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Biomedical subjects

W Fischer

Publications and source records attributed to W Fischer.

At least 109 records · Page 6Linked to original sources
PubMed1995

CNS-derived neural progenitor cells for gene transfer of nerve growth factor to the adult rat brain: complete rescue of axotomized cholinergic neurons after transplantation into the septum.

A CNS-derived conditionally immortalized temperature-sensitive neural progenitor (CINP) cell line was used to generate NGF-secreting cells suitable for intracerebral transplantation. The cells were transduced by repeated retroviral infection, using a vector containing the mouse NGF cDNA under the control of the LTR promoter. Subcloning at the permissive temperature (33 degrees C) identified a highly NGF-secreting clone (NGF-CINP), which contained multiple copies of the transgene and released NGF at a rate of 2 ng/hr/10(5) cells in vitro, both at 33 and 37 degrees C, which was approximately 1 order of magnitude higher than what was possible to achieve in the heterogeneously infected cell cultures. After transplantation to the brain, the NGF-CINPs differentiated into cells with a predominant glia-like morphology and migrated for a distance of 1-1.5 mm from the implantation site into the surrounding host tissue, without any signs of overgrowth and tumor formation. Grafts of NGF-CINP cells implanted into the septum of adult rats with complete fimbria-fornix lesion blocked over 90% of the cholinergic cell loss in the medial septum and grafts placed in the intact striatum induced accumulation of low-affinity NGF receptor positive fibers around the implantation site. Expression of the NGF transgene in vivo was demonstrated by RT-PCR at 2 weeks after grafting. It is concluded that the immortalized neural progenitors have a number of advantageous properties that make them highly useful experimental tools for gene transfer to the adult CNS.

Animals↗
PubMed1994

A redirected proton pathway in the bacteriorhodopsin mutant Tyr-57-->Asp. Evidence for proton translocation without Schiff base deprotonation.

Light-driven proton pumping in bacteriorhodopsin involves deprotonation of the retinylidene Schiff base during M formation and reprotonation during N formation as key steps. This study reports on the spectroscopic characterization of the bacteriorhodopsin mutant Tyr-57-->Asp (Y57D). The results reveal that although formation of the M intermediate and Schiff base deprotonation is blocked, the mutant still exhibits a significant level of light-driven proton translocation. The photocycle of Y57D involves formation of K and L intermediates accompanied by the normal chromophore isomerization and changes in the hydrogen bonding of Asp-96 and Asp-115. However, an additional Asp residue deprotonates during formation of the L intermediate along with a transmembrane alpha-helical structural change that normally occurs upon N formation. We postulate that proton transport in Y57D occurs through a redirected pathway that does not involve the deprotonation of the Schiff base. Chromophore isomerization, which normally results in the transfer of a proton from the Schiff base to Asp-85, instead causes the deprotonation of Asp-57 in Y57D, most likely through an interaction involving Asp-212. This deprotonation of Asp-57 causes the release of a proton into the extracellular medium. Reprotonation of Asp-57 occurs through the Schiff base reprotonation pathway, which consists of a hydrogen-bonded network of residues spanning from Asp-96 to Asp-212. The results also indicate that the transmembrane alpha-helical structural changes observed during N formation (Rothschild, K.J., Marti, T., Sonar, S., He, Y.W., Rath, P., Fischer, W., Bousche, O., and Khorana, H. G. (1993) J. Biol. Chem. 268, 27046-27052) do not require deprotonation of Asp-96 or of the Schiff base.

Aspartic Acid↗
PubMed1994

Reversal of spatial memory impairments in aged rats by nerve growth factor and neurotrophins 3 and 4/5 but not by brain-derived neurotrophic factor.

Aged rats, displaying impairments in spatial learning and memory associated with marked cellular atrophy of forebrain cholinergic neurons, received intracerebroventricular infusions of one of the four neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), or neurotrophin 4/5 (NT-4/5), or a combination of NGF and BDNF, or vehicle. During the 4-week infusion period rats receiving NGF, NT-3, or NT-4/5 showed improved acquisition and retention of spatial memory. With NGF and NT-3, but not NT-4/5, this was accompanied by a significant reduction in cholinergic neuron atrophy in septum, nucleus basalis, and striatum. BDNF, in contrast, was without effect either alone or in combination with NGF. These results show that memory deficits associated with aging can be reversed by several members of the neurotrophin family and that this effect may be mediated through activation of multiple neurotrophin receptors associated with cholinergic and possibly noncholinergic systems in the brain.

Aging↗
PubMed1994

(S)-2-amino-1,3-propanediol-3-phosphate-carrying diradylglyceroglycolipids. Novel major membrane lipids of Clostridium innocuum.

Two novel aminophosphoglycolipids (I, II) were isolated from Clostridium innocuum which constitute 51% (I) and 15% (II) of total polar membrane lipids. The structures, established by quantitative and methylation analyses, fast-atom-bombardment mass spectrometry, and one- and two-dimensional NMR spectroscopy, are (I) S-2-amino-1,3-propanediol-3-phospho-6-alpha-D-galactopyranosyl(1-2)alpha -D- glucopyranosyl(1-3)diradylglycerol and (II) an acylated derivative of (I) that carries an additional fatty acid ester on O6 of the glucosyl moiety. The stereochemical configuration of the 2-amino-1,3-propanediol 3-phosphate residue was elucidated by conversion to N-acetylserine 3-phosphate, with subsequent release and identification of L-serine by HPLC. In addition to diacylglycerol species, both aminophosphoglycolipids contain 15-32% 1-O-(alk-1-enyl)-2-O-acyl-glycerol species in which C14, C16, and C18 vinyl ether are combined predominantly with unsaturated C16 and C18 fatty acid ester. Hydrogenation of the vinyl ether was required to desorb the alkyl, acyl-substituted species in fast-atom-bombardment mass spectrometry. Hydrogenation made it further possible to release the alkyl glycerols by acid hydrolysis and to locate the ether bond at O1 of the glycerol moiety. In contrast to the glycerophosphoglycolipids of other Gram-positive bacteria, the aminophosphoglycolipids are metabolically not related to the lipoteichoic acid of C. innocuum and serve, therefore, exclusively as major membrane components. Their large abundance among membrane lipids suggests bilayer-forming physicochemical properties.

Carbohydrate Sequence↗
PubMed1994

The aqueous solution structure of the tetrasaccharide-ribitol repeat-unit from the lipoteichoic acid of Streptococcus pneumoniae strain R6 determined using a combination of NMR spectroscopy and computer calculations.

High-resolution 1D- and 2D-correlation 1H NMR and 13C NMR, at 500 and 125 MHz, respectively, permitted assignment of the majority of the resonances in the per-N-acetylated, phosphorylated tetrasaccharide-ribitol repeat-unit, and in the complete polymer (n = 5 - 7) containing between five and seven repeating units attached to the deacylated lipid anchor, for the lipoteichoic acid from Streptococcus pneumoniae strain R6; the 31P resonances were also assigned. Comparison of the 31P spectra obtained for the per-N-acetylated oligosaccharide and for the oligosaccharide having the AATG 4-NH2 group still free, indicate a conformational difference brought about by interaction between the amino group and the neighboring phosphate group.

Carbohydrate Conformation↗
PubMed1994

[Delayed abscesses after unstable pelvic ring fractures of the lumbar spine. Case report from the viewpoint of the expert witness].

As a result of medical certificates concerning traumatology and internal medicine the course of disease of a 51-year-old man after serious contusion with pelvic ring dislocation and lumbar vertebral fractures with extensive retroperitoneal abscesses is reported whereby the diagnosis and surgery of this complication has followed only five years after the accident. The significance of nosocomial infections by staphylococcus aureus in connection with closed injuries is pointed out; qualification and quality of the medical certificates are also referred to.

Abscess↗
PubMed1994

[Mortality in proximal femur fractures in elderly people].

Retrospectively we studied 30 patients with fracture of the proximal femur, who were no less than 75 years old and who died during their hospitalization in the Department of Surgery of the Medical University of Lübeck from 1986 to 1991. Mortality was 6% (30/498). The mean time of death was the 13th day after administration. Nineteen patients have had 1, 7 patients 2 serious preexisting diseases. Twelve patients developed 1, 8 patients 2, and 1 patient 3 serious complications. The high amount of patients (30%, 9/30) who could not be operated reflects the great influence of the trauma itself on the mortality of the old multimorbid surgical patient. Intra-operative complications were seldom (1 pulmonary embolism), postoperative complications, however, were the limiting factors of the course of illness and are associated with a poor outcome.

Aged↗
PubMed1994

Nerve growth factor reverses spatial memory impairments in aged rats.

Aged rats, displaying impairments in spatial learning and memory associated with marked cellular atrophy of forebrain cholinergic neurons, received intracerebroventricular infusions of the neurotrophin nerve growth factor (NGF), or vehicle. During the 4-week infusion period rats receiving NGF showed improved acquisition and retention of spatial memory. With NGF this was accompanied by a significant reduction in cholinergic neuron atrophy in both septum, nucleus basalis and striatum. The cause of learning and memory deficits associated with ageing is not known. In the present paper we show that learning and memory deficits in aged rats can be reversed by NGF.

Acetylcholinesterase↗
PubMed1994

Efficacy and tolerability of amitriptylinoxide in the treatment of chronic tension-type headache: a multi-centre controlled study.

Amitriptyline is the medication of first choice in the treatment of chronic tension-type headache. In 197 patients with chronic tension-type headache (87M and 110F with a mean age of 38 +/- 13 (18-68)) efficacy and tolerability of 60-90 mg amitriptylinoxide (AO) were compared with 50-75 mg amitriptyline (AM) and placebo (PL) in a double-blind, parallel-group trial consisting of a four weeks' baseline phase and 12 weeks of treatment. The primary study endpoint was a reduction of at least 50% of the product of headache duration and frequency and a reduction of at least 50% in headache intensity. Statistics used were Fisher's exact test and analysis of variance. No significant difference emerged between AO, AM and PL with respect to the primary study endpoint. Treatment response occurred in 30.3% of the AO, 22.4% of the AM and 21.9% of the PL group. A reduction in headache duration and frequency of at least 50% was found in 39.4% on AO, in 25.4% on AM and in 26.6% on PL (PAO-PL = .1384, PAM-PL = 1.000, PAO-AM = .0973). A reduction in headache intensity of at least 50% was found in 31.8% on AO, in 26.9% on AM and in 26.6% on PL (PAO-PL = .5657, PAM-PL = 1.000, PAO-AM = .5715). Trend analysis with respect to a significant reduction of headache intensity (p < 0.05) and the product of headache duration and frequency revealed a superior effect of AO.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Zopiclone improves sleep quality and daytime well-being in insomniac patients: comparison with triazolam, flunitrazepam and placebo.

In a randomized, double-blind, parallel group study in private practice, zopiclone given for 28 days was compared with flunitrazepam, triazolam and placebo in its effect on quality of sleep and daytime well-being in 1507 patients suffering from insomnia. For quantitative assessment, patients were defined as responders according to either a shortening of sleep latency by at least 15 min, or prolongation of total sleep time by at least 20%, or reduction of the number of nocturnal awakenings to three or less and a fresh feeling in the morning, as well as lack of impairment in daytime well-being as a result of tiredness or anxiety. The responder rate tended to be higher with zopiclone (37.4%) than with flunitrazepam (30%) and triazolam (32.2%) and was significantly greater (p = 0.0017) than with placebo (26.8%). Daytime well-being was particularly responsive to zopiclone and most responsive in severe insomniacs. With the exception of those to triazolam, rates of response were most pronounced in patients with insomnia of a short duration (< or = 1 year) than in those with insomnia of a longer duration (> or = 1 year). Following discontinuation of treatment, all groups showed a moderate reduction in therapeutic effect, but no rebound insomnia occurred.

Azabicyclo Compounds↗
PubMed1994

Novel polar lipid composition of Clostridium innocuum as the basis for an assessment of its taxonomic status.

The extractable polar lipids of Clostridium innocuum have been shown to consist of glycosyldiradylglycerols, phospholipids and phosphoglycolipids. The major glycosyldiradylglycerols are D-Glcp(alpha 1-3)radyl2Gro and D-Galp(alpha 1-2)D-Glcp(alpha 1-3)radyl2Gro. Both glycolipids have some 1-O-(alk-1-enyl)-2-O-acyl species, in addition to diacyl species. The phospholipids include bisphosphatidylglycerol (cardiolipin), lysocardiolipin and phosphatidylglycerol (PG). In addition, several novel lipids have been found, including a PG acetal of cardiolipin plasmalogen, smaller amounts of a lyso form of this lipid, a PG acetal of PG plasmalogen, and two phosphoglycolipids, which represent 65% of total polar lipids. The latter have been identified as 2'-amino-1',3'- dihydroxypropane-3'-P-6-D-Galp(alpha 1-2)D-Glcp(alpha 1-3)radyl2Gro and a derivative of this lipid containing an acyl chain esterified to O-6 of the glucopyranosyl ring. Based on rRNA sequence data, C. innocuum is considered to be a relative of the mycoplasmas. Its unique lipid composition permits an assessment of the taxonomic status of C. innocuum, since the lipid amphiphiles display marked differences from those of Acholeplasma laidlawii.

Carbohydrate Sequence↗
PubMed1994

Continuity and discontinuity of psychopathology: a study of patients examined as children and as adults. III--The infancy of "adult personality disorders".

We undertook a prospective study of all the children who, having consulted the Child Psychiatry Services (Service Médico-Pédagogique) between 1963 and 1967, later consulted the Adult Public Psychiatry Service (720 cases). We looked for specific clinical clusters which would enable us to differentiate statistically the groups of children according to their adult diagnoses. We present here the results for the group of children who were diagnosed as suffering from "personality disorders" in adulthood. We were able to establish an infantile cluster that significantly differentiated these children. It includes: aggressiveness, oppositional behaviour, unsociability, conflicts with peers. 54.6% had already been diagnosed as suffering from personality disorders in childhood. According to these results, the more a consulting child fits this profile, the greater the risk that he will suffer from a "personality disorder" in adulthood. We discuss the continuity/discontinuity of the symptomatology, and the implications for diagnoses of "personality disorders" and "borderline personalities".

Adolescent↗
PubMed1993

Asp96 deprotonation and transmembrane alpha-helical structural changes in bacteriorhodopsin.

The M-->N transition in the photocycle of bacteriorhodopsin involves the transfer of a proton from Asp96 to the retinylidene Schiff base, possibly through a network of hydrogen-bonded amino acid residues and water molecules (Rothschild, K. J., He, Y. W., Sonar, S., Marti, T., and Khorana, H. G. (1992) J. Biol. Chem. 267, 1615-1622). A conformational change of the protein backbone is also observed during this transition. In this work, we have investigated the effects of replacing the residue Thr46, which might be part of this chain, with an aspartic acid. Both Fourier transform infrared and resonance Raman spectroscopy show that the chromophore structure of this mutant (T46D) is normal. However, N formation is accelerated and N decay is significantly slowed compared to wild-type bacteriorhodopsin. This effect causes the N intermediate to accumulate under steady-state illumination thereby facilitating spectroscopic studies under normal pH conditions. Fourier transform infrared difference spectroscopy reveals that like native bacteriorhodopsin, N formation in T46D involves deprotonation of Asp96, reprotonation of the Schiff base, and a change in the backbone secondary structure. However, in contrast to bacteriorhodopsin, bands assigned to the C = O stretch mode of the carboxylic acid group of Asp96 are upshifted by 10 cm-1 reflecting a change in the Asp96 environment and a drop in its effective pKa throughout the photocycle. This change in the pKa can directly account for changes in the photocycle kinetics and indicates that Asp96 deprotonation/protonation are the rate limiting steps in the formation and decay of the N intermediate. By studying the effects of H/D exchange, evidence is found that the backbone structural changes involve transmembrane alpha-helices. It is proposed that these structural changes serve to modulate the local environment and protonation state of Asp96 during the photocycle and are also essential for formation of the proton conducting hydrogen bonded network which functions during Schiff base reprotonation.

Aspartic Acid↗