Protective autoimmunity and prospects for therapeutic vaccination against self-perpetuating neurodegeneration.
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Animals↗
Biomedical subjects
M Schwartz
Publications and source records attributed to M Schwartz.
Self and non-self discrimination is needed for the existence rather than deletion of autoimmunity: the role of regulatory T cells in protective autoimmunity.
Autoimmune T cells have been viewed for decades as an outcome of immune system malfunction, and specifically as a failure to distinguish between components of self and non-self. The need for discrimination between self and non-self as a way to avoid autoimmunity has been repeatedly debated over the years. Recent studies suggest that autoimmunity, at least in the nervous system, is the body's defense mechanism against deviations from the normal. The ability to harness neuroprotective autoimmunity upon need is evidently allowed by naturally occurring CD4+CD25+ regulatory T cells, which are themselves controlled by brain-derived compounds. These findings challenge widely accepted concepts of the need for discrimination between self and non-self, as they suggest that while such discrimination is indeed required, it is needed not as a way to avoid an anti-self response but to ensure its proper regulation. Whereas a response to non-self can be self-limited by a decreased presence of the relevant antigen, the response to self needs a mechanism for strict control, such as that provided by the naturally occurring regulatory T cells.
Animals↗
Accurate method for clinical assessment of right lobe liver weight in adult living-related liver transplant.
INTRODUCTION: Prior to transplantation of segmental liver grafts to adult recipients, it is crucial to confirm that the graft size is safe for the donor, yet adequate for the recipient's metabolic needs. Computed tomography (CT) and magnetic resonance imaging (MRI) are the current best standards. We applied a new formula to estimate right liver lobe weight in living donors and compared our results with CT and MRI. METHODS: Between August 1998 and December 20, 91 adults received right lobes from living donors. Donor liver volumes were assessed by CT or MRI. Actual weights of right lobe grafts were determined after back table flushing. We estimated whole liver weights using the formula: 772 x body surface area (BSA). Right lobe liver weight was calculated as 57% of the estimated whole liver weight (R-57). RESULTS: Mean actual right lobe weight (n = 90) was 855.83 +/- 183.4 g. Estimated right lobe weight was 858.08 +/- 90.80 (R-57, P = NS); 1077.35 +/- 263.07 mL for CT (P = .0001), and 1185.07 +/- 350.10 mL for MRI (P = .0001). Mean graft-recipient weight ratio (GRWR) was 1.23%; there was no significant difference with R-57 GRWR but there was a difference from CT and MRI-GRWR (P = .001). The proportion of cases of estimated right lobe weight and GRWR within 20% of the corresponding actual value were 80% and 90%, respectively, for R-57 versus 36% and 43% for the imaging studies (P = .0001). CONCLUSION: With readily available software to calculate BSA, physicians can predict right lobe weight knowing only the donor's height and weight. CT and MRI will only be necessary for anatomic liver mapping.
Adult↗
Use of the normalcy index for the evaluation of gait pathology.
The normalcy index (NI) has been proposed as a method for quantifying the amount of deviation in a subject's gait, compared to the gait of the average unimpaired person. The NI was computed for a sample of 144 children affected by cerebral palsy, five idiopathic toe-walkers and 12 able-bodied subjects. It was sensitive enough to distinguish unimpaired subjects from idiopathic toe-walkers and to distinguish between the plegic and uninvolved limbs of hemiplegic patients. The NI was robust enough to categorize pathology, ranging from mild disorders to quadriplegia. The NI was found to be clinically applicable, reliable and easy to use, making it a valuable element in the quantitative evaluation of gait pathology.
Adolescent↗
Delineation of brain metastases on CT images for planning radiosurgery: concerns regarding accuracy.
Conformal radiotherapy requires confidence that the images used for target delineation accurately reflect the pathological dimensions of the target. Radiosurgery, which is a conformal radiotherapy technique, is often used to treat brain metastases. The images of brain metastases can be affected by the method of image acquisition. A prospective study was undertaken to evaluate the effect of delay on CT images of brain metastases selected for radiosurgical treatment. A median delay from contrast administration of 65 min resulted in an increase in the volume of the metastases in 86% of cases when compared with the volumes of the same metastases determined from CT images acquired immediately following the administration of contrast medium. The magnitude of the increase in volume was sufficient to cause radiosurgery planners to select larger collimator sizes for radiosurgery plans based on the delayed CT images in 92% of cases. No significant intraobserver or interobserver variation was found in the group of radiosurgery planners. Differences in image acquisition may account in part for the differences in local control reported in the radiosurgical treatment of brain metastases.
Brain Neoplasms↗
Systematic errors in DFT calculations of haloalkane heats of formation.
The B3LYP and B3PW91 density functionals were employed with a large [BS1 = 6-311+G(3df,2p)] and small [BS2 = 6-311G(d,p)] basis set to compute enthalpies of formation (at optimized MP2/6-31G(d) geometries and with scaled HF/6-31G(d) frequencies) in the following series of haloalkanes: (1) the 15 fluoro-, chloro-, and chlorofluoromethanes, (2) the 18 fluorinated and chlorinated ethanes. Similar to earlier higher level calculations on haloalkanes, the computed enthalpies exhibited very large, systematic deviations from experiment. It was found that these errors could be largely eliminated using a very simple Bond Additivity Correction (BAC) formula, Delta(f)H degrees (BAC) = Delta(f)H degrees (calc) - n(CX). Delta(CX) [X = F, Cl], in which the BAC parameters, Delta(CF) and Delta(CCl) were determined by fitting the equation to experimental data on the four fluoroethanes and chloroethanes, respectively. The resultant BAC corrected enthalpies of formation are in excellent agreement with experiment, with RMS deviations in the same range as quoted RMS errors in measured enthalpies. Therefore, this simple BAC procedure may be utilized to provide reliable semiquantitative estimates of enthalpies of formation in larger haloalkanes, for which higher level ab initio calculations are not feasible.
Journal Article↗
Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis.
Therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1) protects motor neurons against acute and chronic degenerative conditions. In acute degeneration after facial nerve axotomy, the number of surviving motor neurons was almost two times higher in Cop-1-vaccinated mice than in nonvaccinated mice, or in mice injected with PBS emulsified in complete Freund's adjuvant (P < 0.05). In mice that express the mutant human gene Cu/Zn superoxide dismutase G93A (SOD1), and therefore simulate the chronic human motor neuron disease amyotrophic lateral sclerosis, Cop-1 vaccination prolonged life span compared to untreated matched controls, from 211 +/- 7 days (n = 15) to 263 +/- 8 days (n = 14; P < 0.0001). Our studies show that vaccination significantly improved motor activity. In line with the experimentally based concept of protective autoimmunity, these findings suggest that Cop-1 vaccination boosts the local immune response needed to combat destructive self-compounds associated with motor neuron death. Its differential action in CNS autoimmune diseases and neurodegenerative disorders, depending on the regimen used, allows its use as a therapy for either condition. Daily administration of Cop-1 is an approved treatment for multiple sclerosis. The protocol for non-autoimmune neurodegenerative diseases such as amyotrophic lateral sclerosis, remains to be established by future studies.
Acute Disease↗
The UCSC Genome Browser Database.
The University of California Santa Cruz (UCSC) Genome Browser Database is an up to date source for genome sequence data integrated with a large collection of related annotations. The database is optimized to support fast interactive performance with the web-based UCSC Genome Browser, a tool built on top of the database for rapid visualization and querying of the data at many levels. The annotations for a given genome are displayed in the browser as a series of tracks aligned with the genomic sequence. Sequence data and annotations may also be viewed in a text-based tabular format or downloaded as tab-delimited flat files. The Genome Browser Database, browsing tools and downloadable data files can all be found on the UCSC Genome Bioinformatics website (http://genome.ucsc.edu), which also contains links to documentation and related technical information.
Animals↗
Intramuscular injection of botulinum toxin as an adjunct to arthrocentesis of the temporomandibular joint: preliminary observations.
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Adult↗
Severe phenotype despite high residual glutaryl-CoA dehydrogenase activity: a novel mutation in a Turkish patient with glutaric aciduria type I.
We report the first patient with the homozygous GCDH mutation M263V, displaying a high residual activity in fibroblasts of 30%, but presenting with a severe clinical phenotype.
DNA Mutational Analysis↗
Successful use of B-domain deleted factor VIII for resection of pituitary adenoma in a paediatric patient with severe haemophilia A.
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Adenoma↗
A tale of three aspirations: foreign bodies in the airway.
Tracheobronchial foreign body aspiration is a serious medical problem, with clinical manifestations ranging from acute asphyxiation to insidious lung damage, as demonstrated by the three presented cases. Patient 1 aspirated during dinner, emergency bronchoscopy retrieved pieces of food, and she fully recovered the following day. Patient 2 presented with recurrent pneumonia and a right lower lobe lung abscess. After right lower lobectomy, pathology revealed a foreign object in the right main stem bronchus, a peanut aspirated one year earlier. Patient 3 became unresponsive several days after spinal surgery. The differential diagnosis included myocardial infarction, stroke, and foreign body aspiration. The patient died and necropsy revealed a foreign body in the right main stem bronchus (cooked meat). Thus, foreign body aspiration is not always suspected clinically, and the pathologist may play an important role in making the diagnosis. Histological identification of the aspirated material may be necessary for definitive diagnosis. Therefore, sections of commonly aspirated foods are presented, together with a 10 year history of aspirated objects received by this institution's surgical pathology department.
Aged↗
No correlation between phenotype and genotype in boys with a truncating MECP2 mutation.
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Adult↗
Erroneous genetic sex determination of a newborn twin girl due to chimerism caused by foetal blood transfusion. A case report.
OBJECTIVE: We present a case of erroneous sex determination in a newborn twin girl (twin A) due to chimerism. CASE REPORT: Amniocentesis and ultrasound examination had pointed towards male sex of both twins. At birth, twin A presented as a phenotypically normal female with 46,XY karyotype, and 46,XY gonadal dysgenesis was suspected. Twin B was a normal male. RESULTS: In our department, further examinations of twin A included undetectable testosterone and inhibin-B and elevated FSH. Ultrasound suspected an infantile uterus, and sequencing of the SRY gene was normal. After gonadectomy, a 46,XX karyotype was demonstrated in both normal infantile ovaries and in the fibroblasts from a skin biopsy. Analysis of X-linked markers in DNA from blood lymphocytes in both twins was identical, consistent with 46,XY karyotypes. CONCLUSION: Twin A is a 46,XX female with a chimeric 46,XY blood cell line due to intrauterine transfusion from her twin brother.
Blood Cells↗
Neuroprotection as a treatment for glaucoma: pharmacological and immunological approaches.
Primary open-angle glaucoma is a chronic, progressive optic neuropathy associated with a gradual decline in visual function, which may lead to blindness. In most cases, the optic neuropathy is associated with increased intraocular pressure. It is now generally accepted, however, that normalization of pressure, although necessary, is often not-sufficient as a remedial measure. This is because of the existence of additional factors, some of which emerge as a consequence of the initial damage. This situation is reminiscent of the response to a traumatic axonal insult, in which some of the damage is immediate and is caused by the insult itself, and some is secondary and is caused by a deficiency of growth-supportive factors as well as by toxic factors derived from the damaged tissue. Accordingly, the author has suggested that glaucoma may be viewed as a neurodegenerative disease and consequently amenable to any therapeutic intervention applicable to neurodegenerative diseases. There is evidence that neuroprotection can be achieved both pharmacologically and immunologically. Pharmacologic intervention neutralizes some of the effects of the nerve-derived toxic factors and possibly increases the ability of the remaining healthy neurons, at any given time, to cope with the stressful conditions. Immunologic intervention boosts the body's repair mechanisms for counteracting the toxicity of physiologic compounds acting as stress signals.
Animals↗
How does fluoride concentration in the tooth affect apatite crystal size?
Despite fluoride's (F) well-documented ability to prevent caries, the effects of F concentrations on enamel and dentin apatite crystals are unknown. The present study examined the hypothesis that tooth F concentration and tooth crystallite size correlate. One hundred human unerupted third molars were studied-53 from Fortaleza-Brazil (F water 0.7 ppm), 23 from Toronto (1.0 ppm), and 24 from Montreal (0.2 ppm). F concentration was analyzed by Neutron Activation Analysis and apatite crystal size by powder x-ray diffraction. A positive correlation between dentin F concentration and enamel crystallite length and width was found. Enamel crystallite length was significantly greater in teeth from Fortaleza than in teeth from Toronto (p = 0.011) and Montreal (p = 0.003). Enamel crystallite widths were significantly greater in Fortaleza teeth compared with those from Toronto (p = 0.020) and Montreal (p < 0.001). No difference in the dentin crystallite size was seen in the 3 regions. Thus, tooth F concentration and crystallite size correlate.
Analysis of Variance↗
Multiple mtDNA deletions with features of MNGIE.
Two sisters developed gastrointestinal malabsorption with pain and unsteady gait due to polyneuropathy at age 15. Both had ophthalmoplegia, neurogenic EMG, and COX-negative muscle fibers. One patient had low muscle complex I-IV activity, multiple mtDNA deletions, and depletion, but no thymidine phosphorylase (TP) or dNT-2 gene mutations. TP activity and brain MRI were normal. The condition resembles mitochondrial neurogastrointestinal encephalomyopathy, except for the absence of leukoencephalopathy, and is likely caused by a nuclear DNA mutation that disrupts intergenomic signaling.
Adult↗
Effects of androstenedione on long term potentiation in the rat dentate gyrus. Relevance for affective and degenerative diseases.
We studied the effects of the androgenic hormone androstenedione, a 17-ketosteroid, on long term potentiation (LTP) in the dentate gyrus (DG) of intact, urethane anesthetized rats. Intravenous injection of 10mg of the hormone dissolved in Nutralipid produced a significant increase of the population spike (PS), but not of the excitatory post-synaptic potentials (EPSPs). The results are discussed in terms of the potential enhancement that androstenedione may have on some aspects of memory processes as reported for other androgenic steroids. Also noted are the plausible beneficial effects of the hormone on depression as well as in recovery following both central and peripheral neural injury.
Action Potentials↗