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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Cellular and molecular life sciences 41 (1985), S. 415-417 
    ISSN: 1420-9071
    Keywords: Facial nerve ; hemifacial spasm ; synkinesis ; intraoperative recordings
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary We show evidence that the motonucleus of the facial nerve is involved in producing the synkinesis in patients with hemifacial spasm. These results were obtained by recording from the intracranial portion of the facial nerve and from the orbicularis oculi muscle in patients operated upon for hemifacial spasm during electrical stimulation of the mandibular branch of the facial nerve. Also, the electromyographic response from the same muscle was recorded when the facial nerve was electrically stimulated at a location near the brainstem. The results show that it is unlikely that the symptoms of patients with hemifacial spasm can be explained on the basis of ephaptic transmission at the site of lesion of the facial nerve.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: Keywords Uncoupling protein 2 ; obesity ; genetics ; insulin resistance ; amino acid polymorphism.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Recently, a gene encoding a novel human uncoupling protein, designated UCP2, was discovered. The murine UCP2 was mapped to a region on mouse chromosome 7 which in several models has been shown to be linked to obesity and hyperinsulinaemia. Single strand conformation polymorphism (SSCP) analysis and direct sequencing of the coding region of the UCP2 gene in 35 obese Caucasian NIDDM patients of Danish ancestry revealed one nucleotide substitution, replacing an alanine with a valine at codon 55. The amino acid polymorphism was present in 24 of the 35 (69 %) examined subjects. The allelic frequency of the A/V55 variant was 48.3 % (95 % CI: 42.5–54.1 %) among 144 subjects with juvenile onset obesity, 45.6 % (40.5–50.7 %) among 182 subjects randomly selected at the draft board examination, and 45.5 % (37.1–53.9 %) among lean control subjects selected from the same study cohort. Within these cohorts there were no differences in BMI values at different ages among wild-type carriers and A/V55 carriers. In a population-based sample of 369 young healthy Caucasians the variant showed no association with alterations in BMI, waist-to-hip ratio, fat mass or weight gain during childhood or adolescence. The A/V55 polymorphism was not related to alterations in fasting values of serum insulin and C-peptide or to an impaired insulin sensitivity index. We conclude that genetic variability in the human UCP2 gene is not a common factor contributing to NIDDM in obese Danish Caucasian subjects and the common A/V55 amino acid polymorphism of the gene is not implicated in the pathogenesis of juvenile or maturity onset obesity or insulin resistance in Caucasians. [Diabetologia (1997) 40: 1227–1230]
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0428
    Keywords: Keywords HNF-1α ; genetics ; mutation ; maturity onset diabetes of the young ; non-insulin-dependent diabetes mellitus.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Non-insulin-dependent diabetes mellitus (NIDDM) is a phenotypically and genetically heterogeneous disorder. A recent random genome mapping study has localized a locus termed NIDDM2 that maps to the region of chromosome 12 that includes MODY3, one of the three genes responsible for maturity-onset diabetes of the young, a monogenic form of NIDDM characterized by early age of onset and autosomal dominant inheritance. These findings suggest that NIDDM2 and MODY3 may represent different alleles of the same gene. MODY3 has recently been shown to be the gene encoding the transcription factor hepatocyte nuclear factor-1α (HNF-1α) thereby allowing us to determine whether mutations in the HNF-1α gene are present in subjects with late-onset NIDDM. We screened 84 white NIDDM patients of Danish ancestry and found four nucleotide substitutions that changed the sequence of HNF-1α, Ile27→Leu, Ala98→Val, Ser487→Asn and Arg583 →Gln, five nucleotide substitutions that were silent and did not change the amino acid, Leu17, Gly288, Leu459 and Thr515, and five substitutions in the intron regions. The frequencies of the codon 27, 98 and 487 amino acid variants were similar in 245 unrelated NIDDM patients and 242 age-matched control subjects. The Arg583→Gln mutation was found in 2 of 245 NIDDM patients and in none of the control subjects. Thus, genetic variation in the HNF-1α gene is not a common factor contributing to NIDDM susceptibility in white subjects of Danish ancestry. [Diabetologia (1997) 40: 473–475]
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Keywords: Keywords Southern hybridization ; in situ hybridization ; total RNA ; skeletal muscle ; RT-PCR-SSCP analysis ; mutations ; NIDDM.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Activation of glycogen synthesis in skeletal muscle in response to insulin results from the combined inactivation of glycogen synthase kinase-3 (GSK-3) and activation of the protein phosphatase-1, changing the ratio between the inactive phosphorylated state of the glycogen synthase to the active dephosphorylated state. In a search for genetic defects responsible for the decreased insulin stimulated glycogen synthesis seen in patients with non-insulin-dependent diabetes mellitus (NIDDM) and their glucose-tolerant first-degree relatives we have performed mutational analysis of the coding region of the 2 isoforms of GSK-3α and GSK-3β in 72 NIDDM patients and 12 control subjects. No structural changes were detected apart from a few silent mutations. Mapping of the GSK-3α to chromosome 19q13.1–13.2 and the GSK-3β to chromosome 3q13.3-q21 outside known genetic loci linked to NIDDM further makes it unlikely that these genes are involved in the pathogenesis of common forms of NIDDM. [Diabetologia (1997) 40: 940–946]
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0428
    Keywords: Keywords Hepatocyte nuclear factor-4α ; non-insulin-dependent diabetes mellitus ; insulin response ; mutations ; transcription factors.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mutations in the hepatocyte nuclear factor-4α (HNF-4α) gene cause the type 1 form of maturity onset diabetes of the young (MODY1). To address the question of whether genetic variability of HNF-4α is associated with late onset non-insulin-dependent diabetes mellitus (NIDDM) we have sequenced the coding region and intron/exon boundaries of the gene in 36 randomly recruited Danish NIDDM patients. Two nucleotide substitutions that changed the sequence of HNF-4α were identified: Thr/Ile130, which has been reported previously and a novel Val/Met255. The Val/Met 255 mutation was found in 4 of 477 Danish NIDDM patients and in none of 217 glucose tolerant control subjects; thus it cannot be excluded that this mutation may have an impact on NIDDM susceptibility. Among 509 NIDDM patients the allelic frequency of the Thr/Ile130 variant was 4.7 % (95 % confidence interval: 3.4–6.0 %) compared to 1.9 % (0.7–3.1 %) among 239 control subjects (p = 0.008). However, in a population sample of 942 Swedish men with an average age of 70 years the allelic frequency of the variant was similar in 246 men with either impaired glucose tolerance (5.6 % [2.6–8.6 %]) or NIDDM (5.4 % [2.7–8.1 %]) as compared to 666 glucose tolerant men (5.1 % [3.9–6.3 %]). Also in a population sample of 369 young healthy Danes the prevalence of the codon 130 variant (4.7 % [3.2–6.2 %]) was similar to what was found in Swedish Caucasians. Thus, the allelic frequency of the Thr/Ile130 variant among the control subjects in the Danish case-control study deviates from the prevalence in the two other studies which is why we consider the significant association between the codon 130 variant and NIDDM an incidental finding. In glucose tolerant subjects the codon 130 variant in its heterozygous form had no major effect on glucose-induced insulin and C-peptide release although a tendency to a lower insulin secretion during an oral glucose tolerance test was seen in middle-aged subjects. In conclusion, variability in the coding region of the HNF-4α gene is not a common cause of NIDDM among whites of Danish ancestry. However, a Val/Met255 mutation was found exclusively in NIDDM patients (0.8 % of cases) and functional as well as family segregation studies are needed to determine whether this HNF-4α variant is a NIDDM causing mutation. [Diabetologia (1997) 40: 980–983]
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0428
    Keywords: Keywords HNF-1α ; Mutations ; IDDM ; MODY3 ; Misclassification ; non-DR3 and non-DR4 genotypes.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mutations in the hepatocyte nuclear factor-1α (HNF-1α) gene are the cause of maturity-onset diabetes of the young type 3 (MODY3), which is characterised by a severe impairment of insulin secretion and an early onset of the disease. Also at onset of diabetes some MODY patients show similar clinical symptoms and signs as patients with Type I (insulin-dependent) diabetes mellitus. The objective of this study was to estimate the prevalence of MODY3 patients misclassified as Type I diabetic patients. From a large population-based sample of unrelated Danish Caucasian Type I diabetic patients with an affected first degree relative, 39 patients (6.7 %) who did not carry any high-risk HLA-haplotypes, i. e. DR3 or DR4 or both were examined by single-strand conformational polymorphism scanning and direct sequencing of the coding region and the minimal promoter of the HNF-1α gene. Four of the 39 Type I diabetic patients (10 %) were identified as carrying mutations in the HNF-1α gene. One patient carried a missense mutation (Glu48Lys) in exon 1, two patients carried a missense mutation (Cys241Gly) in exon 4 and one patient carried a frameshift mutation (Pro291fsdelA) in exon 4. The mutations were all identified in heterozygous form, segregated with diabetes, and were not identified in 84 unrelated, healthy subjects. Furthermore, family history in three of the four families showed diabetes in four consecutive generations, suggestive of an autosomal dominant inheritance. In conclusion, about 10 % of Danish diabetic patients without a high-risk HLA-haplotype, originally classified as having Type I diabetes could have diabetes caused by mutations in the HNF-1α gene. Clinical awareness of family history of diabetes and mode of inheritance might help to identify and reclassify these diabetic subjects as MODY3 patients. [Diabetologia (1998) 41: 1528–1531]
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0428
    Keywords: Keywords Hepatocyte nuclear factor-6 ; Type II diabetes mellitus ; MODY ; insulin secretion ; mutations.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. The transcription factor hepatocyte nuclear factor (HNF)-6 is an upstream regulator of several genes involved in the pathogenesis of maturity-onset diabetes of the young. We therefore tested the hypothesis that variability in the HNF-6 gene is associated with subsets of Type II (non-insulin-dependent) diabetes mellitus and estimates of insulin secretion in glucose tolerant subjects. Methods. We cloned the coding region as well as the intron-exon boundaries of the HNF-6 gene. We then examined them on genomic DNA in six MODY probands without mutations in the MODY1, MODY3 and MODY4 genes and in 54 patients with late-onset Type II diabetes by combined single strand conformational polymorphism-heteroduplex analysis followed by direct sequencing of identified variants. An identified missense variant was examined in association studies and genotype-phenotype studies. Results. We identified two silent and one missense (Pro75Ala) variant. In an association study the allelic frequency of the Pro75Ala polymorphism was 3.2 % (95 % confidence interval, 1.9–4.5) in 330 patients with Type II diabetes mellitus compared with 4.2 % (2.4–6.0) in 238 age-matched glucose tolerant control subjects. Moreover, in studies of 238 middle-aged glucose tolerant subjects, of 226 glucose tolerant offspring of Type II diabetic patients and of 367 young healthy subjects, the carriers of the polymorphism did not differ from non-carriers in glucose induced serum insulin or C-peptide responses. Conclusion/interpretation. Mutations in the coding region of the HNF-6 gene are not associated with Type II diabetes or with changes in insulin responses to glucose among the Caucasians examined. [Diabetologia (1999) 42: 1011–1016]
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 25 (1976), S. 307-321 
    ISSN: 1432-1106
    Keywords: Cochlear nucleus ; Excitation ; Inhibition ; Statistical signal analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The dynamic properties of excitation and two-tone inhibition in the cochlear nucleus were studied from extracellularly recorded unit responses to two simultaneously presented tones. One tone was presented at the unit's characteristic frequency, CF, the other at the unit's best inhibitory frequency, BIF. One or both of the tones were amplitude-modulated with pseudorandom noise. The system under study is in general nonlinear, but can be considered to function as a linear system for small changes in sound intensity around a certain operating point. The dynamic properties are likely to be different at different operating points. A suitable method for the study of dynamic properties of such a system employs tones that are amplitude-modulated with pseudorandom noise. In the present study, the dynamic properties were assessed by cross-correlating the unit discharge rate with the modulation. This was accomplished by computing the crosscovariance function between a period of noise and a period histogram of the discharges, the histogram being locked to the periodicity of the pseudorandom noise. In this way, it has been shown in previous works (Møller, 1973, 1974b), that the cross-covariance function is a valid approximation of the system's impulse response function at a certain sound intensity, provided the modulation is kept at a low value. In the present study the computed cross-covariance function is thus an approximation of the change in discharge rate of the cochlear nucleus units in response to a brief increase in stimulus intensity. As the response of the system under the given circumstances is approximately that of a linear system, the integrated cross-covariance is an approximation of the system's step response function, i.e the change in discharge rate that results from a hypothetical step increase in stimulus intensity. The results of the present study can be summarized as follows: 1. The impulse and step response functions computed from the responses to the modulated inhibitory tone of the great majority of units from which recording was made were found to be virtual mirror images of those obtained when the excitatory tone was modulated, the inhibitory response being somewhat smaller in amplitude than the excitatory. 2. When both tones were modulated simultaneously, the step response function was approximately the algebraic sum of the two responses obtained when the tones were modulated singly, further indicating that the system functions as a linear system when the stimulus amplitude is varied slightly around a certain operating point. 3. The shape of the cross-covariance functions is similar for all three stimulus situations, but varies with stimulus intensity and is different in different units. 4. The implication of the results is that the inhibition studied may either originate from the inhibition (suppression) seen in primary fibers or it may be the result of a true neural inhibition in the cochlear nucleus that occurs without any interneurons.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 43 (1981), S. 93-100 
    ISSN: 1432-1106
    Keywords: Auditory system ; Evoked responses ; Neural delay ; Statistical signal analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Evoked responses from the cochlea and cochlear nucleus in the rat were studied using two types of stimuli: (1) bursts of tones or noise, and (2) continuous tones or noise that were amplitude modulated with pseudorandom noise. While the responses to the first type of stimuli were averaged only in the conventional way, the responses to the continuous and amplitude modulated sounds were averaged over one period of the pseudorandom noise. This average was then cross correlated with one period of the noise. The morphology of these cross correlation functions was in many ways similar to the response to transient sounds. Recordings from the round window of the cochlea and the cochlear nucleus showed that the latencies of these peaks in the responses to tone bursts and those of the cross correlation functions obtained from the continuous tones modulated with pseudorandom noise were similar. However, the latencies of the peaks in the cross correlation functions were slightly shorter and showed less dependency on the stimulus intensity than did the peaks in the responses to tone bursts. When the responses to noise bursts and the responses to noise that was amplitude modulated were compared, it was found that the latencies of the peaks in the cross correlation functions were nearly independent of the stimulus intensity. However, the peaks in the averaged responses to noise bursts showed a decrease in latency with increasing sound intensity.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Acta neurochirurgica 126 (1994), S. 149-157 
    ISSN: 0942-0940
    Keywords: Hemifacial spasm ; vascular compression ; hyperactivity of facial nucleus ; demyelination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary It is generally assumed that hemifacial spasm (HFS) is caused by vascular compression of the facial nerve at the root exit zone (REZ), but the mechanism for the development of HFS is not known. Evidence has been previously presented that the signs of HFS are caused by hyperactivity of the facial motonucleus that is caused by the irritation to the facial nerve from the vascular contact. This assumption has been supported by the finding that daily electrical stimulation of the facial nerve in the rat facilitates the development of an abnormal muscle response that is a characteristic sign of HFS in man and is an indication of an abnormal cross-transmission that makes it possible to elicit a contraction of muscles innervated by one branch of the facial nerve by electrically stimulating another branch of the facial nerve. In the present study we show that close contact between a peripheral branch of the facial nerve and an artery also facilitates the development of an abnormal muscle response, but only if the facial nerve has previously been slightly injured (by a chromic suture) at the location of the arterial contact. We also show that blocking neural conduction in the facial nerve proximal to the artificial vascular compression abolishes the abnormal muscle contraction, which supports the assumption that the anatomical location of cross-transmission that is causing the abnormal muscle response is central to the vascular compression, most likely in the facial motonucleus. These findings may explain why the facial nerve is only susceptible to vascular compression near its REZ, where an injury to its myelin is more likely to occur than where the nerve is covered with schwann cell myelin.
    Type of Medium: Electronic Resource
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