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Biomedical subjects

M Sommer

Publications and source records attributed to M Sommer.

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

Abnormal growth and clonal proliferation of fibroblasts in an animal model of unilateral ureteral obstruction.

The time course for the development of renal interstitial fibrosis (RIF) in rats between days 5 and 25 after unilateral ureteral obstruction (UUO) was studied. In kidneys with UUO under histological examination, an interstitial fibrosis was observed after more than 10 days with progression up to day 25. On day 5, collagen peptidase activity in homogenates of UUO kidneys was about 50% higher than in controls but gradually declined afterwards until reaching the level obtained from contralateral kidneys (CL) on day 25. 10 days after UUO, renal hydroxyproline content was elevated about twofold as compared to CL and sham-operated rats, and increased considerably by day 25 of UUO. In primary cultures of cells obtained from UUO kidneys, fibroblast proliferation increased regardless of the extent of fibrosis. This could be a result of an early inflammatory process. Renal fibroblasts from rats are heterogenous when studied in vitro. When fibroblasts of passage 1 obtained from kidneys 25 days after UUO were plated at low density, the number of mitotic type I clones was elevated 5.5-fold as compared with cultures from CL kidneys. The majority of type I clones in UUO cultures from fibrotic kidneys developed in an unusual fashion with formation of three-dimensional structures. The changes detectable under the unfavorable conditions of clonal culture suggest phenotypical differentiation of a small fraction of fibroblasts from kidneys with RIF. These cells are able to overgrow cell monolayers forming circular growing colonies. Obviously, one needs to distinguish between intensive proliferation as a consequence of acute inflammation, and the changes in phenotype of a small fraction of renal fibroblasts which are resistant to normal physiologic regulative mechanisms in cell culture. The latter may contribute to matrix disorders and RIF.

Animals↗
PubMed1999

Effects of constraint-induced movement therapy on patients with chronic motor deficits after stroke: a replication.

BACKGROUND AND PURPOSE: Constraint-induced movement therapy (CI therapy) has previously been shown to produce large improvements in actual amount of use of a more affected upper extremity in the "real-world" environment in patients with chronic stroke (ie, >1 year after the event). This work was carried out in an American laboratory. Our aim was to determine whether these results could be replicated in another laboratory located in Germany, operating within the context of a healthcare system in which administration of conventional types of physical therapy is generally more extensive than in the United States. METHODS: Fifteen chronic stroke patients were given CI therapy, involving restriction of movement of the intact upper extremity by placing it in a sling for 90% of waking hours for 12 days and training (by shaping) of the more affected extremity for 7 hours on the 8 weekdays during that period. RESULTS: Patients showed a significant and very large degree of improvement from before to after treatment on a laboratory motor test and on a test assessing amount of use of the affected extremity in activities of daily living in the life setting (effect sizes, 0.9 and 2.2, respectively), with no decrement in performance at 6-month follow-up. During a pretreatment control test-retest interval, there were no significant changes on these tests. CONCLUSIONS: Results replicate in Germany the findings with CI therapy in an American laboratory, suggesting that the intervention has general applicability.

Adult↗
PubMed1998

Motor cortex plasticity during constraint-induced movement therapy in stroke patients.

Stroke patients in the chronic phase received constraint-induced (CI) movement therapy. The motor cortex was spatially mapped using focal transcranial magnetic stimulation (TMS) before and after 2 weeks of treatment. Motor-output areas of the abductor pollicis brevis muscle, motor evoked potential (MEP) amplitudes and location of centre of gravity (CoG) of motor cortex output were studied. After CI therapy, motor performance improved substantially in all patients. There was also an increase of motor output area size and MEP amplitudes, indicating enhanced neuronal excitability in the damaged hemisphere for the target muscles. The mean centre of gravity of the motor output maps was shifted considerably after the rehabilitation, indicating the recruitment of motor areas adjacent to the original location. Thus, even in chronic stroke patients, reduced motor cortex representations of an affected body part can be enlarged and increased in level of excitability by an effective rehabilitation procedure. The data therefore demonstrate a CNS correlate of therapy-induced recovery of function after nervous system damage in humans.

Brain Mapping↗
PubMed1998

[Depersonalization syndrome after acquired brain damage. Overview based on 3 case reports and the literature and discussion of etiological models].

Depersonalization after brain damage is still only rarely reported and poorly understood. We describe three patients between the ages of 21 and 25 who experienced depersonalization and derealization for periods of 6 weeks to 4 months, two after traumatic brain injury, the third after surgical and radiation treatment of a pineocytoma. Each one believed to be living in a nightmare and thought about committing suicide in order to wake up. One patient developed symptoms as described in Cotard delusion. Aspects of neuroanatomy, psychodynamics, and anthropology are discussed with reference to the literature. Frontal and temporal lesions seem only to play a facilitating role but not to be a necessary condition. There is evidence for additional influence of psychological and premorbid personality factors. Summarizing the current state of information we consider depersonalization with the experience of being in a dream or being dead as a heuristic reaction to brain damage. Similar models have already been discussed in neuropsychological disorders as for instance reduplicative paramnesias, neglect, and anosognosia.

Adult↗
PubMed1998

Analysis of the glycoproteins I and E of varicella-zoster virus (VZV) using deletional mutations of VZV cosmids.

The contributions of the glycoproteins gI (ORF67) and gE (ORF68) to varicella-zoster virus (VZV) replication were investigated in deletion mutants made by using cosmids with VZV DNA derived from the Oka strain. These experiments demonstrated that gI was not required for VZV replication in vitro but gE appeared to be. Although VZV gI was not required, its deletion or mutation resulted in a significant decrease in infectious virus yields, and it disrupted syncytial formation and altered the conformation and distribution of gE in infected cells. Normal cell-to-cell spread and replication kinetics were restored when gI was expressed from a non-native locus in the VZV genome. The expression of intact gI, the ORF67 gene product, is required for efficient VZV replication.

Cell Line↗
PubMed1998

Voluntary eyelid contraction modifies the blink reflex recovery cycle.

In order to determine the extent to which the recovery cycle of the blink reflex is modified by voluntary contraction of the eyelids we investigated the electrically elicited blink reflex with paired stimuli of identical intensity in 9 healthy subjects. We pseudorandomly administered two interstimulus intervals (150 ms and 250 ms) in three different conditions of voluntary contraction of the orbicularis oculi muscle (relaxed, mild lid closure and strong lid closure). Our results show that inhibition of the R2 response following the second stimulus is significantly reduced with voluntary contraction. In addition, we found significantly larger amplitudes and shorter latencies of R1 and R2 with voluntary contraction. We conclude that in healthy subjects, voluntary eyelid contraction causes facilitation or disinhibition not only in the nuclei of the seventh cranial nerve, but also in the polysynaptic pathway of the R2. The possible implications on the interpretation of clinical data are discussed.

Adult↗
PubMed1998

Low endotoxic potential of Legionella pneumophila lipopolysaccharide due to failure of interaction with the monocyte lipopolysaccharide receptor CD14.

Legionella pneumophila, a gram-negative bacterium causing Legionnaires' disease and Pontiac fever, was shown to be highly reactive in in vitro gelation of Limulus lysate but not able to induce fever and the local Shwartzman reaction in rabbits and mice. We analyzed the capacity of purified L. pneumophila lipopolysaccharide (LPS-Lp) to induce activation of the human monocytic cell line Mono Mac 6, as revealed by secretion of proinflammatory cytokines and desensitization to subsequent LPS stimulation. We showed that despite normal reactivity of LPS-Lp in the Limulus amoebocyte lysate assay, induction of cytokine secretion in Mono Mac 6 cells and desensitization to an endotoxin challenge required LPS-Lp concentrations 1,000 times higher than for LPS of Salmonella enterica serovar Minnesota. Therefore, we examined the interaction of LPS-Lp with the LPS receptor CD14. We demonstrated that LPS-Lp did not bind to membrane-bound CD14 expressed on transfected CHO cells, nor did it react with soluble CD14. Our results suggest that the low endotoxic potential of LPS-Lp is due to a failure of interaction with the LPS receptor CD14.

Animals↗
PubMed1997

[Pathogenesis of interstitial kidney fibrosis. Studies in the rat model of unilateral ureteral obstruction].

BACKGROUND: The animal model of unilateral ureteral obstruction (UUO) of the rat is suitable to cause a renal interstitial fibrosis within a few weeks. Prior to the 10th day after UUO, no fibrotic changes were detectable in ureter-ligated kidneys, whereas after day 20 fibrosis was developing strongly. METHOD: Using cell cultures it was examined whether any in vivo changes in proliferation and function of fibroblasts are also detectable in cell cultures and whether, due to their persistency, they are of fundamental importance for the development of renal interstitial fibrosis. RESULTS: The comparison of the proliferation in cell cultures established 5 and 21 days after UUO showed that the cultures of the two experimental groups behave similarly. Consequently, the action of acute inflammatory processes on fibroblast proliferation without any existing fibrosis is comparable with that of pronounced fibrosis in the animal model. High concentrations of fetal calf serum in the culture medium cause a stimulation of the cell proliferation as well as a selection of mitotically active differentiation stages of fibroblasts. CONCLUSION: Obviously, the loss of inhibition of the fibroblast proliferation under the conditions of cell culture causes similar changes to those effected by pathogenic mechanisms in the kidneys of rats with UUO. If the behaviour of fibroblasts in organs is to be assessed using results of cell culture experiments, the stimulating action of the culture conditions and the missing influence of other cells present in the tissue should be considered. These factors make the recognition of remaining differences between cells from normal and damaged kidneys more difficult under the conditions of primary cell cultures.

Animals↗
PubMed1997

Mutational analysis of the role of glycoprotein I in varicella-zoster virus replication and its effects on glycoprotein E conformation and trafficking.

The contributions of the glycoproteins gI (ORF67) and gE (ORF68) to varicella-zoster virus (VZV) replication were investigated in deletion mutants made by using cosmids with VZV DNA derived from the Oka strain. Deletion of both gI and gE prevented virus replication. Complete deletion of gI or deletions of 60% of the N terminus or 40% of the C terminus of gI resulted in a small plaque phenotype as well as reduced yields of infectious virus. Melanoma cells infected with gI deletion mutants formed abnormal polykaryocytes with a disrupted organization of nuclei. In the absence of intact gI, gE became localized in patches on the cell membrane, as demonstrated by confocal microscopy. A truncated N-terminal form of gI was transported to the cell surface, but its expression did not restore plaque morphology or infectivity. The fusogenic function of gH did not compensate for gI deletion or the associated disruption of the gE-gI complex. These experiments demonstrated that gI was dispensable for VZV replication in vitro, whereas gE appeared to be required. Although VZV gI was dispensable, its deletion or mutation resulted in a significant decrease in infectious virus yields, disrupted syncytium formation, and altered the conformation and distribution of gE in infected cells. Normal cell-to-cell spread and replication kinetics were restored when gI was expressed from a nonnative locus in the VZV genome. The expression of intact gI, the ORF67 gene product, is required for efficient membrane fusion during VZV replication.

Biological Transport↗
PubMed1996

Three missense mutations in the galactose-1-phosphate uridyltransferase gene of three families with mild galactosaemia.

UNLABELLED: Classical galactosaemia caused by deficiency of galactose-1-phosphate uridyltransferase (GALT) is characterized by acute symptoms of hepatocellular dysfunction, sepsis, cataracts and failure to thrive. Galactose limitation reverses these complications immediately, however, most of these children have a long-term complication of verbal dyspraxia mental retardation and ovarian failure. The GALT gene was cloned and several mutations including the common Q188R have been reported. In this study the coding region of GALT was amplified by polymerase chain reaction from genomic DNA of classical galactosaemic individuals and characterized by direct sequencing of the products. Three missense mutations were identified in three patients with a mild galactosaemic variant: (1) replacement of threonine-138 by methionine (T138M); (2) replacement of arginine by tryptophan (R259W); and (3) replacement of threonine by alanine (T350A). All three galactosaemic individuals, one girl and two boys, have varying degrees of residual GALT activity in RBC and their galactose-1-phosphate levels decreased much faster than in other galactosaemic patients. These missense mutations occur in regions that are not highly conserved domains. CONCLUSION: The study of the molecular basis related to the phenotype variation may indeed help to prognosticate the outcome of patients with classical galactosaemia.

Amino Acid Sequence↗
PubMed1996

Prognostic factors for response and survival in patients with metastatic melanoma receiving immunotherapy.

Sixty-five patients with advanced melanoma treated in phase II trials with interferon-alpha and high dose interleukin-2 were analysed for pretreatment prognostic parameters. Three levels of response were used: objective remission [three complete response (CR)/14 partial response (PR)], stable disease and progression. Elevated lactate dehydrogenase (LDH), impaired performance status and high tumor load were associated with poor response. Multivariate analysis considering two levels of response [CR/PR vs stable disease (SD)/progressive disease (PD)] did not reveal any model with more than one significant factor. Considering survival, LDH was also a strong factor. Additional prognostic factors here were performance status, metastatic sites, alkaline phosphatase and tumor load. A Cox regression analysis revealed LDH, performance status and metastatic sites as independent factors. The prognostic values of these parameters will have to be confirmed in a larger patient cohort. Using the landmark method, it was estimated whether the response obtained after two cycles of treatment predicted survival. Patients with PD at this time had a median further survival of 6 months, SD of 27 months, and PR/CR of more than 31 months. This observation may help making decisions at this time.

Dose-Response Relationship, Drug↗
PubMed1995

Characterization of two stop codon mutations in the galactose-1-phosphate uridyltransferase gene of three male galactosemic patients with severe clinical manifestation.

Classical galactosemia, which is caused by deficiency of galactose-1-phosphate uridyltransferase, is characterized by acute problems of hepatocellular dysfunction, sepsis, cataracts and failure to thrive. Galactose limitation reverses these symptoms immediately; however, the long-term complications, such as mental retardation and ovarian failures are major problems in most of these patients. In order to investigate the molecular basis for phenotype variation in galactosemia, we have screened the most common mutation in the GALT gene, Q188R. We have further examined those patients who are heterozygous for Q188R or negative for this mutation by SSCP analysis and direct sequencing. In three male patients, we have identified, for the first time, two stop-codon mutations in the GALT gene, G212X (exon 7) and E340X (exon 10). Two patients of 8 and 28 years of age, respectively, who are compound heterozygotes for Q188R and G212X, have severe mental retardation and their general clinical condition is more severe than that of patients with missense mutations. The third patient, who is 8 years of age and who is homozygous for E340X, the N314D polymorphism and a silent substitution L218L, presents with a relatively normal physical and mental condition to date.

Adult↗
PubMed1995

Evaluation of low dose prostaglandin E1 treatment for ductus dependent congenital heart disease.

UNLABELLED: This study reports our experience with low-dose prostaglandin E1 (PGE1) treatment of 91 newborns with ductus dependent congenital heart disease (CHD). PGE1 efficacy, side-effects as well as the cardiovascular and respiratory profile of the patients were analysed. PGE1 doses > 0.02 microgram/kg per minute were used for only 5.3% of the total 23,656 h of treatment. The mean systolic blood pressures did not differ from the normal mean for patients with cyanotic CHD, while the diastolic values were lowered. Respiratory support was required only during 13.7% of the total treatment time. Apnoeas occurred in 21 (38%) of the 55 spontaneously breathing infants, who all had a cyanotic CHD. The incidence of apnoeas was lower during treatment with doses < 0.01 microgram/kg per minute. CONCLUSION: PGE1 can be successfully administered in lower doses than previously recommended. Especially high initial doses can be avoided and low maintenance doses allow long-term treatment without serious complications.

Alprostadil↗
PubMed1995

Mutations in the galactose-1-phosphate uridyltransferase gene of two families with mild galactosaemia variants.

Classical galactosaemia, deficiency of galactose-1-phosphate uridyltransferase (GALT), is characterized by acute symptoms of hepatomegaly, jaundice, sepsis, cataracts and growth retardation. Treatment with dietary galactose restriction corrects these complications immediately; however, most of these children develop long-term complications of verbal dyspraxia, mental retardation and ovarian failure. Our previous molecular study showed that the most common mutation of the GALT gene is a missense mutation of Q188R (replacement of glutamine-188 by arginine) in approximately 60-65% of the German galactosaemic population. The coding region of GALT was amplified by the polymerase chain reaction from genomic DNA of classical galactosaemic individuals, who are negative or heterozygous for Q188R, and was further characterized by direct sequencing. Three new disease-causing mutations, two missense and a stop codon mutation, were identified in three patients from two families with mild galactosaemic variants: firstly R67C, replacement of arginine-67 by cysteine and W316X, the stop codon at tryptophan-316 in one male; secondly A330V, replacement of alanine-330 by valine in two female siblings. In the first family the patient was also heterozygous for the polymorphism N314D and in the second family both girls were compound heterozygotes for Q188R and A330V. All three galactosaemic individuals have a considerable amount of the residual GALT activity in RBC and the galactose-1-phosphate (GALP) level decreased much faster on treatment than that of other galactosaemic patients with missense mutations such as Q188R. The clinical and biochemical data of these patients were much more favourable in comparison with those of two female galactosaemic individuals, one homozygous for L195P and the other compound heterozygous for Q188R and L195P. These three missense mutations (R67C, L195P and A330V) also occur in highly conserved regions. These observations suggest that the phenotypic variation in galactosaemic individuals may be due to different molecular aetiologies.

Adolescent↗
PubMed1993

In vivo and in vitro analysis of transcriptional activation mediated by the human cytomegalovirus major immediate-early proteins.

To define mechanistically how the human cytomegalovirus (HCMV) major immediate-early (IE) proteins induce early-gene transcription, the IE1 72-kDa protein, the IE2 55-kDa protein, and the IE2 86-kDa protein were analyzed for their ability to activate transcription from an HCMV early promoter in vivo and in vitro. In transient-expression assays in U373MG astrocytoma/glioblastoma and HeLa cells, only the IE2 86-kDa protein was able to activate the HCMV early promoter to high levels. In HeLa cells, the IE1 72-kDa protein was able to activate the promoter to a low but detectable level, and the level of promoter activity observed in response to the IE2 86-kDa protein was increased synergistically following cotransfection of the constructs expressing both IE proteins. To examine the interaction of the HCMV IE proteins with the RNA polymerase II transcription machinery, we assayed the ability of Escherichia coli-synthesized proteins to activate the HCMV early promoter in nuclear extracts prepared from U373MG cells, HeLa cells, and Drosophila embryos. The results of the in vitro experiments correlated well with those obtained in vivo. The basal activity of the promoter was minimal in both the HeLa and U373MG extracts but was stimulated 6- to 10-fold by the IE2 86-kDa protein. With a histone H1-deficient extract from Drosophila embryos, the HCMV early promoter was quite active and was stimulated two- to fourfold by the IE2 86-kDa protein. Addition of histone H1 at 1 molecule per 40 to 50 bp of DNA template significantly repressed basal transcription from this promoter. However, the IE2 86-kDa protein, but none of the other IE proteins, was able to counteract the H1-mediated repression and stimulate transcription at least 10- to 20-fold. The promoter specificity of the activation was demonstrated by the inability of the IE2 86-kDa protein to activate the Drosophila Krüppel promoter in either the presence or absence of histone H1. These results suggest that one mechanism of transcription activation by the IE2 86-kDa protein involves antirepression.

Base Sequence↗