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Biomedical subjects

M Schubert

Publications and source records attributed to M Schubert.

At least 73 records · Page 4Linked to original sources
PubMed1999

Characterization of an amphioxus paired box gene, AmphiPax2/5/8: developmental expression patterns in optic support cells, nephridium, thyroid-like structures and pharyngeal gill slits, but not in the midbrain-hindbrain boundary region.

On the basis of developmental gene expression, the vertebrate central nervous system comprises: a forebrain plus anterior midbrain, a midbrain-hindbrain boundary region (MHB) having organizer properties, and a rhombospinal domain. The vertebrate MHB is characterized by position, by organizer properties and by being the early site of action of Wnt1 and engrailed genes, and of genes of the Pax2/5/8 subfamily. Wada and others (Wada, H., Saiga, H., Satoh, N. and Holland, P. W. H. (1998) Development 125, 1113-1122) suggested that ascidian tunicates have a vertebrate-like MHB on the basis of ascidian Pax258 expression there. In another invertebrate chordate, amphioxus, comparable gene expression evidence for a vertebrate-like MHB is lacking. We, therefore, isolated and characterized AmphiPax2/5/8, the sole member of this subfamily in amphioxus. AmphiPax2/5/8 is initially expressed well back in the rhombospinal domain and not where a MHB would be expected. In contrast, most of the other expression domains of AmphiPax2/5/8 correspond to expression domains of vertebrate Pax2, Pax5 and Pax8 in structures that are probably homologous - support cells of the eye, nephridium, thyroid-like structures and pharyngeal gill slits; although AmphiPax2/5/8 is not transcribed in any structures that could be interpreted as homologues of vertebrate otic placodes or otic vesicles. In sum, the developmental expression of AmphiPax2/5/8 indicates that the amphioxus central nervous system lacks a MHB resembling the vertebrate isthmic region. Additional gene expression data for the developing ascidian and amphioxus nervous systems would help determine whether a MHB is a basal chordate character secondarily lost in amphioxus. The alternative is that the MHB is a vertebrate innovation.

Alternative Splicing↗
PubMed1999

MR angiography versus color Doppler sonography in the evaluation of renal vessels and the inferior vena cava in abdominal masses of pediatric patients.

OBJECTIVE: Involvement of renal vessels and the inferior vena cava (IVC) plays a decisive role during operative planning for removal of abdominal masses in pediatric patients. Advantages and limitations of MR angiography and color Doppler sonography for determining these factors were evaluated. MATERIALS AND METHODS: MR angiography and color Doppler sonography were performed preoperatively in 42 neonates, infants, and children with abdominal masses and were compared with spin-echo MR imaging and with surgical findings. Variables evaluated were anatomic variants, vessel displacement, patency of vessels, collateral circulation, and intravascular tumor extension. Quality of vessel visualization was assessed in vessels not affected by tumor. RESULTS: In 88% of unaffected renal vessels, the entire vessel course could be visualized on MR angiography compared with 58% on color Doppler sonography and 43% on spin-echo MR imaging. In four of nine cases, color Doppler sonography revealed an accessory renal artery, whereas MR angiography revealed these variants in seven of nine cases. MR angiography showed 79% and color Doppler sonography 66% of displaced vessels. Unlike MR angiography, color Doppler sonography did not reveal five stenotic renal veins because they could not be completely imaged. In two cases, however, MR angiography falsely indicated an occlusion of the IVC, whereas color Doppler sonography showed residual flow. CONCLUSION: Anatomic variants, vessel displacement, collateral circulation, and neoplastic vessel infiltration were revealed more accurately by MR angiography than by color Doppler sonography. In cases in which patency of the IVC is unclear on MR angiography, color Doppler sonography should also be performed.

Abdominal Neoplasms↗
PubMed1998

Walking and fatigue in multiple sclerosis: the role of the corticospinal system.

Transcranial magnetic stimulation was used to study motor evoked potentials (MEPs) of leg muscles in controls and patients with multiple sclerosis (MS) before and after walking. In controls, MEP areas were significantly reduced after walking. A similar or greater reduction was seen in most patients, although there was a wide range of values. The M waves were unchanged. We conclude that walking induces functional changes of the corticospinal system and/or connected neurons contributing to central fatigue, especially in patients with MS.

Adult↗
PubMed1998

Enhanced GFAP expression in astrocytes of transgenic mice expressing the human brain-specific trypsinogen IV.

We recently identified a cDNA encoding a human brain specific trypsinogen (trypsinogen IV). In order to test whether trypsinogen IV is involved in CNS diseases of, or injury response in, mammalian brain, a mouse model was developed in which the human trypsinogen IV was expressed specifically in neurons. Immunocytochemical analysis of the brains of transgenic mice revealed a striking enhancement of glial fibrillar acidic protein (GFAP) expression in astrocytes. This remarkable astrocytic reaction was detected in the brains of mice as young as 2 months and did not diminish in the older animals we tested. However, we did not find gross evidence for neurodegeneration, nor for reactive microglial cells. The long-term survival of these animals should provide a model with which to study the mechanism of nerve-astroglia interactions. In addition, the possible participation of trypsin IV in the metabolism of the Alzheimer precursor protein (APP) was investigated by immunostaining brains from transgenic mice with beta-amyloid (betaA4) antibodies. Immunocytochemical staining of brains from one year old transgenic mice revealed an intense intracellular betaA4-like signal in neurons.

Amyloid beta-Peptides↗
PubMed1998

Differential effects of two motor tasks on ERPs in an auditory classification task: evidence of shared cognitive resources.

The aim of the study was to assess cognitive demands and fatigue during the execution of two different motor tasks. Event-related brain potentials (ERPs) were recorded from 15 healthy subjects while they concurrently performed, (1) one of two motor tasks, and (2) a three stimulus (70% standard tones, 15% target tones, 15% novel stimuli) auditory classification task. Both motor tasks required the externally paced adduction of the right thumb with the force task requiring a precise movement (feedback given) with about 50% of maximum force output (6 s on task, 4 s rest) while the displacement task required the same precise movement with only minimal force requirements. In separate sessions, both tasks were performed for about an hour with the subjects concurrently paying attention to the auditory task with button presses required for the target stimuli. This provided a dual task situation with trade-offs in P3b amplitude as a function of difficulty of the primary (motor) task. The P3b to the auditory target stimuli was reduced during the force session compared to the displacement session, indicating that the force-task placed a higher demand on cognitive resources. No differential effect of fatigue (time on task) could be ascertained over six consecutive parts of the session. The P3a component, a putative correlate of orienting of attention, showed a rapid attenuation over time but, attesting to its automatic nature, no effect of concurrent motor task. ERP components recorded timelocked to the movements showed a marked difference between the two tasks with the displacement task giving rise to higher amplitudes. Moreover, only for the force task an influence of time on task (fatigue) on the MP was found. The dual task methodology is a potentially useful tool to disentangle cognitive and motor components of central fatigue.

Acoustic Stimulation↗
PubMed1998

Stumbling reactions in man: influence of corticospinal input.

The aim of this study was to evaluate the degree of contribution of supraspinal input to the generation of the compensatory leg muscle activation following stance perturbation. Therefore, evoked motor response (EMR) input-output relations of two different motor tasks were compared at 3 distinct periods: (1) the basic period of muscular activity during standing, i.e. when no additional cortical or spinal activity due to the different tasks is to be expected, (2) the pre-movement period with low background activity, when different spinal and cortical inputs to the motoneuronal pool can be assumed and (3) the period of plateau EMG activity of compensatory and voluntary motor task. Transcranial magnetic stimulation (TMS) just below the motor threshold was applied randomly at 19 different time-intervals before and during the onset of stance perturbation and for comparison during an equivalent voluntary foot-dorsiflexion task. Recordings of electromyographic (EMG) activity from the tibialis anterior (TA) and corresponding ankle-joint movements were made from both legs. Forward-directed displacements were induced by randomly-timed ramp impulses of constant acceleration upon a moveable platform. For comparison, leg muscle EMG was recorded during isometric foot dorsiflexion during stance while leaning back against a support. The stance perturbations were followed by a compensatory response (CR) in the TA with a mean onset time of 81 ms. During the basic period of muscular activity and the period of plateau EMG activity there was no significant difference of the input-output relation between stance perturbation and the voluntary motor task. However, in the voluntary task compared with the CR, there was significantly greater input-output relation (facilitation) of the EMR in the TA following TMS, which may be related to an increased cortical influence. In contrast to this result of the CR following stance perturbation, a facilitation of the EMR was described for hand muscles under corresponding conditions of automatic compensation for muscle stretch, suggesting a transcortical reflex loop. This difference in the results from upper and lower extremity muscles favors the assumption of a predominantly spinal generation of the TA-CR following stance perturbation.

Adult↗
PubMed1998

Amphioxus AmphiDRAL encoding a LIM-domain protein: expression in the epidermis but not in the presumptive neuroectoderm

The sequence and developmental expression have been determined for amphioxus AmphiDRAL, which encodes a homolog of vertebrate DRAL (down-regulated in rhabdomyosarcoma LIM-protein). This is the first clear example of a DRAL homolog in an invertebrate. Detectable developmental expression begins at the gastrula stage in the epidermis, but not in the neuroectoderm; thus the early stages of AmphiDRAL expression indicate the neural/non-neural boundary. During subsequent embryonic stages, expression continues in the epidermis (but not in the developing central nervous system) until it fades during the later larval stages. Copyright 1998 Elsevier Science Ireland Ltd. All Rights Reserved

Journal Article↗
PubMed1998

Genetic and biochemical evidence for distinct key functions of two highly divergent GAPDH genes in catabolic and anabolic carbon flow of the cyanobacterium Synechocystis sp. PCC 6803.

Cyanobacterial genomes harbour two separate highly divergent glyceraldehyde-3-phosphate dehydrogenase (GAPDH) genes, gap1 and gap2, which are closely related at the sequence level to the nuclear genes encoding cytosolic and chloroplast GAPDH of higher plants, respectively. Genes gap1 and gap2 of the unicellular cyanobacterium Synechocystis sp. PCC 6803 were cloned and sequenced and subsequently inactivated by insertional mutagenesis to understand their metabolic functions. We obtained homozygous gap1- mutants which have lost the capacity to grow on glucose under dim light while growth on organic acids as well as photosynthetic growth under CO2 and high light is not impaired. Homozygous gap2- mutants show the reciprocal phenotype. Under dim light they only grow on glucose but not on organic acids nor do they survive under photosynthetic conditions. Measurements of the anabolic activities (reduction of 1,3-bisphosphoglycerate) in extracts from wild type and mutant cells show that Gap2 is a major enzyme with dual cosubstrate specificity for NAD and NADP, while Gap1 displays a minor NAD-specific GAPDH activity. However, if measured in the catabolic direction (oxidation of glyceraldehyde-3-phosphate) Gap2 activity is very low and increases three- to fivefold after gel filtration of extracts over Sephadex G25. Our results suggest that enzymes Gap1 and Gap2, although coexpressed in cyanobacterial wild-type cells, play distinct key roles in catabolic and anabolic carbon flow, respectively. While Gap2 operates in the photosynthetic Calvin cycle and in non-photosynthetic gluconeogenesis, Gap1 seems to be essential only for glycolytic glucose breakdown, conditions under which the catabolic activity of Gap2 seems to be repressed by a specific low-molecular-weight inhibitor.

Amino Acid Sequence↗
PubMed1998

The development of chronic graft-versus-host disease: an analysis of screening studies and the impact of corticosteroid use at 100 days after transplantation.

The value of routine chronic graft-versus-host disease (GVHD) screening studies performed between 70 and 120 days after allogeneic marrow transplantation was retrospectively evaluated among 241 patients. All patients received methotrexate and cyclosporine for GVHD prophylaxis and survived without relapse more than 4 months after transplant. Ninety-one patients (38%) developed clinical extensive chronic GVHD requiring systemic therapy. Data on patients who developed clinical extensive chronic GVHD were compared with those on patients without chronic GVHD to determine which of the following screening tests predicted the subsequent development of clinical extensive chronic GVHD: skin biopsy, oral exam, lip biopsy, Schirmer's test, serum alkaline phosphatase, aspartate transaminase, immunoglobulin level and platelet count. In a univariable analysis, a positive oral examination and a low platelet count were predictive of chronic extensive GVHD development. In a multivariable analysis which adjusted for the contribution of other chronic GVHD risk factors, such as age and a history of acute GVHD none of the screening tests were predictive of chronic GVHD development. The risk factors in this multivariable analysis which had the strongest association with the development of chronic GVHD was a history of acute GVHD and use of corticosteroids at day 100 (RR = 3.9, P = 0.001). The use of corticosteroids for acute GVHD at day 100 had a predictive effect on chronic GVHD development independent of the grade of acute GVHD (RR = 2.1, P = 0.004). Based on these study results, the use of chronic GVHD screening tests may not be of value in predicting who will develop this complication. Patients on corticosteroids at day 100 should be considered for clinical trials to determine the efficacy of new immunosuppressive agents in preventing chronic GVHD.

Adrenal Cortex Hormones↗
PubMed1998

Aspergillus spondylodiscitis in an immunocompetent paraplegic patient.

A case of an immunocompetent 60 year old patient is reported, who suffered extensive thoracic spinal injury and paraplegia after polytrauma. In the course of rehabilitation he developed aspergillus spondylodiscitis in a part of the thoraco-lumbar spine which was primarily uninjured. The diagnostic assessment and therapeutic approach of this rare disorder is elucidated and discussed in the context of paraplegia and polytrauma. Possible mechanisms of inoculation and spreading of the moulds as well as predisposing factors of the disease are discussed in this paper and a review of the recent literature is provided.

Aspergillosis↗
PubMed1998

Compound heterozygosity for a recessive glycine substitution and a splice site mutation in the COL7A1 gene causes an unusually mild form of localized recessive dystrophic epidermolysis bullosa.

Type VII collagen is the major component of anchoring fibrils, adhesion structures of stratified epithelia that span the basement membrane region and papillary dermis. Mutations in the gene COL7A1 encoding type VII collagen cause dystrophic epidermolysis bullosa, a clinically heterogeneous autosomal dominant or recessive blistering disorder of the skin and mucous membranes. In this report, we investigate three siblings affected by an unusually mild form of localized recessive dystrophic epidermolysis bullosa who were shown to be compound heterozygotes for novel mutations affecting COL7A1. The maternally inherited mutation is a G-->C transversion that converts a codon for glycine to a codon for arginine (G1347R). The paternal mutation is a neutral G-->A transition at the last base of exon 70(5820G-->A) that alters the correct splicing of COL7A1 pre-mRNA, giving rise to an aberrant mRNA carrying the in-frame skipping of exon 70 in addition to the full-length RNA transcript carrying the G-->A substitution. Consistent with the normal levels of COL7A1 mRNA transcripts detected by northern analysis, immunoblotting and immunofluorescence studies evidenced that the patient keratinocytes synthesize and secrete normal amounts of stable type VII collagen, which is correctly deposited at the dermal-epidermal junction. In addition, mutated type VII collagen molecules assemble to form numerous, normally shaped anchoring fibrils, as shown by electron microscopic examination. The combination of a recessive glycine substitution with a splice site mutation that permits partially correct splicing therefore leads to a normal expression of mutated type VII collagen molecules with marginally altered biologic activity, and to the extremely mild phenotype observed in our patients.

Amino Acid Substitution↗
PubMed1997

Low energy Helium-Neon laser in the prevention of oral mucositis in patients undergoing bone marrow transplant: results of a double blind randomized trial.

PURPOSE: To evaluate the efficiency of Helium-Neon (He-Ne) laser in the prevention of oral mucositis induced by high dose chemoradiotherapy before autologous bone marrow transplantation (BMT). METHODS AND MATERIALS: Between 1993 and 1995, 30 consecutive patients receiving an autologous peripheral stem-cell or bone marrow transplant (BMT) after high dose chemoradiotherapy were randomized to possibly receive prophylactic laser to the oral mucosa after giving informed consent. Chemotherapy consisted of cyclophosphamide, 60 mg/kg intravenously (I.V.) on day (d)-5 and d-4 in 27 cases, or melphalan 140 mg/kg I.V. on d-4 in three cases. Total body irradiation (TBI) consisted of 12 Gy midplane dose in six fractions (4 Gy/day for three days). He-Ne laser (632.8 nm wavelength, power 60 mW) applications were performed daily from d-5 to d-1 on five anatomic sites of the oral mucosa. Oral examination was performed daily from d0 to d + 20. Mucositis was scored according to an oral exam guide with a 16 item scale of which four were assessed by the patients themselves. Mean daily self assessment scores for oral pain, ability to swallow and oral dryness were measured. A daily mucositis index (DMI) and a cumulative oral mucositis score (COMS) were established. Requirement for narcotics and parenteral nutrition was recorded. RESULTS: The COMS was significantly reduced among laser treated (L+) patients (p = 0.04). The improvement of DMI in L+ patients was also statistically significant (p < 0.05) from d + 2 to d + 7. Occurrence and duration of grade III oral mucositis were reduced in L+ patients (p = 0.01). Laser applications reduced oral pain as assessed by patients (p = 0.05) and L+ patients required less morphine (p = 0.05). Xerostomia and ability to swallow were improved among the L+ patients (p = 0.005 and p = 0.01, respectively). Requirement for parenteral nutrition was not reduced (p = NS). CONCLUSION: Helium-Neon laser treatment was well tolerated, feasible in all cases, and reduced high dose chemoradiotherapy-induced oral mucositis. Optimal laser treatment schedules still needs to be defined.

Adolescent↗
PubMed1997

Defective HIV-1 provirus encoding a multitarget-ribozyme inhibits accumulation of spliced and unspliced HIV-1 mRNAs, reduces infectivity of viral progeny, and protects the cells from pathogenesis.

A HeLa T4 cell line containing a defective human immunodeficiency virus type 1 (HIV-1) DNA (HD4) was isolated. After transactivation with Tat, the HD4 DNA was transcribed into a single 3.7-kb mRNA that encodes a chimeric CD4/Env protein and a multitarget-ribozyme directed against multiple sites within the gp120 coding region of HIV-1 RNA (Chen et al., 1992). Early steps in HIV infection such as entry, reverse transcription, and proviral DNA formation were not affected in HD4 cells, and HD4 was efficiently transactivated after either HIV-1 or HIV-2 infections. HIV-2, which lacks all of the HIV-1-specific ribozyme target sites, replicated to high levels in HD4 cells whereas HIV-1 replication was selectively inhibited. Despite a reduced accumulation of all HIV-1 transcripts, transactivation of HD4 was efficient. Surprisingly, the most abundant, multiply spliced mRNAs were reduced even though they lack all of the ribozyme target sites. These results strongly suggest that the ribozyme co-localizes with unspliced HIV-1 pre-mRNA and/or genomic HIV-1 RNA in the nucleus. Cleavage of these precursor RNAs explains the reduction of all spliced and unspliced HIV-1 RNAs. Cleavage of genomic RNA probably contributed to the three-fold reduction in the infectivity of viral progeny. Thus, the HD4 ribozyme RNA functioned as a ribozyme in the nucleus and as a mRNA for a chimeric CD4/Env protein in the cytoplasm. Its unusual large size for a ribozyme (3.7 kb) indicates that, in the future, other antiviral proteins, like negative transdominant mutant HIV-1 proteins, may also be encoded to increase its antiviral potential in a gene therapy approach.

CD4 Antigens↗
PubMed1997

Visual influence on human locomotion. Modulation to changes in optic flow.

The effect of an optic flow pattern on human locomotion was studied in subjects walking on a self-driven treadmill. During walking an optic flow pattern was presented, which gave subjects the illusion of walking in a tunnel. Visual stimulation was achieved by a closed-loop system in which optic flow and treadmill velocity were automatically adjusted to the intended walking velocity (WV). Subjects were instructed to keep their WV constant. The presented optic flow velocity was sinusoidally varied relative to the WV with a cycle period of 2 min. The independent variable was the relative optic flow (rOF), ranging from -1, i.e., forward flow of equal velocity as the WV, and 3, i.e., backward flow 3 times faster than WV. All subjects were affected by rOF in a similar way. The results showed, firstly, an increase in stride-cycle variability that suggests a larger instability of the walking pattern than in treadmill walking without optic flow; and, secondly, a significant modulating effect of rOF on the self-chosen WV. Backward flow resulted in a decrease, whereas forward flow induced an increase of WV. Within the analyzed range, a linear relationship was found between rOF and WV. Thirdly, WV-related modulations in stride length (SL) and stride frequency (SF) were different from normal walking: whereas in the latter a change in WV is characterized by a stable linear relationship between SL and SF (i.e., an approximately constant SL to SF ratio), optic flow-induced changes in WV are closely related to a modulation of SL (i.e., a change of SL-SF ratio). Fourthly, this effect of rOF diminished by about 45% over the entire walking distance of 800 m. The results suggest that the adjustment of WV is the result of a summation of visual and leg-proprioceptive velocity informations. Visual information about ego-motion leads to an unintentional modulation of WV by affecting specifically the relationship between SL and SF. It is hypothesized that the space-related parameter (SL) is influenced by visually perceived motion information, whereas the temporal parameter (SF) remains stable. The adaptation over the entire walking distance suggests that a shift from visual to leg-proprioceptive control takes place.

Adaptation, Physiological↗
PubMed1997

Corticospinal input in human gait: modulation of magnetically evoked motor responses.

Transcranial magnetic stimulation (TMS) of the motor cortex was applied during locomotion to investigate the significance of corticospinal input upon the gait pattern. Evoked motor responses (EMR) were studied in the electromyogram (EMG) of tibialis anterior (TA), gastrocnemius (GM) and, for reference, abductor digiti minimi (AD) muscles by applying below-threshold magnetic stimuli during treadmill walking in healthy adults. Averages of 15 stimuli introduced randomly at each of 16 phases of the stride cycle were analysed. Phase-dependent amplitude modulation of EMR was present in TA and GM which did not always parallel the gait-associated modulation of the EMG activity. No variation of onset latency of the EMR was observed. The net modulatory response was calculated by comparing EMR amplitudes during gait with EMR amplitudes obtained (at corresponding background EMG activities) during tonic voluntary muscle contraction. Large net responses in both muscles occurred prior to or during phasic changes of EMG activity in the locomotor pattern. This facilitation of EMR was significantly higher in leg flexor than extensor muscles, with maxima in TA prior to and during late swing phase. A comparison of this facilitation of TA EMR prior to swing phase and prior to a phasic voluntary foot dorsiflexion revealed a similar onset but an increased amount of early facilitation in the gait condition. The modulated facilitation of EMR during locomotion could in part be explained by spinal effects which are different under dynamic and static motor conditions. However, we suggest that changes in corticospinal excitability during gait are also reflected in this facilitation. This suggestion is based on: (1) the similar onset yet dissimilar size of facilitatory effects in TA EMR prior to the swing phase of the stride cycle and during a voluntary dynamic activation, (2) the inverse variation of EMR and EMG amplitudes during this phase, and (3) the occurrence of this inversion at stimulation strengths below motor threshold (motor threshold was determined during weak tonic contraction and EMR were facilitated during gait). It is hypothesized that the facilitation is phase linked to ensure postural stability and is most effective during the phases prior to and during rhythmical activation of the leg muscles resulting in anticipatory adjustment of the locomotor pattern.

Adult↗
PubMed1997

The development of subretinal microphotodiodes for replacement of degenerated photoreceptors.

There are presently several concepts to restore vision in blind or highly visually handicapped persons by implanting electronic devices into the eye in order to partially restore vision. Here, the approach to replace retinal photoreceptors by a subretinally implanted microphotodiode array (MPDA) is summarized. A survey is given on the present state of the development of MPDAs, the possibility of in vitro and in vivo tests as well as first results on biocompatibility and histology. Additionally, electrophysiological recordings in rabbits and rats are presented which have received such subretinal implants.

Animals↗