Biomedical subjects

M Koenig

Publications and source records attributed to M Koenig.

At least 73 records · Page 4Linked to original sources

PubMed1999

[The bronchorelaxant effect of helicidine, a Helix pomatia extract, interferes with prostaglandin E2].

Helicidine is a biological extract prepared from the snail Helix pomatia L. and used in man as an anti-tussive agent. However, its mechanisms of action are not fully defined. In this study, we have investigated a possible relaxant effect of helicidine on guinea-pig airway smooth muscle and evaluated the role of prostanoids and airway epithelium in this relaxation. H. pomatia extract (0.001-1 mg/ml) induced a dose-dependent relaxation of guinea-pig trachea pre-contracted with histamine both in the presence and absence of tracheal epithelium. No significant difference in dose-dependency or magnitude of the relaxation was observed between tracheal segments with or without epithelium (maximal relaxant response of 35 +/- 7 and 25 +/- 7.5%, respectively). Relaxation of the trachea induced by H. pomatia extract (0.001-1 mg/ml) was inhibited by pre-treatment with the cyclooxygenase inhibitor, indomethacin, both in the presence or absence of tracheal epithelium. H. pomatia extract (1 mg/ml) induced a marked and significant increase in prostaglandin E2 release in tracheal segments with and without epithelium. These results indicate that helicidine possesses a broncho-relaxant activity which is independent of epithelium integrity and which is partly mediated by the release of the relaxant prostanoid, prostaglandin E2. The origin of prostaglandin E2 production in the airways remains to be defined.

Animals↗

PubMed1999

Discordant radiograph interpretation between emergency physicians and radiologists in a pediatric emergency department.

OBJECTIVES: To describe the types of discrepancies in radiograph interpretation between emergency physicians and radiologists in a pediatric emergency department, and to determine the impact of discrepant interpretations on patient care. METHODS: Prospective cohort study of discordant radiographs from the period beginning March 1, 1995 and ending March 31, 1996. During this period, 2083 radiographs were coded by the radiologist as concordant or discordant. Three hundred forty-nine were coded as discordant, and 324 were eligible for the study. Charts were reviewed for relevant physical examination findings and emergency department management. Discrepancies that affected patient care were deemed clinically significant. RESULTS: Twenty-three (1.1%) of 2083 radiographs were interpreted differently by the emergency physician and the radiologist in a way that might have changed patient management. This represents 7% (23/324) of the radiographs originally coded by a radiologist as discrepant. The most common discrepancy was a patient with a normal chest examination and a radiograph interpreted as having an infiltrate by the emergency physician, but subsequently read as having no infiltrate by a radiologist (12/324). These patients may have received antibiotics unnecessarily. Two discrepant interpretations had the potential to have serious consequences to the patient if not identified. One patient with cardiomegaly and another patient with free air on abdominal radiograph were not noted by the emergency physician. CONCLUSIONS: Emergency physicians would benefit from more rigorous interpretation of chest x-rays to avoid unnecessary treatment with antibiotics. Emergency physicians do a good job interpreting plain radiographs, but occasionally miss significant findings that could lead to adverse outcomes. The presence of radiologists to immediately read radiographs 24 hours a day could prevent missed findings, but, given the small number of significant misinterpretations, is unlikely to be cost effective.

Bone and Bones↗

PubMed1998

Supplemental therapy in isolated vitamin E deficiency improves the peripheral neuropathy and prevents the progression of ataxia.

A 24-year-old male, who suffered since childhood from a progressive form of ataxia associated with peripheral neuropathy, was found severely deficient in serum vitamin E. He walked with bilateral aid and presented severe dysmetria of the limbs and dysarthric speech; muscular strength and trophism were slightly diminished in the distal muscles of four limbs and there was hypotonia of the arms; he presented absent deep tendon reflexes, bilateral Babinski's sign, reduced proprioception at four limbs, pes cavus and fasciculations of the tongue. Intestinal fat malabsorption and other gastrointestinal or haematological conditions associated with deficiency of this vitamin were ruled out. In this patient, after 2 years of a daily supplement of high doses of vitamin E, a further progression of the disease was not observed and, moreover, the neurophysiological characteristics of his neuropathy appeared clearly improved. A longitudinal evaluation of serum vitamin E levels showed values in the normal range after 13 months of therapy. The patient had molecular genetic analysis of chromosome 8 and was found homozygous for the unusual mutation 513insTT in the alpha-tocopherol transfer protein gene.

Administration, Oral↗

PubMed1998

Familial spinocerebellar ataxia with cerebellar atrophy, peripheral neuropathy, and elevated level of serum creatine kinase, gamma-globulin, and alpha-fetoprotein.

Here, we report a familial spinocerebellar ataxia (FSCA), which has clinical features similar to Friedreich's ataxia, an ataxia with isolated vitamin E deficiency, and ataxia telangiectasia. However, the serum levels of creatine kinase, gamma-globulin, and alpha-fetoprotein were elevated, and biochemical and genetic analyses ruled out diagnosis of these three ataxias as well as other FSCAs. Thus, this family is thought to have a new type of FSCA.

Adult↗

PubMed1998

Mutation of the start codon in the FRDA1 gene: linkage analysis of three pedigrees with the ATG to ATT transversion points to a unique common ancestor.

Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder caused by loss-of-function mutations in the gene encoding frataxin. Most patients with FRDA have trinucleotide repeat expansions in both alleles of the FRDA 1 gene. In patients heterozygous for the expansion the second allele may be inactivated by a point mutation. We identified the ATG-->ATT (M11) mutation of the start codon in three independent families. Individuals with symptoms of FRDA in these families are compound heterozygous for the repeat expansion and the ATG mutation. To look for a common founder of the M11 mutation, a detailed linkage analysis employing six polymorphic chromosome 9 markers was performed. We found complete haplotype identity for two of the three chromosomes with the point mutation. The third case shows partial conformity and may be the result of a single recombination event.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families.

Ataxia with vitamin E deficiency (AVED), or familial isolated vitamin E deficiency, is a rare autosomal recessive neurodegenerative disease characterized clinically by symptoms with often striking resemblance to those of Friedreich ataxia. We recently have demonstrated that AVED is caused by mutations in the gene for alpha-tocopherol transfer protein (alpha-TTP). We now have identified a total of 13 mutations in 27 families. Four mutations were found in >=2 independent families: 744delA, which is the major mutation in North Africa, and 513insTT, 486delT, and R134X, in families of European origin. Compilation of the clinical records of 43 patients with documented mutation in the alpha-TTP gene revealed differences from Friedreich ataxia: cardiomyopathy was found in only 19% of cases, whereas head titubation was found in 28% of cases and dystonia in an additional 13%. This study represents the largest group of patients and mutations reported for this often misdiagnosed disease and points to the need for an early differential diagnosis with Friedreich ataxia, in order to initiate therapeutic and prophylactic vitamin E supplementation before irreversible damage develops.

Adolescent↗

PubMed1998

Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase.

Frataxin is a mitochondrial protein deficient in Friedreich ataxia (FRDA) and which is associated with abnormal intramitochondrial iron handling. We identified the mitochondrial processing peptidase beta (MPPbeta) as a frataxin protein partner using the yeast two-hybrid assay. In in vitro assays, MPPbeta binds frataxin which is cleaved by the reconstituted MPP heterodimer. MPP cleavage of frataxin results in an intermediate form (amino acids 41-210) that is processed further to the mature form. In vitro and in vivo experiments suggest that two C-terminal missense mutations found in FRDA patients modulate interaction with MPPbeta, resulting in a slower maturation process at the normal cleavage site. The slower processing rate of frataxin carrying such missense mutations may therefore contribute to frataxin deficiency, in addition to an impairment of its function.

Animals↗

PubMed1998

Operation Red Box: a pilot project of needle and syringe drop boxes for injection drug users in East Baltimore.

We assessed the acceptability and the use of a community-based needle and syringe disposal project designed to serve injection drug users. In June 1996, three surplus U.S. mail collection boxes were painted red and used as syringe and needle drop boxes in locations with high drug use in East Baltimore. Acceptance of the drop boxes was measured by focus groups of residents, drug users, and police, held before and after project implementation. Use was measured by weekly counts of needles recovered from the red boxes. A sample of all deposited needles was randomly chosen for needle washing and subsequent HIV antibody testing. Community impact was measured by systematic surveys of needles discarded on public sidewalks, in areas with and areas without drop boxes. Before implementation, members of focus groups expressed concerns that drop boxes could convey mixed messages to youth (e.g., seeming to condone drug use), might result in increased loitering, and could further community stigmatization. After project implementation, all focus groups expressed support of project expansion. In the first 10 months, 2971 needles were collected. Of 156 needles tested, 10.9% were positive for HIV antibody. Needle counts on the street showed no significant change in red box areas compared with control areas. In this pilot project, red boxes were accepted by the community and drug users. Police officers also used the boxes to dispose of confiscated needles. Although limited in the number of drop boxes and follow-up time, this pilot project shows promise as a community-based method of safe needle disposal.

Adolescent↗

PubMed1998

Perfusion CT of the brain: diagnostic approach for early detection of ischemic stroke.

PURPOSE: To determine the value of perfusion computed tomography (CT) in a clinical study of patients with stroke and compare the results with single photon emission CT (SPECT) findings. MATERIALS AND METHODS: Perfusion CT was performed within 6 hours of symptom onset in 32 patients with possible stroke. Cerebral blood volume (CBV), cerebral blood flow (CBF), and time to peak contrast material enhancement were calculated on the basis of the CT results. Cerebral SPECT was also performed in a subgroup of 18 patients. Perfusion CT and SPECT findings were compared in a lesion-by-lesion analysis. Perfusion CT results were compared with follow-up CT and magnetic resonance imaging findings. RESULTS: Areas of reduced CBF were detected with the aid of perfusion CT in 25 of 28 patients with a proved infarct (sensitivity, 89%). The results of the CBF maps corresponded well to SPECT findings in 13 (81%) of 16 patients, but ischemia was located outside the scanning level in the other three patients and was therefore missed. Perfusion CT revealed various changes in CBF, CBV, and time to peak enhancement in ischemic territories. CONCLUSION: Perfusion CT not only allows early detection of cerebral ischemia but also yields valuable information about the extent of perfusion disturbances.

Adult↗

PubMed1997

Evolution of the Friedreich's ataxia trinucleotide repeat expansion: founder effect and premutations.

Friedreich's ataxia, the most frequent inherited ataxia, is caused, in the vast majority of cases, by large GAA repeat expansions in the first intron of the frataxin gene. The normal sequence corresponds to a moderately polymorphic trinucleotide repeat with bimodal size distribution. Small normal alleles have approximately eight to nine repeats whereas a more heterogeneous mode of large normal alleles ranges from 16 to 34 GAA. The latter class accounts for approximately 17% of normal alleles. To identify the origin of the expansion mutation, we analyzed linkage disequilibrium between expansion mutations or normal alleles and a haplotype of five polymorphic markers within or close to the frataxin gene; 51% of the expansions were associated with a single haplotype, and the other expansions were associated with haplotypes that could be related to the major one by mutation at a polymorphic marker or by ancient recombination. Of interest, the major haplotype associated with expansion is also the major haplotype associated with the larger alleles in the normal size range and was almost never found associated with the smaller normal alleles. The results indicate that most if not all large normal alleles derive from a single founder chromosome and that they represent a reservoir for larger expansion events, possibly through "premutation" intermediates. Indeed, we found two such alleles (42 and 60 GAA) that underwent cataclysmic expansion to pathological range in a single generation. This stepwise evolution to large trinucleotide expansions already was suggested for myotonic dystrophy and fragile X syndrome and may relate to a common mutational mechanism, despite sequence motif differences.

Alleles↗

PubMed1997

Correlation between left ventricular hypertrophy and GAA trinucleotide repeat length in Friedreich's ataxia.

BACKGROUND: Friedreich's ataxia (FA), the most common inherited ataxia, is associated frequently with cardiac hypertrophy, and death is often cardiac related. Recently, the disease has been associated with a mutation that consists of an unstable expansion of GAA repeats in the first intron of the gene encoding frataxin on chromosome 9. METHODS AND RESULTS: We studied 44 consecutive patients with FA, determined the size of GAA expansions in the frataxin gene, and examined the relation between the genotype and cardiac phenotype assessed by M-mode and two-dimensional echocardiography. All the patients were homozygous for the mutation. The size of the GAA expansion on the smaller allele varied from 270 to 1200. We found a correlation between the size of GAA expansion and the left ventricular wall thickness (r = .51, P < .001) and the left ventricular mass index (r = .45, P = .002). Left ventricular hypertrophy was observed in 81% of patients with a number of GAA repeats above the median value of 770 compared with only 14% in the other group (P = .002). CONCLUSIONS: These data demonstrate that in FA, the severity of left ventricular hypertrophy is related to the number of GAA repeats. These results suggest that abnormalities of the gene encoding frataxin, a protein of unknown function highly expressed in the normal heart, may play an important role in the modulation of cardiac hypertrophy.

Adult↗

PubMed1997

Homozygosity mapping of giant axonal neuropathy gene to chromosome 16q24.1.

Giant axonal neuropathy (GAN) is a rare autosomal recessive disorder described as a symmetrical distal neuropathy, with peripheral axons dilated by accumulation of 10 nm neurofilaments (NF) and a severe course of the disease. The observation of kinky or curly hairs is not a constant finding. The GAN1 locus was localized by homozygosity mapping to chromosome 16 q24.1 in a 3 (4) cM interval flanked by the markers D16S3073 and D16S505 (D16S511) in three non-related Tunisian families, showing a genetic homogeneity in these families. Two point lod-score calculation between the linked haplotype and the disease locus was 14.2 at theta(max) = 0. The patients share a slow course of the disease. The differences in the course of the disease between Tunisian and non-Tunisian patients suggest a possible genetic heterogeneity, which is why the present linkage has been referred to as GAN1. The biochemical defect in GAN1 should help to understand the mechanisms involved in NF accumulations as in other neurological diseases (ALS, SMA).

Axons↗

PubMed1997

Deciphering the cause of Friedreich ataxia.

Friedreich ataxia (FA), the most frequent cause of recessive ataxia, is attributable, in most cases, to a large expansion of an intronic GAA repeat, resulting in decreased expression of the target frataxin gene. This gene encodes a novel mitochondrial protein that has homologues of unknown function in yeast and even in gram-negative bacteria. Yeast deficient in the frataxin homologue accumulate iron in their mitochondria and show increased sensitivity to oxidative stress. This finding suggests that FA patients suffer from a mitochondrial dysfunction that causes free-radical toxicity, reminiscent of the clinically similar ataxia caused by inherited isolated vitamin E deficiency.

Animals↗

PubMed1997

Frataxin fracas.

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Female↗

PubMed1997

Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin.

Friedreich's ataxia is due to loss of function mutations in the gene encoding frataxin (FRDA). Frataxin is a protein of unknown function. In situ hybridization analyses revealed that mouse frataxin expression correlates well with the main site of neurodegeneration, but the expression pattern is broader than expected from the pathology of the disease. Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate, including liver, kidney, brown fat and heart. We found that mouse and yeast frataxin homologues contain a potential mitochondrial targeting sequence in their N-terminal domains and that disruption of the yeast gene results in mitochondrial dysfunction. Finally, tagging experiments demonstrate that human frataxin co-localizes with a mitochondrial protein. Friedreich's ataxia is therefore a mitochondrial disease caused by a mutation in the nuclear genome.

Amino Acid Sequence↗

PubMed1997

Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia.

Friedreich ataxia (FRDA) is a common autosomal recessive degenerative disease (1/50,000 live births) characterized by a progressive-gait and limb ataxia with lack of tendon reflexes in the legs, dysarthria and pyramidal weakness of the inferior limbs. Hypertrophic cardiomyopathy is observed in most FRDA patients. The gene associated with the disease has been mapped to chromosome 9q13 (ref. 3) and encodes a 210-amino-acid protein, frataxin. FRDA is caused primarily by a GAA repeat expansion within the first intron of the frataxin gene, which accounts for 98% of mutant alleles. The function of the protein is unknown, but an increased iron content has been reported in hearts of FRDA patients and in mitochondria of yeast strains carrying a deleted frataxin gene counterpart (YFH1), suggesting that frataxin plays a major role in regulating mitochondrial iron transport. Here, we report a deficient activity of the iron-sulphur (Fe-S) cluster-containing subunits of mitochondrial respiratory complexes I, II and III in the endomyocardial biopsy of two unrelated FRDA patients. Aconitase, an iron-sulphur protein involved in iron homeostasis, was found to be deficient as well. Moreover, disruption of the YFH1 gene resulted in multiple Fe-S-dependent enzyme deficiencies in yeast. The deficiency of Fe-S-dependent enzyme activities in both FRDA patients and yeast should be related to mitochondrial iron accumulation, especially as Fe-S proteins are remarkably sensitive to free radicals. Mutated frataxin triggers aconitase and mitochondrial Fe-S respiratory enzyme deficiency in FRDA, which should therefore be regarded as a mitochondrial disorder.

Aconitate Hydratase↗

PubMed1997

Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes.

Friedreich ataxia is a progressive neurodegenerative disorder caused by loss of function mutations in the frataxin gene. In order to unravel frataxin function we developed monoclonal antibodies raised against different regions of the protein. These antibodies detect a processed 18 kDa protein in various human and mouse tissues and cell lines that is severely reduced in Friedreich ataxia patients. By immunocytofluorescence and immunocytoelectron microscopy we show that frataxin is located in mitochondria, associated with the mitochondrial membranes and crests. Analysis of cellular localization of various truncated forms of frataxin expressed in cultured cells and evidence of removal of an N-terminal epitope during protein maturation demonstrated that the mitochondrial targetting sequence is encoded by the first 20 amino acids. Given the shared clinical features between Friedreich ataxia, vitamin E deficiency and some mitochondriopathies, our data suggest that a reduction in frataxin results in oxidative damage.

Amino Acid Sequence↗

PubMed1996

Clinical and genetic abnormalities in patients with Friedreich's ataxia.

BACKGROUND: Friedreich's ataxia, the most common inherited ataxia, is associated with a mutation that consists of an unstable expansion of GAA repeats in the first intron of the frataxin gene on chromosome 9, which encodes a protein of unknown function. METHODS: We studied 187 patients with autosomal recessive ataxia, determined the size of the GAA expansions, and analyzed the clinical manifestations in relation to the number of GAA repeats and the duration of disease. RESULTS: One hundred forty of the 187 patients, with ages at onset ranging from 2 to 51 years, were homozygous for a GAA expansion that had 120 to 1700 repeats of the trinucleotides. About one quarter of the patients, despite being homozygous, had atypical Friedreich's ataxia; they were older at presentation and had intact tendon reflexes. Larger GAA expansions correlated with earlier age at onset and shorter times to loss of ambulation. The size of the GAA expansions (and particularly that of the smaller of each pair) was associated with the frequency of cardiomyopathy and loss of reflexes in the upper limbs. The GAA repeats were unstable during transmission. CONCLUSIONS: The clinical spectrum of Friedreich's ataxia is broader than previously recognized, and the direct molecular test for the GAA expansion on chromosome 9 is useful for diagnosis, determination of prognosis, and genetic counseling.

Adolescent↗