Biomedical subjects

M Koenig

Publications and source records attributed to M Koenig.

At least 55 records · Page 3Linked to original sources

PubMed2001

Comparison of Light-Cycler PCR, enzyme immunoassay, and tissue culture for detection of herpes simplex virus.

A rapid PCR method was developed using the Roche LightCycler technology for detection of Herpes Simplex Virus I and II. The Lightcycler method was compared with tissue culture and direct HSV antigen detection using routine clinical samples. The LightCycler PCR was shown to be more sensitive than isolation by tissue culture (sensitivity of culture versus PCR 78%) and HSV antigen detection (sensitivity of EIA versus PCR 56%). The amplified product may be typed without additional tests. The LightCycler PCR method provides a rapid method for HSV detection that correlates well with established tests.

Animals↗

PubMed2001

Alternative study designs for research on women's gynaecological morbidity in developing countries.

Although community-based studies are considered to be the 'gold standard' for research on gynaecological morbidity among women, there is growing appreciation of the significant challenges to successfully undertaking such studies in developing countries. In this review, the constraints to undertaking community-based studies are discussed and alternative study designs are evaluated. Our review suggests that these alternative designs have both limitations as well as strengths compared to community-based designs. An important limitation concerns possible selection bias in the populations studied and the extent to which findings can be generalized to the broader population. Important advantages include higher feasibility, lower respondent refusal rates especially for medical procedures, lower costs, and potentially a more direct link between research and utilization. We conclude that the alternative study designs considered provide researchers with an expanded array of tools for investigating the issue of women's gynaecological morbidity in developing countries.

Adolescent↗

PubMed2001

Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits.

Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy and increased incidence in diabetes. FRDA is caused by severely reduced levels of frataxin, a mitochondrial protein of unknown function. Yeast knockout models as well as histological and biochemical data from heart biopsies or autopsies of FRDA patients have shown that frataxin defects cause a specific iron-sulfur protein deficiency and intramitochondrial iron accumulation. We have recently shown that complete absence of frataxin in the mouse leads to early embryonic lethality, demonstrating an important role for frataxin during mouse development. Through a conditional gene-targeting approach, we have generated in parallel a striated muscle frataxin-deficient line and a neuron/cardiac muscle frataxin-deficient line, which together reproduce important progressive pathophysiological and biochemical features of the human disease: cardiac hypertrophy without skeletal muscle involvement, large sensory neuron dysfunction without alteration of the small sensory and motor neurons, and deficient activities of complexes I-III of the respiratory chain and of the aconitases. Our models demonstrate time-dependent intramitochondrial iron accumulation in a frataxin-deficient mammal, which occurs after onset of the pathology and after inactivation of the Fe-S-dependent enzymes. These mutant mice represent the first mammalian models to evaluate treatment strategies for the human disease.

Animals↗

PubMed2001

The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin.

The newly recognized ataxia-ocular apraxia 1 (AOA1; MIM 208920) is the most frequent cause of autosomal recessive ataxia in Japan and is second only to Friedreich ataxia in Portugal. It shares several neurological features with ataxia-telangiectasia, including early onset ataxia, oculomotor apraxia and cerebellar atrophy, but does not share its extraneurological features (immune deficiency, chromosomal instability and hypersensitivity to X-rays). AOA1 is also characterized by axonal motor neuropathy and the later decrease of serum albumin levels and elevation of total cholesterol. We have identified the gene causing AOA1 and the major Portuguese and Japanese mutations. This gene encodes a new, ubiquitously expressed protein that we named aprataxin. This protein is composed of three domains that share distant homology with the amino-terminal domain of polynucleotide kinase 3'- phosphatase (PNKP), with histidine-triad (HIT) proteins and with DNA-binding C2H2 zinc-finger proteins, respectively. PNKP is involved in DNA single-strand break repair (SSBR) following exposure to ionizing radiation and reactive oxygen species. Fragile-HIT proteins (FHIT) cleave diadenosine tetraphosphate, which is potentially produced during activation of the SSBR complex. The results suggest that aprataxin is a nuclear protein with a role in DNA repair reminiscent of the function of the protein defective in ataxia-telangiectasia, but that would cause a phenotype restricted to neurological signs when mutant.

Amino Acid Sequence↗

PubMed2001

Quantitative assessment of the ischemic brain by means of perfusion-related parameters derived from perfusion CT.

BACKGROUND AND PURPOSE: Besides the delineation of hypoperfused brain tissue, the characterization of ischemia with respect to severity is of major clinical relevance, because the degree of hypoperfusion is the most critical factor in determining whether an ischemic lesion becomes an infarct or represents viable brain tissue. CT perfusion imaging yields a set of perfusion related parameters which might be useful to describe the hemodynamic status of the ischemic brain. Our objective was to determine whether measurements of the relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), and relative time to peak (rTP) can be used to differentiate areas undergoing infarction from reversible ischemic tissue. METHODS: In 34 patients with acute hemispheric ischemic stroke <6 hours after onset, perfusion CT was used to calculate rCBF, rCBV, and rTP values from areas of ischemic cortical and subcortical gray matter. Results were obtained separately from areas of infarction and noninfarction, according to the findings on follow-up imaging studies. The efficiency of each parameter to predict tissue outcome was tested. RESULTS: There was a significant difference between infarct and peri-infarct tissue for both rCBF and rCBV but not for rTP. Threshold values of 0.48 and 0.60 for rCBF and rCBV, respectively, were found to discriminate best between areas of infarction and noninfarction, with the efficiency of the rCBV being slightly superior to that of rCBF. The prediction of tissue outcome could not be increased by using a combination of various perfusion parameters. CONCLUSIONS: The assessment of cerebral ischemia by means of perfusion parameters derived from perfusion CT provides valuable information to predict tissue outcome. Quantitative analyses of the severity of ischemic lesions should be implemented into the diagnostic management of stroke patients.

Aged↗

PubMed2000

Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation.

Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is caused in almost all cases by homozygous intronic expansions resulting in the loss of frataxin, a mitochondrial protein conserved through evolution, and involved in mitochondrial iron homeostasis. Yeast knockout models, and histological and biochemical data from patient heart biopsies or autopsies indicate that the frataxin defect causes a specific iron-sulfur protein deficiency and mitochondrial iron accumulation leading to the pathological changes. Affected human tissues are rarely available to further examine this hypothesis. To study the mechanism of the disease, we generated a mouse model by deletion of exon 4 leading to inactivation of the Frda gene product. We show that homozygous deletions cause embryonic lethality a few days after implantation, demonstrating an important role for frataxin during early development. These results suggest that the milder phenotype in humans is due to residual frataxin expression associated with the expansion mutations. Surprisingly, in the frataxin knockout mouse, no iron accumulation was observed during embryonic resorption, suggesting that cell death could be due to a mechanism independent of iron accumulation.

Animals↗

PubMed2000

Recent advances in the molecular pathogenesis of Friedreich ataxia.

Friedreich ataxia, the most frequent cause of recessive ataxia, is due in most cases to a homozygous intronic expansion resulting in the loss of function of frataxin. Frataxin is a mitochondrial protein conserved through evolution. Yeast knock-out models and histological data from patient heart autopsies have shown that frataxin defect causes mitochondrial iron accumulation. Biochemical data from patient heart biopsies or autopsies have revealed a specific deficiency in the activities of aconitases and of mitochondrial iron-sulfur proteins. These results suggest that frataxin may play a role either in mitochondrial iron transport or in iron-sulfur cluster assembly or transport. Iron abnormalities suggest a pathogenic mechanism involving free radical production and oxidative stress, a process that might be sensitive to antioxidant therapies.

Friedreich Ataxia↗

PubMed2000

The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy.

Disorganization of the neurofilament network is a prominent feature of several neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy and axonal Charcot-Marie-Tooth disease. Giant axonal neuropathy (GAN, MIM 256850), a severe, autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system, is characterized by neurofilament accumulation, leading to segmental distension of the axons. GAN corresponds to a generalized disorganization of the cytoskeletal intermediate filaments (IFs), to which neurofilaments belong, as abnormal aggregation of multiple tissue-specific IFs has been reported: vimentin in endothelial cells, Schwann cells and cultured skin fibroblasts, and glial fibrillary acidic protein (GFAP) in astrocytes. Keratin IFs also seem to be alterated, as most patients present characteristic curly or kinky hairs. We report here identification of the gene GAN, which encodes a novel, ubiquitously expressed protein we have named gigaxonin. We found one frameshift, four nonsense and nine missense mutations in GAN of GAN patients. Gigaxonin is composed of an amino-terminal BTB (for Broad-Complex, Tramtrack and Bric a brac) domain followed by a six kelch repeats, which are predicted to adopt a beta-propeller shape. Distantly related proteins sharing a similar domain organization have various functions associated with the cytoskeleton, predicting that gigaxonin is a novel and distinct cytoskeletal protein that may represent a general pathological target for other neurodegenerative disorders with alterations in the neurofilament network.

Abnormalities, Multiple↗

PubMed2000

Giant axonal neuropathy locus refinement to a < 590 kb critical interval.

Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder, characterised clinically by the development of chronic distal polyneuropathy during childhood, mental retardation, kinky or curly hair, skeletal abnormalities and, ultrastructurally, by axons in the central and peripheral nervous systems distended by masses of tightly woven neurofilaments. We recently localised the GAN locus in 16q24.1 to a 5-cM interval between the D16S507 and D16S511 markers by homozygosity mapping in three consanguineous Tunisian families. We have now established a contig-based physical map of the region comprising YACs and BACs where we have placed four genes, ten ESTs, three STSs and two additional microsatellite markers, and where we have identified six new SSCP polymorphisms and six new microsatellite markers. Using these markers, we have refined the position of our previous flanking recombinants. We also identified a shared haplotype between two Tunisian families and a small region of homozygosity in a Turkish family with distant consanguinity, both suggesting the occurrence of historic recombinations and supporting the conclusions based on the phase-known recombinations. Taken together, these results allow us to establish a transcription map of the region, and to narrow down the GAN position to a < 590 kb critical interval, an important step toward the identification of the defective gene.

Axons↗

PubMed2000

Homozygosity mapping of spinocerebellar ataxia with cerebellar atrophy and peripheral neuropathy to 9q33-34, and with hearing impairment and optic atrophy to 6p21-23.

With the availability of a simple molecular test that distinguishes Friedreich ataxia, the most frequent form of inherited ataxia, from other recessive ataxias, it now becomes possible to unravel the genetic heterogeneity of the latter. We have now localised two genes causing autosomal recessive spinocerebellar ataxia in two consanguineous families. In the first family, the four affected Japanese sibs had spinocerebellar ataxia associated with elevated levels of serum creatine kinase, gamma-globulin, and alpha-foetoprotein. Homozygosity over a 20 cM region allowed to demonstrate linkage at 9q33.3-34.3 with a lod score of 3.0. Genotyping two unrelated Japanese patients from first degree consanguineous parents revealed that one was homozygous for the same region but did not share the biochemical features. In the second family, an Israeli uncle and a niece were affected by an early-onset recessive ataxia and subsequently developed hearing impairment and optic atrophy. Homozygosity over a 17 cM region allowed demonstration of linkage at 6p21-23 with a lod score of 3.25. These two localisations of autosomal recessive ataxia genes represent a first step toward the identification of genetically homogenous, non-Friedreich, ataxic patients and subsequent cloning of the genes.

Chromosome Mapping↗

PubMed2000

Explanations for the observed increase in fast electron penetration in laser shock compressed materials

We analyze recent experimental results on the increase of fast electron penetration in shock compressed plastic [Phys. Rev. Lett. 81, 1003 (1998)]. It is explained by a combination of stopping power and electric field effects, which appear to be important even at laser intensities as low as 10(16) W cm-2. An important conclusion is that fast electron induced heating must be taken into account, changing the properties of the material in which the fast electrons propagate. In insulators this leads to a rapid insulator to conductor phase transition.

Journal Article↗

PubMed2000

Foam-induced smoothing studied through laser-driven shock waves

The influence of foams on the uniformity of laser energy deposition has been studied by measuring laser-driven shock waves breakout from foam-aluminum layered targets. Well characterized laser nonuniformities have been produced first by using phase zone plates to get a smooth beam and then by inserting different opaque grids before the foam. Smoothing has been studied as a function of foam density and grid materials (producing different radiative effects).

Journal Article↗

PubMed2000

Experimental evidence of electric inhibition in fast electron penetration and of electric-field-limited fast electron transport in dense matter

Fast electron generation and propagation were studied in the interaction of a green laser with solids. The experiment, carried out with the LULI TW laser (350 fs, 15 J), used K(alpha) emission from buried fluorescent layers to measure electron transport. Results for conductors (Al) and insulators (plastic) are compared with simulations: in plastic, inhibition in the propagation of fast electrons is observed, due to electric fields which become the dominant factor in electron transport.

Journal Article↗

PubMed2000

Frataxin point mutations in two patients with Friedreich's ataxia and unusual clinical features.

Two patients with a progressive ataxia are presented with clinical features consistent with classic Friedreich's ataxia (FRDA), but also with features unusual for FRDA. Analysis of DNA showed that each patient is heterozygous for the expanded GAA repeat of FRDA, but carries a base change on his other frataxin allele. For one patient a non-conservative arginine to cysteine amino acid change is predicted at amino acid 165 whereas the other mutation is found at the junction of exon one and intron one. Muscle biopsy showed an absence of frataxin immunoreactivity in the patient harbouring the intronic mutation, confirming the pathological nature of the base change. These mutations extend the range of point mutations seen in FRDA, and agree with recent reports suggesting phenotypic variation in patients with FRDA harbouring point mutations in conjunction with an expanded GAA repeat.

Child↗

PubMed1999

Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes.

Friedreich's ataxia is the most common inherited ataxia. Ninety-six percent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. We report here the identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families. Most truncating mutations were in exon 1. All missense mutations were in the last three exons coding for the mature frataxin protein. The clinical features of 25 patients with identified frataxin point mutations were compared with those of 196 patients homozygous for the GAA expansion. A similar phenotype resulted from truncating mutations and from missense mutations in the carboxy-terminal half of mature frataxin, suggesting that they cause a comparable loss of function. In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function. The incidence of optic disk pallor was higher in compound heterozygotes than in expansion homozygotes, which might correlate with a very low residual level of normal frataxin produced from the expanded allele.

Adolescent↗

PubMed1999

G130V, a common FRDA point mutation, appears to have arisen from a common founder.

Friedreich ataxia (FRDA) is the most common inherited ataxia. About 98% of mutant alleles have an expansion of a GAA trinucleotide repeat in intron 1 of the affected gene, FRDA. The other 2% are point mutations. Of the 17 point mutations so far described, three appear to be more common. One of these is the G130V mutation in exon 4 of FRDA. G130V, when present with an expanded GAA repeat on the other allele, is associated with an atypical FRDA phenotype. Haplotype analysis was undertaken on the four families who have been described with this mutation. The results suggest a common founder for this mutation. Although marked differences in extragenic marker haplotypes were seen in one family, similar intragenic haplotyping suggests the same mutation founder for this family with the differences explicable by two recombination events.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Chirped pulse reflectivity and frequency domain interferometry in laser driven shock experiments.

We show the simultaneous applicability of the frequency domain interferometry and the chirped pulse reflectometry techniques to measure shock parameters. The experiment has been realized with the laser at the Laboratoire pour l'Utilisation des Lasers Intenses (LULI) with a 550-ps pulse duration and an intensity on target approximately 5 x 10(13) W/cm(2) to produce a shock in a layered aluminum-fused silica target. A second low energy, partially compressed chirped probe beam was used to irradiate the target rear side and the reflected light has been analyzed with a spectrometer, achieving a temporal resolution of the order of 1 ps.

Journal Article↗

PubMed1999

Clinical nosologic and genetic aspects of Joubert and related syndromes.

Joubert syndrome is an autosomal-recessive disorder characterized by cerebellar hypoplasia, hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The biochemical and genetic basis of Joubert syndrome is unknown and a specific chromosomal locus for this disorder has not been identified. Review of this disorder and related syndromes suggests that (1) hypoplasia of the cerebellar vermis in Joubert syndrome is frequently associated with a complex brain stem malformation represented as the "molar tooth sign" on magnetic resonance imaging, (2) the "molar tooth sign" could be present in association with the Dandy-Walker malformation and occipital encephalocele, (3) cerebellar hypoplasia is present in conditions related to Joubert syndrome such as Arima syndrome; Senior-Loken syndrome; cerebellar vermian hypoplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis syndrome; and juvenile nephronophthisis due to NPH1 mutations, and (4) the brainstem-vermis malformation spectrum is probably caused by at least two and probably several genetic loci. We have ascertained previously a cohort of 50 patients with a putative diagnosis of Joubert syndrome in order to evaluate the presence of associated malformations, and to initiate studies leading to the identification of genes causing Joubert and related syndromes. Among the associated malformations found in patients ascertained as having Joubert syndrome, 8% of patients had polydactyly, 4% had ocular colobomas, 2% had renal cysts, and 2% had soft-tissue tumors of the tongue. The WNT1 gene has been tested as a candidate gene for Joubert syndrome based on its expression in the developing cerebellum and an associated mutation in the swaying mouse. A search for mutations in WNT1 in a series of patients with Joubert syndrome did not detect mutations at this locus. This analysis suggested that mutations in WNT1 might not have a significant role in Joubert syndrome, and other functional candidate genes related to development of the cerebellum need to be examined. A genome-wide linkage analysis carried out in 10 Joubert syndrome pedigrees did not identify a specific chromosomal locus for this disorder. This observation, along with those from clinical studies, provides further evidence that Joubert and related syndromes are genetically heterogeneous.

Animals↗