extract of birch pollen (BP extract). TCL proliferation induced by the BP extract, by natural Bet v 1, rBet v 1a, rBet v 2 or 5 selected immunodominant Bet v 1a-derived peptides was determined. RESULTS: Consistent with the knowledge that Bet v 1 is the major IgE-binding allergen of birch pollen, we found comparable T cell reactivity to natural Bet v 1 and the BP extract within the majority of the TCL. Accordingly, the response to rBet v 2 was low compared with the reactivity to the BP extract. The response of the TCL to rBet v 1a proved to be highly heterogeneous. Furthermore, the TCL response to the 5 immunodominant Bet v 1a-derived peptides showed considerable diversity. The proliferative responses of most TCL (with one exception) following stimulation by these peptides were low, in relation to the expansion induced by the BP extract. CONCLUSION: These findings argue against the use of selected peptides derived from Bet v 1a in specific immunotherapy of patients with birch allergy.