Technical advances, financial problems and ethics.
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Ethics, Medical↗
Biomedical subjects
M Aebi
Publications and source records attributed to M Aebi.
Immunolocalization of type X collagen in human lumbar intervertebral discs during ageing and degeneration.
Type X collagen has so far not been reported to occur in human intervertebral discs. The objective of this study was therefore to investigate the occurrence of type X collagen in human lumbar intervertebral discs during ageing and degeneration. Ninety intervertebral discs with adjacent endplates were excised in toto from individuals (0-86 years) without known spinal disease and were processed for routine decalcified histology. Appropriate slices of each disc were processed for immunohistochemistry using a type-specific, monoclonal antibody raised against human type X collagen. Each intervertebral disc was examined for macroscopic and histomorphological features of disc degeneration. Immunohistochemically, a positive specific type X staining was observed in the hypertrophic zone of the growth plate and only in the interstitial matrix of juvenile (<2 years) nucleus pulposus. In adult discs, type X collagen could be localized in conjunction with advanced disc degeneration and first occurred in the disc matrix (i.e., pericellular region) of a 47-year-old specimen. Positive type X staining of the disc matrix was more frequently found in senile (>70 years) discs with end stages of disc degeneration. This study provides the first evidence for the occurrence of type X collagen in human lumbar intervertebral discs and it appears that type X collagen is re-expressed in late stages of disc degeneration.
Adolescent↗
Restriction enzyme-mediated DNA integration in Coprinus cinereus.
Restriction enzyme-mediated DNA integration (REMI) has recently received attention as a new technique for the generation of mutants by transformation in fungi. Here we analyse this method in the basidiomycete Coprinus cinereus using the homologous pabI gene as a selectable marker and the restriction enzymes BamHI, EcoRI and PstI. Addition of restriction enzymes to transformation mixtures results in an earlier appearance of transformants and influences transformation rates in an enzyme- and concentration-dependent manner. Low concentrations of restriction enzyme result in increased numbers of transformation rates decrease with higher enzyme concentrations. If protoplasts are made from cells stored in the cold, the transformation rates drop drastically even in the presence of low amounts of enzyme. In several transformants, plasmid integration directly correlated with the action of restriction enzyme at random chromosomal restriction sites. In some cases, restriction enzymes appear to reduce the number of integration events per transformant. Simultaneously, mutation rates can be enhanced due to the presence of restriction enzymes. Although restriction enzymes clearly promote plasmid integration into the host genome they also have cytotoxic and possibly mutagenic effects that result from processes other than plasmid integration. In consequence, for any given enzyme used in REMI mutagenesis, the enzyme concentration that gives the highest number of transformants must be defined experimentally. Such optimal transformation conditions should give the highest probability of obtaining mutations caused by a single restriction enzyme-mediated integration of the selection marker.
Blotting, Southern↗
The STT3 protein is a component of the yeast oligosaccharyltransferase complex.
N-linked protein glycosylation is an essential process in eukaryotic cells. In the central reaction, the oligosaccharyltransferase (OTase) catalyzes the transfer of the oligosaccharide Glc3Man9GlcNac2 from dolicholpyrophosphate onto asparagine residues of nascent polypeptide chains in the lumen of the endoplasmic reticulum. The product of the essential gene STT3 is required for OTase activity in vivo, but is not present in highly purified OTase preparations. Using affinity purification of a tagged Stt3 protein, we now demonstrate that other components of the OTase complex, namely Ost1p, Wbp1p and Swp1p, specifically co-purify with the Stt3 protein. In addition, different conditional stt3 alleles can be suppressed by overexpression of either OST3 and OST4, which encode small components of the OTase complex. These genetic and biochemical data show that the highly conserved Stt3p is a component of the oligosaccharyltransferase complex.
Alleles↗
Solitary plasma-cell myeloma of the spine in an adolescent. Case report of an unusual presentation.
We report an unusual presentation of a solitary plasma-cell myeloma of the spine in an adolescent patient. Our case indicates the need to consider plasma-cell myeloma as a differential diagnosis even in younger patients.
Adolescent↗
Adult spondylolisthesis treated with posterolateral lumbar fusion and pedicular instrumentation with AO DC plates.
Attainment of successful lumbar fusion in adults with spondylolisthesis has historically been unpredictable. Recent results and conclusions have been conflicting regarding the role of instrumentation in improving the fusion rate and clinical outcome in this patient population. In a retrospective multicenter clinical study, we assessed the outcome of 42 adults with spondylolisthesis who underwent posterolateral lumbar fusion by using pedicular instrumentation with AO DC plates. No attempt was made to reduce slippage. Follow-up clinical outcome was obtained from a patient questionnaire administered and assessed by an independent reviewer. Fusion status was assessed by anteroposterior, lateral, and oblique radiographs at the most recent follow-up examination. Spondylolisthesis was classified as degenerative in 21 patients and isthmic in 21 patients. Solid fusion was achieved in 32 (76%) patients; pseudoarthrosis occurred in two (5%) patients; the fusion mass was indeterminate in eight (19%) patients. Clinical outcome parameters rated 73% excellent to good and 27% fair to poor. Complications included four infections and two screw breakages. Poor results correlated strongly with cigarette smoking and multiple previous surgeries. In this study, fusion rate and clinical outcome were consistent with previous reports of adult spondylolisthesis. Rates of successful fusion varied according to the type of spondylolisthesis.
Adult↗
Yeast Gpi8p is essential for GPI anchor attachment onto proteins.
Glycosylphosphatidylinositol (GPI) anchors are added onto newly synthesized proteins in the ER. Thereby a putative transamidase removes a C-terminal peptide and attaches the truncated protein to the free amino group of the preformed GPI. The yeast mutant gpi8-1 is deficient in this addition of GPIs to proteins. GPI8 encodes for an essential 47 kDa type I membrane glycoprotein residing on the luminal side of the ER membrane. GPI8 shows significant homology to a novel family of vacuolar plant endopeptidases one of which is supposed to catalyse a transamidation step in the maturation of concanavalin A and acts as a transamidase in vitro. Humans have a gene which is highly homologous to GPI8 and can functionally replace it.
Amino Acid Sequence↗
The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration.
Very little is known about the turnover of extracellular matrix in the human intervertebral disc. We measured concentrations of specific molecules reflecting matrix synthesis and degradation in predetermined regions of 121 human lumbar intervertebral discs and correlated them with ageing and Thompson grade of degeneration. Synthesis in intervertebral discs, measured by immunoassay of the content of a putative aggrecan biosynthesis marker (846) and the content of types I and II procollagen markers, is highest in the neonatal and 2-5-yr age groups. The contents of these epitopes/molecules progressively diminished with increasing age. However, in the oldest age group (60-80 yr) and in highly degenerated discs, the type I procollagen epitope level increased significantly. The percentage of denatured type II collagen, assessed by the presence of an epitope that is exposed with cleavage of type II collagen, increased twofold from the neonatal discs to the young 2-5-yr age group. Thereafter, the percentage progressively decreased with increasing age; however, it increased significantly in the oldest group and in highly degenerate discs. We identified three matrix turnover phases. Phase I (growth) is characterized by active synthesis of matrix molecules and active denaturation of type II collagen. Phase II (maturation and ageing) is distinguished by a progressive drop in synthetic activity and a progressive reduction in denaturation of type 11 collagen. Phase III (degeneration and fibrotic) is illustrated by evidence for a lack of increased synthesis of aggrecan and type II procollagen, but also by an increase in collagen type II denaturation and type I procollagen synthesis, both dependent on age and grade of tissue degeneration.
Adult↗
Stepwise assembly of the lipid-linked oligosaccharide in the endoplasmic reticulum of Saccharomyces cerevisiae: identification of the ALG9 gene encoding a putative mannosyl transferase.
The core oligosaccharide Glc3Man9GlcNAc2 is assembled at the membrane of the endoplasmic reticulum on the lipid carrier dolichyl pyrophosphate and transferred to selected asparagine residues of nascent polypeptide chains. This transfer is catalyzed by the oligosaccharyl transferase complex. Based on the synthetic phenotype of the oligosaccharyl transferase mutation wbp1 in combination with a deficiency in the assembly pathway of the oligosaccharide in Saccharomyces cerevisiae, we have identified the novel ALG9 gene. We conclude that this locus encodes a putative mannosyl transferase because deletion of the gene led to accumulation of lipid-linked Man6GlcNAc2 in vivo and to hypoglycosylation of secreted proteins. Using an approach combining genetic and biochemical techniques, we show that the assembly of the lipid-linked core oligosaccharide in the lumen of the endoplasmic reticulum occurs in a stepwise fashion.
Amino Acid Sequence↗
The human lumbar endplate. Evidence of changes in biosynthesis and denaturation of the extracellular matrix with growth, maturation, aging, and degeneration.
STUDY DESIGN: The authors measured concentrations of specific molecules reflecting matrix synthesis and degradation in 121 human endplates and correlated them with aging and grade of degeneration. OBJECTIVES: Abnormal endplate development has been implicated in many spinal abnormalities, yet little is known about endplate matrix component turnover. SUMMARY OF BACKGROUND DATA: Techniques are available to perform an in situ investigation of matrix component turnover with aging and degeneration. METHODS: Newly synthesized aggrecan and Type I and Type II procollagens were measured with recently developed immunoassays. Percentage of denatured Type II collagen was assessed with a new enzyme-linked immunosorbent inhibition assay. RESULTS: Synthesis in endplates, measured by content of an aggrecan marker (846) and content of Types I and II procollagen markers (CPI and CPII), is highest in the neonatal and 2- to 5-year age groups and steadily diminishes with increasing age. However, in the oldest age group and in highly degenerated discs, the CPI epitope level increased significantly. Percentage of denatured Type II collagen, assessed by the presence of an epitope exposed with the cleavage of Type II collagen, increased from the neonatal to the 2- to 5-year age groups. The percentage progressively decreased with increasing age. However, it significantly increased in endplates from highly degenerated discs. CONCLUSIONS: The authors identified three matrix turnover phases, related to age and grade of degeneration. Phase I (growth) is characterized by active synthesis of matrix molecules and active denaturation of Type II collagen. Phase II (aging and maturation) is distinguished by a drop in synthetic activity and a reduction in denaturation of Type II collagen. Phase III (degenerative) is illustrated by an increase in Type II collagen denaturation and Type I procollagen synthesis, both related to grade of tissue degeneration.
Adolescent↗
Allele-specific suppression of a Saccharomyces cerevisiae prp20 mutation by overexpression of a nuclear serine/threonine protein kinase.
The yeast PRP20 protein is homologous to the RCC1 protein of higher eukaryotes and is required for mRNA export and maintenance of nuclear structure. RCC1/PRP20 act as guanine nucleotide exchange factors for the nuclear Ras-like Ran/GSP1 proteins. In a search for prp20-10 allele-specific high-copy-number suppressors, the KSP1 locus, encoding a serine/threonine protein kinase was isolated. Ksp1p is a nuclear protein that is not essential for vegetative growth of yeast. Inactivation of the kinase activity by a mutation affecting the catalytic center of the Ksp1p eliminated the suppressing activity. Based on the isolation of a protein kinase as a high-copy-number suppressor, the phosphorylation of Prp20p was examined. In vivo labeling experiments showed that Prp20p is a phosphoprotein; however, deletion of the KSP1 kinase did not affect Prp20p phosphorylation.
Alleles↗
A new magnetic resonance imaging analysis method for the measurement of disc height variations.
STUDY DESIGN: A new magnetic resonance image analysis method is proposed which is based on the definition of the borders of the vertebral bodies adjacent to the intervertebral disc and their varying relationships. The reproducibility of this method (the so-called "centroid" method) was assessed by consecutive measurements. Its potential to depict diurnal disc height variations was studied using randomized groups of volunteers. OBJECTIVE: To determine if magnetic resonance imaging can reliably measure disc height variations in the lumbar spine in vivo. SUMMARY OF BACKGROUND DATA: A review of the literature indicates that noninvasive, accurate methods to study the effect of load on intervertebral discs in vivo are needed. METHODS: The reproducibility of the centroid method was assessed in 10 healthy volunteers in 2 consecutive measurements and compared to a conventional method (mean anterior and posterior disc height). To investigate the potential for the depiction of diurnal disc height variations, 10 volunteers were randomized in a study group (1 measurement in the morning, 1 measurement in the evening) and a control group (2 consecutive measurements in the morning). RESULTS: The centroid method allows the depiction of disc height variations as small as 0.85 mm with a 95% confidence (tolerance limits), whereas a conventional method needs variations of at least 1.66 mm. In the study (diurnal) group, the disc height decreased significantly (P < 0.0001) during the day (mean, -0.9 mm), while no variation (P < 0.8) was found in the control group. CONCLUSIONS: These results indicate that the centroid method can reliably detect disc height variations in an experimental setting. The centroid method provides the potential for evaluations of the effects of various work places, work equipment, work tasks, and postures.
Adult↗
Spinal surgery: where is it coming from? what is it? where is it going to?
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Humans↗
Predominantly posterior instrumentation and fusion in neuromuscular and neurogenic scoliosis in children and adolescents.
We studied the results in 46 patients with neuromuscular and neurogenic scoliosis (average age 13.5 years, range 6-19 years) who had had posterior fusion with a modified Luque technique between May 1985 and June 1992. The main criteria to recommend surgery were curve progression, loss of balance when sitting, control of the head and difficulties in wearing an external orthotic support. The mean preoperative curve was 63 degrees, the postoperative value was 24 degrees, representing a correction of about 62%. The average number of stabilized segments was 13. In 39 out of 46 patients, lumbosacral fixation was included in the construct. Failure of implants, pseudarthroses and major losses of correction in purely neuromuscular scolioses could be avoided by using rigid segmental fixation and a dorsolateral fusion with a mixture of autologous and allogenous bone. The scoliosis most difficult to influence was found to be Friedreich's ataxia. In Duchenne muscular dystrophy the best method of treatment was surgery performed as early as possible, i.e. at the time of loss of walking capacity in the case of a scoliosis exceeding 20 degrees and with two consecutive X-rays proving curve progression. Analysis of our series does not confirm the morbidity and complication rates of previous studies.
Adolescent↗
Cloning and characterization of the ALG3 gene of Saccharomyces cerevisiae.
The Saccharomyces cerevisiae alg3-1 mutant is described as defective in the biosynthesis of dolichol-linked oligosaccharides (Huffaker and Robbins, Proc. Natl. Acad. Sci. USA, 80, 7466-7470, 1983). Man5GlcNAc2-PP-Dol accumulates in alg3 cells and Endo H resistant carbohydrates are transferred to protein by the oligosaccharyltransferase complex. In this study, we describe the cloning of the ALG3 locus by complementation of the temperature sensitive growth defect of the alg3 stt3 double mutant. The isolated ALG3 gene complements both the defect in the biosynthesis of lipid-linked oligosaccharides of the alg3-mutant and the under-glycosylation of secretory proteins. The inactivation of the nonessential ALG3 gene results in the accumulation of lipid-linked Man5GlcNac2 and protein-bound carbohydrates which are completely Endo H resistant. The ALG3 locus encodes a potential ER-transmembrane protein of 458 amino acids (53 kDa) with a C-terminal KKXX-retrieval sequence.
Amino Acid Sequence↗
Isolation of the ALG6 locus of Saccharomyces cerevisiae required for glucosylation in the N-linked glycosylation pathway.
N-Linked protein glycosylation in most eukaryotic cells initiates with the transfer of the oligosaccharide Glc3Man9GlcNAc2 from the lipid carrier dolichyl pyrophosphate to selected asparagine residues. In the yeast Saccharomyces cerevisiae, alg mutations which affect the assembly of the lipid-linked oligosaccharide at the membrane of the endoplasmic reticulum result in the accumulation of lipid-linked oligosaccharide intermediates and a hypoglycosylation of proteins. Exploiting the synthetic growth defect of alg mutations in combination with mutations affecting oligosaccharyl transferase activity (Stagljar et al., 1994), we have isolated the ALG6 locus. alg6 mutants accumulate lipid-linked Man9GlcNAc2, suggesting that this locus encodes an endoplasmic glucosyltransferase. Alg6p has sequence similarity to Alg8p, a protein required for glucosylation of Glc1Man9GlcNAc2.
Amino Acid Sequence↗
1995 Volvo Award in clinical sciences. The diagnostic accuracy of magnetic resonance imaging, work perception, and psychosocial factors in identifying symptomatic disc herniations.
STUDY DESIGN: This was a prospective study of patients (study group) with symptomatic disc herniations and asymptomatic volunteers (control group) matched for age, sex, and work-related risk factors. OBJECTIVE: To determine the prevalence of disc herniation in a matched group of asymptomatic volunteers and to access the diagnostic accuracy of magnetic resonance imaging, work perception, and psychosocial factors in identifying symptomatic disc herniations. SUMMARY OF BACKGROUND DATA: Disc herniations have been reported to occur in 20-36% of asymptomatic volunteers. A valid comparison of asymptomatic individuals and patients with disc herniations has not been performed. METHODS: Forty-six patients with low back pain and sciatica severe enough to require a discectomy were compared with 46 age-, sex-, and risk factor-matched (heavy lifting, twisting and bending, vibration, and sedentary activity) asymptomatic volunteers. Both groups had a complete clinical and magnetic resonance imaging examination and completed a questionnaire to assess differences in the psychosocial and work perception profiles. The prevalence and the severity of morphologic alterations (disc herniation, disc degeneration, and neural compromise) was analyzed by tow independent radiologists in a blinded fashion. Differences between both groups regarding MRI findings, work perception (occupational mental stress, intensity of concentration, job satisfaction, and job-related resignation) and psychosocial factors (anxiety, depression, self-control, social support, and marital status) were compared using multivariate techniques. Stepwise discriminating analysis was used to identify the best discriminating variables within the magnetic resonance image, work perception, and psychosocial categories in terms of the diagnostic accuracy to predict group membership (study [pain] or control [no pain] group). RESULTS: Matched controls had significantly more risk factors than a group of normal individuals. The present study has presented evidence that an age-, gender-, and occupational risk factors-matched group of asymptomatic patients shows a high incidence rate of disc herniations (76%). Although significantly less than the symptomatic group incidence of 96%, this represents a much higher prevalence rate than generally expected and reported in other studies of unmatched asymptomatic volunteers. Patients had more severe disc herniations (disc extrusions) than asymptomatic volunteers (35% vs. 13%). There was no significant differences regarding disc degeneration between both groups (96% vs. 85%). The only substantial morphologic difference between both groups was the presence of a neural compromise (83% vs. 22%), which was highly significant (P < 0.0001). There were significant differences between both groups regarding work perception (occupational mental stress, intensity of concentration, job satisfaction, and resignation; P < 0.027) and psychosocial factors (anxiety, depression, self-control, marital status; P < 0.0001). The best single predictor of a group membership was the extent of neural compromise. A combination of this factor with occupational mental stress, depression, and marital status was the best predictive model. With this model, the false-negative rate (potential overtreatment of disc morphology) was reduced by more than half compared with morphologic factors (nerve root compression) alone (22% vs. 11%). CONCLUSIONS: In an age-, sex-, and risk factor-matched group of asymptomatic individuals, disc herniation had a substantially higher prevalence (76%) than previously reported in an unmatched group. Individuals with minor disc herniations (i.e., protrusion, contained discs) are at a very high risk that their magnetic resonance images are not a causal explanation of pain because a high rate of asymptomatic subjects (63%) had comparable morphologic findings. The only highly significant difference between the study group and control group regarding morphologic fi
Adult↗