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Biomedical subjects

W Berger

Publications and source records attributed to W Berger.

At least 55 records · Page 3Linked to original sources
PubMed2000

The retinitis pigmentosa GTPase regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors.

Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene cause X-linked retinitis pigmentosa type 3 (RP3), a severe, progressive and degenerative retinal dystrophy eventually leading to complete blindness. RPGR is ubiquitously expressed, yet mutations in the RPGR gene lead to a retina-restricted phenotype. To date, all RP3 associated missense mutations that have been identified are located in the RCC1-homologous domain (RHD) of RPGR. To investigate the molecular pathogenesis of RP3, we screened retinal yeast two-hybrid libraries with the RHD of RPGR. We identified several alternatively spliced gene products, some with retina-restricted expression, that interact specifically with RPGR in vivo and in vitro. Thus, these proteins were named RPGR-interacting protein 1 (RPGRIP1) isoforms. They contain a C-terminal RPGR-interacting domain and stretches of variable coiled-coil domains homologous to proteins involved in vesicular trafficking. The interaction between RPGR and RPGRIP1 isoforms was impaired in vivo by RP3-associated mutations in RPGR. Moreover, RPGR and RPGRIP1 co-localize in the outer segment of rod photoreceptors, which is in full agreement with the retinitis pigmentosa phenotype observed in RP3 patients. The localization of RPGRIP1 at 14q11 makes it a strong candidate gene for RP16. These results provide a clue for the retina-specific pathogenesis in RP3, and hint towards the involvement of RPGR and RPGRIP1 in mediating vesicular transport-associated processes.

3' Untranslated Regions↗
PubMed2000

[Long-term outcome of metatarsal head resection in rheumatoid arthritis].

Between January 1983 and December 1987, metatarsal head-resections were performed on 203 patients, comprising a total of 370 feet, using the Hueter/Mayo and Hoffmann procedure. Seventy-two patients, comprising a total of 126 feet, were available for post-operative review after an average of 11.4 years from the date of the original operations. The information obtained from standardized questionnaires was compared to the information found in each patient's file. In addition, every available pre- and post-operative x-ray taken from 1983 to 1987 was analyzed. Thus, with an average follow-up period of 5.6 years, the changes found in the pre- and post-operative x-rays from a total of 183 feet could be compared. Before the operations, nearly 100% of the examined feet suffered from painful synovial hypertrophy and erosion of the metatarsophalangeal joints with dislocation and subluxation, causing approximately 70% of all patients to have great difficulties in walking. After the operations, however, 90.2% of the patients reported that this condition had noticeably improved or had completely disappeared. In fact, 87.5% of all patients reported a lasting improvement in their ability to walk longer distances. As the main criteria in determining the success of an operation (namely, the noticeable reduction of pain and increased mobility) were achieved in 87.5% of the patients, we consider the metatarsal head-resection a reliable method of correcting forefoot deformities in rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed2000

Physical mapping and exclusion of GPR34 as the causative gene for congenital stationary night blindness type 1.

X-linked congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder characterized by impaired night vision, variably involving high myopia, nystagmus, decreased visual acuity, and strabismus. Linkage studies have identified two distinct loci for X-linked CSNB1 and CSNB2 on the short arm of chromosome X. The gene mutated in families displaying the "incomplete phenotype" of CSNB (i.e., CSNB2) has recently been identified. To identify novel candidate genes for the "complete form" of CSNB (i.e., CSNB1) we screened the physically vast region Xp11.3-Xp11.4 for cDNA sequences. This led us to identify and map the G protein coupled receptor (GPCR) gene GPR34 to Xp11.4 within 650 kb of the marker DXS993. Deletion screening via Southern blotting and direct sequencing of GPR34 revealed no mutations in 19 unrelated men with CSNB1, excluding a causal role in the disease. However, because of its expression in retinal and neural tissue and the involvement of GPCRs in transmembrane signal transduction, GPR34 remains a putative candidate gene for a number of ocular diseases which also map to the Xp11.4 region.

Blotting, Southern↗
PubMed2000

The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein.

X-linked congenital stationary night blindness (XLCSNB) is characterized by impaired scotopic vision with associated ocular symptoms such as myopia, hyperopia, nystagmus and reduced visual acuity. Genetic mapping in families with XLCSNB revealed two different loci on the proximal short arm of the X chromosome. These two genetic subtypes can be distinguished on the basis of electroretinogram (ERG) responses and psychophysical testing as a complete (CSNB1) and an incomplete (CSNB2) form. The CSNB1 locus has been mapped to a 5-cM linkage interval in Xp11.4 (refs 2,5-7). Here we construct and analyse a contig between the markers DXS993 and DXS228, leading to the identification of a new gene mutated in CSNB1 patients. It is partially deleted in 3 families and mutation analysis in a further 21 families detected another 13 different mutations. This gene, designated NYX, encodes a protein of 481 amino acids (nyctalopin) and is expressed at low levels in tissues including retina, brain, testis and muscle. The predicted polypeptide is a glycosylphosphatidylinositol (GPI)-anchored extracellular protein with 11 typical and 2 cysteine-rich, leucine-rich repeats (LRRs). This motif is important for protein-protein interactions and members of the LRR superfamily are involved in cell adhesion and axon guidance. Future functional analysis of nyctalopin might therefore give insight into the fine-regulation of cell-cell contacts in the retina.

Amino Acid Motifs↗
PubMed2000

Inhaled mometasone furoate reduces oral prednisone requirements while improving respiratory function and health-related quality of life in patients with severe persistent asthma.

BACKGROUND: Inhaled corticosteroid therapy in severe persistent asthma has been shown to reduce or eliminate oral corticosteroid (OCS) use while retaining effective asthma control. OBJECTIVE: We sought to evaluate the ability of mometasone furoate (MF) delivered by means of dry powder inhaler to reduce daily oral prednisone requirements in OCS-dependent patients with severe persistent asthma. METHODS: We performed a 12-week, double-blind, placebocontrolled trial (21 centers, 132 patients) comparing 2 doses of MF (400 and 800 microg administered twice daily) with placebo, followed by a 9-month open-label phase in which 128 patients received treatment with MF. RESULTS: At the endpoint of the double-blind trial, MF 400 and 800 mg twice daily reduced daily OCS requirements by 46.0% and 23.9%, respectively, whereas placebo increased OCS requirements by 164.4% (P <.01). Oral steroids were eliminated in 40%, 37%, and 0% of patients in the MF 400 and 800 mg twice daily and placebo groups, respectively. Pulmonary function and quality of life significantly increased for MF-treated patients. Further reductions in OCS requirements were achieved with long-term MF treatment in the open-label phase. CONCLUSION: MF inhaled orally as a dry powder is an effective alternative to systemic corticosteroids in patients with severe persistent asthma.

Administration, Inhalation↗
PubMed1999

Evidence for a role of FGF-2 and FGF receptors in the proliferation of non-small cell lung cancer cells.

Basic fibroblast growth factor (FGF-2) has been implicated in the progression of human tumours via both autocrine and paracrine (angiogenic) activities. We investigated the expression of FGF-2 and FGF receptors (FGFR-1 to -4) in NSCLC cell lines (N = 16), NSCLC surgical specimens (N = 21) and 2 control cell lines. Our data show that almost all NSCLC cells produce elevated levels of FGF-2 and FGFR in vitro and in vivo. FGF-2 expression did correlate with a short doubling time as well as with potent anchorage-independent growth of NSCLC cell lines. In contrast with control cells, NSCLC cells did not secrete considerable amounts of FGF-2 into the extracellular space. Expression levels of FGFR-1 and -2 in NSCLC cell lines correlated with FGF-2 production. FGFR were located at the plasma membranes in some low FGF-2-producing NSCLC and control cell lines. These cells were sensitive to the proliferative effect of recombinant FGF-2 (rFGF-2). In NSCLC cell lines with an enhanced FGF-2 production, representing the majority studied, FGFR localisation was predominantly intracellular. These cells were insensitive to both the proliferative effect of rFGF-2 and growth inhibition by FGF-2-neutralising antibodies. In contrast, several agents antagonised FGF-2 intracellularly impaired growth of almost all NSCLC cell lines. Our data suggest a role of FGF-2 and FGFR in the growth stimulation of NSCLC cells possibly via an intracrine mechanism.

3T3 Cells↗
PubMed1999

Modulation of the biceps femoris tendon jerk reflex during human locomotion.

During gait it is generally accepted that there is a reduction in amplitude of H-reflexes as compared to standing. For short-latency stretch reflexes, however, it is less clear whether a similar reduction in reflex gain is present during locomotion. Stretches of constant amplitude are hard to produce under these circumstances and for this reason some previous studies on the biceps femoris (BF) have used "reduced gait" in which the stimulated leg is stepping on the spot while the contralateral leg is walking on a treadmill. With this method it was possible to show that BF tendon jerk reflexes are larger at end swing and therefore are likely to contribute to the EMG burst normally occurring in that part of the step cycle when the BF is rapidly stretched. In the present study two questions were addressed: first, whether the reflex is different in size during gait compared to standing and, second, whether it is modulated in size during the gait cycle not only during reduced but also during normal gait. It was found that during both types of gait there was a general reflex depression with regard to the respective control values obtained during standing at similar EMG activity levels. In previous studies on soleus and quadriceps, discrepancies between EMG activity and reflex amplitude have been ascribed to changes in presynaptic inhibition of Ia terminals mediating the afferent volley of the reflex. Based on the data presented, this may also be true for the BF. In both normal and reduced gait the reflex was similarly modulated in size, showing a maximum at the end of swing. This similarity implies that reduced gait may be useful as an acceptable alternative for normal gait in studies on phase-dependent reflex modulation during locomotion.

Adult↗
PubMed1999

Voluntary control of human gait: conditioning of magnetically evoked motor responses in a precision stepping task.

The aim of this study was to investigate visuomotor control during human gait. It was assumed that visual input should modulate transcranially evoked motor potentials (EMPs) during walking. The effect of transcranial magnetic stimulation (TMS) in a visually guided precision stepping task was compared with that during normal gait. EMPs were studied in tibialis anterior (TA), gastrocnemius (GM), and abductor digiti minimi (AD) muscles during treadmill walking. In both stepping tasks, a facilitation of EMPs was observed prior to activation of the respective leg muscle. EMP facilitation proved to be modulated throughout the stride cycle when normalising EMP with respect to the underlying electromyogram (EMG). Facilitation was strongest in TA prior to the swing phase. Significant differences of EMP facilitation between the visual and control tasks were present. In the visual task, maximal facilitation of TA EMPs prior to and during the swing phase was decreased compared to the control task. Conversely, there was increased facilitation of GM EMPs during swing phase of the visual task, prior to the heel strike and prior to the plantarflexion, which was the moment when the target was hit. Thus, the effect of visual input upon EMPs in TA and GM was differential and reciprocal according to the respective functional state. The results support the hypothesis of a conditioning effect of visual or, alternatively volitional, drive on EMPs during stepping.

Adult↗
PubMed1999

Higher incidence of severe hypoglycaemia leading to hospital admission in Type 2 diabetic patients treated with long-acting versus short-acting sulphonylureas.

AIMS: A comparison of the frequency of severe hypoglycaemia leading to hospital admission in people with Type 2 diabetes mellitus (DM) treated with long vs. short-acting sulphonylureas. METHODS: A community based study over a 12-year period in the population of the city of Basle, Switzerland. The number of diabetic patients treated with oral hypoglycaemic agents was established on the basis of tablet consumption and a defined daily dose, e.g. 7.5 mg for glibenclamide, and 50 mg for glibornuride. RESULTS: Twenty-eight Type 2 diabetic patients were admitted for severe hypoglycaemia, with a median age of 73 years. There were no deaths. Sixteen of these admissions were patients treated with long-acting sulphonylureas and 12 were patients treated with short-acting forms. Only 23.5% of the population with Type 2 DM in Basle were treated with long-acting sulphonylureas. With 30345 person-years of observation, the incidence of severe hypoglycaemia was 2.24 per 1000 person-years for long-acting sulphonylureas vs. 0.75 per 1000 person-year for short-acting forms, odds ratio 3.01 (95% confidence interval 1.35-6.77). Decreased food intake (nine patients) was a major contributing factor. CONCLUSIONS: Severe hypoglycaemia leading to hospital admission is more common in elderly Type 2 diabetic patients treated with long-acting compared to short-acting sulphonylureas. Such long-acting sulphonylureas should be avoided.

Aged↗
PubMed1999

The influence of valerian treatment on "reaction time, alertness and concentration" in volunteers.

A randomised, controlled, double-blind trial was performed on 102 male and female volunteers to determine whether reaction time, alertness and concentration might be impaired by treatment with a native valerian root extract (VRE). The effect was first examined the morning after a single evening dose of VRE (600 mg LI 156) vs. flunitrazepam (FNZ) (1 mg) and placebo (PL) (trial section A), and then after two weeks of evening administration of VRE (600 mg LI 156) vs. PL (trial section B). 99 volunteers were analysed in section A and 91 in section B. The primary criterion was the median of reaction time (MRT) measured with the Vienna Determination Test. Secondary criteria were cognitrones (alertness test), tracking test (two-handed co-ordination), sleep quality (VIS-A, Vis-M), further VDT parameters, and safety criteria. The single administration of LI 156 did not impair the reaction abilities, concentration and co-ordination. After 14 days of treatment, the equivalence of VRE and PL was proven by confirmative analysis concerning the improvement of MRT (p = 0.4481). Evaluation of the secondary criteria were consistent with the results of the primary criterion. It is concluded that neither single nor repeated evening administrations of 600 mg of VRE have a relevant negative impact on reaction time, alertness and concentration the morning after intake.

Adult↗
PubMed1999

Genotype-phenotype correlation in X-linked retinitis pigmentosa 2 (RP2).

PURPOSE: To identify possible correlations between the putative mutations and the clinical characteristics in X-linked retinitis pigmentosa, RP2. DESIGN: A retrospective, descriptive clinical study. MATERIAL: The ophthalmological files on affected persons from three Danish families with identified pathogenic mutations in the RP2 gene. RESULTS: Mutation analysis in 14 Danish families with X-linked retinitis pigmentosa revealed disease-associated sequence alterations in eight of them. Five mutations were detected in the RP3 gene (RPGR) and three in the RP2 gene. Genotype-phenotype comparison in the three RP2 families revealed striking interfamilial phenotypic differences. Severe phenotypes were associated with a null mutation Gln26stop and a missense mutation Arg118His. These families differed mutually with respect to retinal appearance. Affected carriers had a delayed onset by three decades. Tapetal reflexes were not observed in the carriers. An in-frame deletion DeltaSer6 was associated with a milder phenotype. CONCLUSIONS: Interfamilial differences in RP2 phenotype might be related to the type and location of the mutational event. Due to a considerable overlap between RP2 and RP3 phenotypes, the genotype cannot safely be deduced from conventional clinical examination methods.

Adult↗
PubMed1999

Impaired modulation of quadriceps tendon jerk reflex during spastic gait: differences between spinal and cerebral lesions.

In healthy subjects, functionally appropriate modulation of short latency leg muscle reflexes occurs during gait. This modulation has been ascribed, in part, to changes in presynaptic inhibition of Ia afferents. The changes in modulation of quadriceps tendon jerk reflexes during gait of healthy subjects were compared with those of hemi- or paraparetic spastic patients. The spasticity was due to unilateral cerebral infarction or traumatic spinal cord injury, respectively. The modulation of the quadriceps femoris tendon jerk reflex at 16 phases of the step cycle was studied. The reflex responses obtained during treadmill walking were compared with control values obtained during gait-mimicking standing postures with corresponding levels of voluntary muscle contraction and knee angles. In healthy subjects the size of the reflexes was profoundly modulated and was generally depressed throughout the step cycle. In patients with spinal lesion the reflex depression during gait was almost removed and was associated with weak or no modulation during the step cycle. In patients with cerebral lesion there was less depression of the reflex size associated with a reduced reflex modulation on the affected side compared with healthy subjects. On the 'unaffected' side of these patients reflex modulation was similar to that of healthy subjects, but the reflex size during gait was not significantly different from standing control values. These observations suggest that the mechanisms responsible for the depression of reflex size and the modulation normally seen during gait in healthy subjects are impaired to different extents in spasticity of spinal or cerebral origin, possibly due to the unilateral preservation of fibre tracts in hemiparesis.

Adolescent↗
PubMed1999

Full-length human L1 insertions retain the capacity for high frequency retrotransposition in cultured cells.

Functional L1 elements are autonomous retrotransposons that can insert into human genes and cause disease. To date, 10 of 12 known L1 retrotranspositions into human genes have been found to be 5"-truncated and incapable of further retrotransposition. Here we report the nucleotide sequences of the two full-length L1 elements, L1beta-thal and L1RP, that have inserted into the beta-globin and retinitis pigmentosa-2 (RP2) genes, respectively. L1beta-thal is 99. 4% identical to a consensus sequence of active human L1s, while L1RP is 99.9% identical. Both elements retain impressive capacity for high frequency retrotransposition in cultured HeLa cells. Indeed, L1RP is the most active L1 isolated to date. Our data indicate that not all L1 insertions into human genes are 'dead on arrival'. Our findings also lend further credence to the concept of cis preference, that the proteins encoded by a particular L1 preferentially act upon their encoding RNA as opposed to other L1 RNAs.

Consensus Sequence↗
PubMed1999

RPGR transcription studies in mouse and human tissues reveal a retina-specific isoform that is disrupted in a patient with X-linked retinitis pigmentosa.

X-linked retinitis pigmentosa (XLRP) is a genetically heterogeneous group of progressive retinal degenerations. The disease process is initiated by premature apoptosis of rod photoreceptor cells in the retina, which leads to reduced visual acuity and, eventually, complete blindness. Mutations in the retinitis pigmentosa GTPase regulator ( RPGR ), a ubiquitously expressed gene at the RP3 locus in Xp21.1, account for approximately 20% of all X-linked cases. We have analysed the expression of this gene by northern blot hybridization, cDNA library screening and RT-PCR in various organs from mouse and man. These studies revealed at least 12 alternatively spliced isoforms. Some of the transcripts are tissue specific and contain novel exons, which elongate or truncate the previously reported open reading frame of the mouse and human RPGR gene. One of the newly identified exons is expressed exclusively in the human retina and mouse eye and contains a premature stop codon. The deduced polypeptide lacks 169 amino acids from the C-terminus of the ubiquitously expressed variant, including an isoprenylation site. Moreover, this exon was found to be deleted in a family with XLRP. Our results indicate tissue-dependent regulation of alternative splicing of RPGR in mouse and man. The discovery of a retina-specific transcript may explain why phenotypic abberations in RP3 are confined to the eye.

Adult↗
PubMed1998

A novel bioassay for P-glycoprotein functionality using cytochalasin D.

The functional contribution of both P-glycoprotein (P-gp) and the multidrug resistance-associated protein (MRP) to multidrug resistance (MDR) in tumor cells is commonly determined by drug cytotoxicity and/or accumulation/efflux tests. We report on a bioassay developed for the specific detection of functional P-gp levels and the efficacy of related chemosensitizers (CD-P-gp-assay). The assay is based on the flow cytometric measurement of changes in the > or = G2M cell cycle compartment which are due to the induction of polykaryons after exposure of proliferating cells to three defined cytochalasin D (CD) concentrations with and without verapamil. As demonstrated in 13 well-characterized MDR cell models (20 resistant sublines), there is a significant correlation between cytokinesis-blocking CD doses, as well as responsiveness to chemosensitizers and MDR1 gene expression (mRNA and P-gp) allowing discrimination between different levels of P-gp-MDR. CD-P-gp-assay specificity was assessed by testing 23 compounds: 19 known as potent inhibitors of P-gp-MDR, some of them, though to a lesser extent, also of MRP-MDR; 1 inhibiting MRP-but not P-gp-MDR; 3 inactive in both types of MDR. A modulation of CD activity was confined exclusively to both P-gp-expressing cell lines and P-gp chemosensitizers. CD cytoskeletal activity measured by FACS is a specific and sensitive tool with which to detect functional P-gp and related chemosensitizers.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Localization of the somatostatin sst2(a) receptor in human cerebral cortex, hippocampus and cerebellum.

The distribution and cellular localization of the somatostatin sst2(a) receptor was investigated in selected human brain areas using an anti-peptide antibody raised against a carboxy-terminal portion of the receptor protein. The sst2(a) receptor was found to be present on neurones and processes in the deep layers of the cerebral cortex, in the subicular complex and the hippocampal formation. Further signals were obtained in the molecular and granular layer of the cerebellum, with occasional weakly stained Purkinje cells. The regional distribution of the receptor protein was compared with quantitative autoradiography using a sst2 receptor selective ligand [125I]BIM23027.

Autoradiography↗