Showing papers by "University of Copenhagen published in 1994"

Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report.

Abstract: The Committee of the European Concerted Action for Multiple Sclerosis (Charcot Foundation) organised five workshops to discuss CSF analytical standards in the diagnosis of multiple sclerosis. This consensus report from 12 European countries summarises the results of those workshops. It is hoped that neurologists will confer with their colleagues in clinical chemistry to arrange the best possible local practice. The most sensitive method for the detection of oligoclonal immunoglobulin bands is isoelectric focusing. The same amounts of IgG in parallel CSF and serum samples are used and oligoclonal bands are revealed with IgG specific antibody staining. All laboratories performing isoelectric focusing should check their technique at least annually using "blind" standards for the five different CSF and serum patterns. Quantitative measurements of IgG production in the CNS are less sensitive than isoelectric focusing. The preferred method for detection of blood-CSF barrier dysfunction is the albumin quotient. The CSF albumin or total protein concentrations are less satisfactory. These results must be interpreted with reference to the age of the patient and the local method of determination. Cells should be counted. The normal value is no more than 4 cells/microliters. Among evolving optional tests, measurement of the combined local synthesis of antibodies against measles, rubella, and/or varicella zoster could represent a significant advance if it offers higher specificity (not sensitivity) for identifying chronic rather than acute inflammation. Other tests that may have useful correlations with clinical indices include those for oligoclonal free light chains, IgM, IgA, or myelin basic protein concentrations.

Two molecular pathways to transitional cell carcinoma of the bladder.

Abstract: Noninvasive transitional cell carcinomas of the bladder can have two distinct morphologies suggesting they contain different genetic alterations. Papillary transitional cell carcinomas (T(a) tumors) are often multifocal and only occasionally progress, whereas flat tumors (carcinomas in situ, CIS), frequently progress to invasive disease. We examined 216 bladder tumors of various stages and histopathologies for two genetic alterations previously described to be of importance in bladder tumorigenesis. Loss of heterozygosity of chromosome 9 was observed in 24 of 70 (34%) T(a) tumors but was present in only 3 of 24 (12%) CIS and dysplasia lesions (P = 0.04). In contrast, only 1 of 36 (3%) T(a) tumors contained a p53 gene mutation compared to 15 of 23 (65%) CIS and dysplasias (P < 0.001), a frequency comparable to that observed in muscle invasive tumors (25 of 49; 51%). The presence of p53 mutations in CIS and dysplasia could explain their propensities to progress since these mutations are known to destabilize the genome. Analysis of several tumor pairs involving a CIS and an invasive cancer provided evidence that the chromosome 9 alteration may in some cases be involved in the progression of CIS to more invasive tumors, in addition to its role in the initiation of T(a) tumors. However, the CIS and secondary tumor were found to contain different genetic alterations in some patients suggesting divergent progression pathways. Bladder carcinogenesis may therefore proceed through two distinct genetic alteration pathways responsible for generating superficial tumors with differing morphologies and pathologies.

Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate.

Abstract: The nationwide Danish polyposis register includes all known Danish cases of familial adenomatous polyposis (FAP) and their relatives. By identifying all FAP patients born between 1920 and 1949, we found the frequency of the disease to be 1 in 13,528. By comparing the number of affected and nonaffected offspring born to affected parents during the same period we found the penetrance of the disease for inherited cases to be close to 100% at the age of 40 years. The mutation rate found by the direct method was 9 mutations per million gametes per generation and the proportion of new mutants was estimated to 25%. Fitness for patients between 15 and 29 years was found close to one, while for patients older than 30 the fitness was reduced, but increasing during the three decades (from 0.44 to 0.71) probably because treatment became more widespread and efficient. As we have used the overall fitness in the period, 0.87, to estimate the mutation rate by the indirect method, we found a lower value than by the direct method, namely 5 mutations per million gametes per generation.

High-resolution climate records from the North Atlantic during the last interglacial

Abstract: THE two deep ice cores recovered by the GRIP1 and GISP22 projects at Summit, Greenland, agree in detail over the past 100,000 years3 and demonstrate dramatic climate variability in the North Atlantic region during the last glacial, before the current period of Holocene stability. This glacial climate instability has subsequently been documented in the marine sedimentary record of surface-ocean conditions in the North Atlantic4. Before 100 kyr ago the two ice core records are discrepant, however, casting doubt on whether the oxygen isotope fluctuations during the last interglacial (Eemian) seen in the GRIP core1,5 represent a true climate signal. Here we present high-resolution records of foraminiferal assemblages and ice-rafted detritus from two North Atlantic cores for the interval 65 kyr to 135 kyr ago, extending the surface-ocean record back to the Eemian. The correlation between our records and the Greenland ice-core records is good throughout the period in which the two ice cores agree, suggesting a regionally coherent climate response. During the Eemian, our marine records show a more stable climate than that implied by the GRIP ice core, suggesting that localized phenomena may be responsible for the variability in the latter record during the Eemian.

Inflation and primordial black holes as dark matter

Abstract: We discuss the hypothesis that a large (or even a major) fraction of dark matter in the Universe consists of primordial black holes (PBH's). PBH's may arise from adiabatic quantum fluctuations appearing during inflation. We demonstrate that the inflation potential V(cphi) leading to the formation of a great number of PBH's should have a feature of the ``plateau''-type in some range ${\mathit{cphi}}_{1}$cphi${\mathit{cphi}}_{2}$ of the inflation field cphi. The mass spectrum of PBH's for such a potential is calculated.

Murine muscular dystrophy caused by a mutation in the laminin alpha 2 (Lama2) gene.

Abstract: The classic murine muscular dystrophy strain, dy, was first described almost 40 years ago. We have identified the molecular basis of an allele of dy, called dy2J, by detecting a mutation in the laminin α2 chain gene — the first identified mutation in laminin-2. The G to A mutation in a splice site consensus sequence causes abnormal splicing and expression of multiple mRNAs. One mRNA is translated into an α2 polypeptide with a deletion in domain VI. The truncated protein apparently lacks important qualities of the wild type protein and is unable to provide sufficient muscle stability.

Climate variations in Europe over the past 140 kyr deduced from rock magnetism

Abstract: RAPID shifts in climate during the last glacial are now well documented, particularly from the oxygen isotope records of the two Greenland ice cores GRIP1,2 and GISP23. In the GRIP record1,2 these climate events are also seen during the preceding (Eemian) interglacial which may be an analogue for the future climate, warmed by the greenhouse effect. But these shifts are not found in the Eemian section of the GISP2 core3, casting doubt on whether the rapid shifts in the GRIP oxygen isotope record really do represent a climate signal. Here we present magnetic susceptibility, pollen and organic carbon records from maar lake deposits in the Massif Central, France. These data provide an independent record of past climate and we find that they correlate well with the ice-core records during the last glacial. During the Eemian, two rapid cooling events seen in our record also correlate with those seen in the GRIP ice core, supporting the idea that rapid climate change did occur in the Eemian interglacial and demonstrating that it extended to continental Europe.

Implementation of the typed call-by-value λ-calculus using a stack of regions

Abstract: We present a translation scheme for the polymorphically typed call-by-value l-calculus. All runtime values, including function closures, are put into regions. The store consists of a stack of regions. Region inference and effect inference are used to infer where regions can be allocated and de-allocated. Recursive functions are handled using a limited form of polymorphic recursion. The translation is proved correct with respect to a store semantics, which models as a region-based run-time system. Experimental results suggest that regions tend to be small, that region allocation is frequent and that overall memory demands are usually modest, even without garbage collection.

The origin of the major cystic fibrosis mutation (ΔF508) in European populations

Abstract: delta F508 is the most frequent cystic fibrosis (CF) mutation and accounts for approximately 70% of CF chromosomes worldwide. Three highly polymorphic microsatellite markers have been used to study the origin and evolution of delta F508 chromosomes in Europe. Haplotype data demonstrate that delta F508 occurred more than 52,000 years ago, in a population genetically distinct from any present European group, and spread throughout Europe in chronologically distinct expansions, which are responsible for the different frequencies of delta F508 in Europe.

Logistic Regression Analysis

Abstract: In chapter 8 the connection to log-linear models for contingency tables was stressed. The direct connection to regression analysis for continuous response variables will now be brought more clearly into focus. Assume as before that the response variable is binary and that it is observed together with p explanatory variables. For n cases the data will then consist of n vectors $$\left( {{y_V},{z_{1V}}, \ldots ,{z_{pV}}} \right),v = 1, \ldots ,n$$ of jointly observed values of the response variable and the explanatory variables.

Transcranial Doppler is valid for determination of the lower limit of cerebral blood flow autoregulation.

Abstract: This study validates transcranial Doppler sonography (TCD) for determination of the lower limit of cerebral blood flow (CBF) autoregulation and establishes a relation between global CBF and mean flow velocity (Vmean) in the middle cerebral artery.Relative changes in CBF and in Vmean were compared in 12 normal volunteers (2 women and 10 men; median age, 30 years [range, 21 to 61 years]). Catheters was placed in the left radial artery and in the bulb of the right internal jugular vein, respectively. Baseline CBF was measured by single-photon emission computed tomography scanning; concomitantly, blood samples were drawn for calculation of the cerebral arteriovenous oxygen difference. Then changes in mean arterial pressure (MAP) were induced, and relative changes in global CBF were calculated according to Fick's principle assuming a constant cerebral oxygen metabolism. MAP was increased 30 mm Hg by norepinephrine infusion and was decreased by lower body negative pressure. Vmean was measured in the right middl...

Transmission in a locomotor-related group Ib pathway from hindlimb extensor muscles in the cat.

Abstract: It has been previously shown that phasic stimulation of group I afferents from ankle and knee extensor muscles may entrain and/or reset the intrinsic locomotor rhythm; these afferents are thus acting on motoneurones through the spinal rhythm generators. It was also concluded that the major part of these effects originates from Golgi tendon organ Ib afferents. Transmission in this pathway to lumbar motoneurones has now been investigated during fictive locomotion in spinal cats injected with nialamide and L-DOPA, and in decerebrate cats with stimulation of the mesencephalic locomotor region. In spinal cats injected with nialamide and L-DOPA, it was possible to evoke long-latency, long-lasting reflexes upon stimulation of high threshold afferents before spontaneous fictive locomotion commenced. During that period, stimulation of ankle and knee extensor group I afferents evoked oligosynaptic excitation of extensor motoneurones, rather than the "classical" Ib inhibition. Furthermore, a premotoneuronal convergence (spatial facilitation) between this group I excitation and the crossed extensor reflex was established. During fictive locomotion, in both preparations, the transmissions in these groups I pathway was phasically modulated within the step cycle. During the flexor phase, the group I input cut the depolarised (active) phase in flexor motoneurones and evoked EPSPs in extensor motoneurones; during the extensor phase the group I input evoked smaller EPSPs in extensor motoneurones and had virtually no effect on flexor motoneurones. The above results suggest that the group I input from extensor muscles is transmitted through the spinal rhythm generator and more particularly, through the extensor "half-centre". The locomotor-related group I excitation had a central latency of 3.5-4.0 ms. The excitation from ankle extensors to ankle extensors remained after a spinal transection at the caudal part of L6 segment; the interneurones must therefore be located in the L7 and S1 spinal segments. Candidate interneurones for mediating these actions were recorded extracellularly in lamina VII of the 7th lumbar segment. Responses to different peripheral nerve stimulation (high threshold afferents and group I afferents bilaterally) were in concordance with the convergence studies in motoneurones. The interneurones were rhythmically active in the appropriate phases of the fictive locomotor cycle, as predicted by their response patterns. The synaptic input to, and the projection of these candidate interneurones must be fully identified before their possible role as components of the spinal locomotor network can be evaluated.

A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks.

Abstract: Supersensitivity to induction of headache and arterial dilatation by a donor of nitric oxide (nitroglycerin) has recently been demonstrated in migraine sufferers. The aims of the present study were to examine whether the nitric oxide donor nitroglycerin may induce a typical migraine attack, to exclude placebo-related effects and to describe the relation between middle cerebral artery dilatation and provoked migraine. Nitroglycerin (0.5 μg/kg/min for 20 min) or placebo was infused into 12 migraine patients in a double-blind cross-over trial. Blood velocity in the middle cerebral artery was measured with transcranial Doppler and characteristics of headache and accompanying symptoms were recorded frequently. Headache occurred during the nitroglycerin infusion as previously described but peak headache intensity did first occur 5.5 h after infusion. At this time the induced headaches in 8 of 10 completing patients fulfilled the diagnostic criteria for migraine without aura of the International Headache Society. Furthermore, all patients who normally had unilateral spontaneous migraine attacks also had unilateral headaches after nitroglycerin. Only one subject developed migraine after placebo (p < 0.03). The time pattern of headache and estimated middle cerebral artery dilatation corresponded well. The study therefore demonstrates that activation of the nitric oxide cGMP pathway may cause typical migraine attacks.

The evolution of plumage brightness in birds is related to extrapair paternity.

Abstract: A positive association between plumage brightness of male birds and the degree of polygyny may be the result of sexual selection. Although most birds have a socially monogamous mating system, recent paternity analyses show that many offspring are fathered by nonmates. Extrapair paternity arises from extrapair copulations which are frequently initiated by females. Not all females will be able to mate with a male of the preferred phenotype, because of the mating decisions of earlier paired females; extrapair copulations may be a means for females to adjust their precopulation mate choice. We use two comparative analyses (standardized linear contrasts and pairwise comparisons between closely related taxa) to test the idea that male plumage brightness is related to extrapair paternity. Brightness of male plumage and sexual dimorphism in brightness were positively associated with high levels of extrapair paternity, even when potentially confounding variables were controlled statistically. This association between male brightness and extrapair paternity was considerably stronger than the association between male brightness and the degree of polygyny. Cuckoldry thus forms an important component of sexual selection in birds.

Consistent intergenic splicing and production of multiple transcripts between AML1 at 21q22 and unrelated genes at 3q26 in (3;21)(q26;q22) translocations

Abstract: Two genes have been implicated in leukemias of patients with abnormalities of chromosome 3, band q26: EVI1, which can be activated over long distances by chromosomal rearrangements involving 3q26, and EAP, a ribosomal gene that fuses with AML1 in a therapy-related myelodysplasia patient with a t(3;21)(q26.2;q22). AML1 was identified by its involvement in the t(8;21)(q22;q22) of acute myeloid leukemia. Here we report the consistent identification of fusion transcripts between AML1 and EAP or between AML1 and previously unidentified sequences that we named MDS1 (MDS-associated sequences) in the leukemic cells of four patients with therapy-related myelodysplasia/acute myeloid leukemia and in one patient with chronic myelogenous leukemia in blast crisis, all of whom had a t(3;21). In addition, we have identified a third chimeric transcript, AML1/EVI1, in one of the therapy-related acute myeloid leukemia patients. Pulsed-field gel electrophoresis established the order of the genes as EAP, the most telomeric, and EVI1, the most centromeric, gene. The results indicate that translocations could involve multiple genes and affect gene expression over long distances.

Osteoporosis: A Risk Factor in Periodontal Disease

Abstract: Osteoporosis is suspected as a risk factor in periodontal disease, but previous studies have failed to establish a relationship. Possible explanations for this could be lack of precise methods for assessment of osteoporosis in the jaws and confounding of the result by other factors such as age, gender, or smoking. In the present study 12 female patients with osteoporotic fractures (Group O) and 14 normal women (Group N) were examined clinically for plaque (VPI), gingival bleeding (GBI), and loss of attachment on the 6 Ramfjord index teeth. Bone mineral content (BMC) of the mandible and forearm was determined by dual photon scanning. Results were presented as arithmetic means +/- standard error, and differences between groups were tested by 2-sample t-test. The two groups were comparable with respect to age (O: 68.3 +/- 1.8 years, N: 68.1 +/- 1.5 years), menopausal age (O: 47.5 +/- 1.8 years, N: 47.2 +/- 1.3 years), and smoking habits (O: 4 smokers, N: 3 smokers). The osteoporotic women had significantly lower BMC values than controls in the mandible (O: 0.63 +/- 0.04 in U/cm2; N: 0.78 +/- 0.02 in U/cm2, P < 0.01) and forearm (O: 1.05 +/- 0.05 in U/cm; N: 1.28 +/- 0.05 in U/cm, P < 0.01). No significant differences were found with respect to plaque (O: 46.67 +/- 10.00%, N: 36.67 +/- 6.67%) and gingival bleeding (O: 46.67 +/- 11.67%, N: 43.33 +/- 10.00%), whereas significantly greater loss of attachment was seen in osteoporotic women (O: 3.65 +/- 0.18 mm, N: 2.86 +/- 0.19 mm, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Low-power operation using self-timed circuits and adaptive scaling of the supply voltage

Abstract: Recent research has demonstrated that for certain types of applications like sampled audio systems, self-timed circuits can achieve very low power consumption, because unused circuit parts automatically turn into a stand-by mode. Additional savings may be obtained by combining the self-timed circuits with a mechanism that adaptively adjusts the supply voltage to the smallest possible, while maintaining the performance requirements. This paper describes such a mechanism, analyzes the possible power savings, and presents a demonstrator chip that has been fabricated and tested. The idea of voltage scaling has been used previously in synchronous circuits, and the contributions of the present paper are: 1) the combination of supply scaling and self-timed circuitry which has some unique advantages, and 2) the thorough analysis of the power savings that are possible using this technique. >

Physical Training Increases Muscle GLUT4 Protein and mRNA in Patients With NIDDM

Abstract: Patients with non-insulin-dependent diabetes mellitus (NIDDM) exhibit insulin resistance and decreased glucose transport in skeletal muscle. Total content of muscle GLUT4 protein is not affected by NIDDM, whereas GLUT4 mRNA content is reported, variously, to be unaffected or increased. Physical training is recommended in the treatment of NIDDM, but the effect of training on muscle GLUT4 protein and mRNA content is unknown. To clarify the effect of training in NIDDM, seven men with NIDDM (58 +/- 2 years of age [mean +/- SE]) and eight healthy men (59 +/- 1 years of age) (control group) performed one-legged ergometer bicycle training for 9 weeks, 6 days/week, 30 min/day. Biopsies were obtained from the vastus lateralis leg muscle before and after training. GLUT4 protein analyses was performed along with analyses of muscle biopsies from five young (23 +/- 1 years of age) (young group), healthy subjects who participated in a previously published identical study. In response to training, maximal oxygen uptake increased (delta 3.3 +/- 1.8 in NIDDM subjects and 4.5 +/- 1.2 ml.min-1.kg-1 in control subjects [both P < 0.05]). Before training, GLUT4 protein content was similar in NIDDM, control, and young subjects (0.35 +/- 0.02, 0.34 +/- 0.03, and 0.41 +/- 0.03 arbitrary units, respectively), and it increased (P < 0.05) in all groups during training (to 0.43 +/- 0.03, 0.40 +/- 0.03, and 0.57 +/- 0.08 arbitrary units, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Sodium valproate has a prophylactic effect in migraine without aura: A triple‐blind, placebo‐controlled crossover study

Abstract: We included 43 patients with migraine without aura in a triple-blind, placebo- and dose-controlled, crossover study of the prophylactic effect of slow-release sodium valproate; 34 patients completed the trial. The number of days with migraine was 3.5 per 4 weeks during treatment with sodium valproate and 6.1 during placebo (p = 0.002). The severity and duration of the migraine attacks that did occur were not affected by sodium valproate when compared with placebo. Fifty percent of the patients were responders, ie, their initial migraine frequency was reduced to 50% or less during sodium valproate as compared with 18% during placebo. The number of responders increased during the trial to 65% in the last 4 weeks of the active treatment period. There were no serious side effects requiring withdrawal of patients from the study. We conclude that sodium valproate is an effective and well-tolerated prophylactic medication for migraine without aura.

Notes on protozoa in agricultural soil with emphasis on heterotrophic flagellates and naked amoebae and their ecology

Abstract: Heterotrophic flagellates and naked amoebae are usually very numerous in agricultural soils; with numbers in the magnitude of 10000 to 100000 (active+ encysted) cells per gram of soil. In ‘hotspots’ influenced by living roots or by dead organic material, the number may occasionally be as high as several millions per gram of soil. An exact enumeration of these organisms is virtually impossible. As they most often adhere closely to the soil particles, direct counting will underestimate numbers since the organisms will be masked. The method usually applied for enumeration of these organisms, the ‘most probable umber (MPN) method’, is based on the ability of the organisms to grow on particular culture media. This method will in many cases underestimate the total protozoan number (active+ encysted). It is uncertain how many of the heterotrophic flagellates and naked amoebae are actively moving and how many are encysted at a particular time; the ‘HCI-method’ which has usually been used to discriminate between active and encysted has proven to be highly unreliable. Despite the methodological difficulties many investigations of these organisms indicate that they play an important role in agricultural soils as bacterial consumers, and to a minor extent as consumers of fungi. Because of their small size and their flexible body they are able to graze bacteria in small pores in the soil in which larger organisms are precluded from coming. Key factors restricting the number and activity of heterotrophic flagellates and naked amoebae in soils seem to be water potential and soil structure and texture. In micro-corm experiments, small heterotrophic flagellates and naked amoebae regulate the size and composition of the bacterial community. Bacterial activity seems to be stimulated by these organisms in most cases as well as the mineralization of carbon and nitrogen and possibly other mineral nutrients. In the rhizosphere of living plants the activity of protozoa has proven to stimulate uptake of nitrogen inpot experiments, and it has been hypothesized that organic matter liberated by plants in the root zone will stimulate bacterial and protozoan activity, leading to mineralization of organic soil nitrogen which is subsequently taken up by the plants.

The RNA chain elongation rate in Escherichia coli depends on the growth rate.

Abstract: We determined the rates of mRNA and protein chain elongation on the lacZ gene during exponential growth on different carbon sources. The RNA chain elongation rate was calculated from measurements of the time elapsing between induction of lacZ expression and detection of specific hybridization with a probe near the 39 end of the mRNA. The elongation rate for the transcripts decreased 40% when the growth rate decreased by a factor of 4, and it always correlated with the rate of translation elongation. A similar growth rate dependency was seen for transcription on the infB gene and on a part of the rrnB gene fused to a synthetic, inducible promoter. However, the untranslated RNA chain specified by the rrnB gene was elongated nearly twice as fast as the two mRNA species encoded by infB and lacZ. Images

CD3 gamma contains a phosphoserine-dependent di-leucine motif involved in down-regulation of the T cell receptor.

Abstract: Several cell surface receptors including the T cell receptor (TCR) are phosphorylated and down-regulated following activation of protein kinase C (PKC). Among other substrates the activated PKC in T cells phosphorylates the CD3 gamma subunit of the TCR. To investigate the role of CD3 gamma phosphorylation in PKC-mediated TCR down-regulation, point mutated CD3 gamma cDNA was transfected into the CD3 gamma-negative T cell line JGN and CD3 gamma transfectants were analysed. Phosphorylation at S126 but not S123 in the cytoplasmic tail of CD3 gamma was required for PKC-mediated down-regulation of the TCR. Furthermore, analysis of a series of CD3 gamma truncation mutants indicated that in addition to S126 phosphorylation a motif C-terminal of S126 was required for TCR down-regulation. Point mutation analyses confirmed this observation and demonstrated that a membrane-proximal di-leucine motif (L131 and L132) in the cytoplasmic tail of CD3 gamma was required for PKC-mediated TCR down-regulation in addition to phosphorylation at S126. Incubation of T cells in hypertonic medium known to disrupt normal clathrin lattices severely inhibited PKC-mediated TCR down-regulation in non-mutated T cells, indicating that the TCR was down-regulated by endocytosis via clathrin coated pits. Based on the present results and previously published observations on intracellular receptor sorting, a general model for intracellular sorting of receptors containing di-leucine- or tyrosine-based motifs is proposed.