Pathophysiology of brain ischemia: penumbra, gene expression, and future therapeutic options.
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Brain Ischemia↗
Biomedical subjects
M Bahr
Publications and source records attributed to M Bahr.
Acute neuronal apoptosis in a rat model of multiple sclerosis.
Demyelination caused by inflammation of the CNS has been considered to be a major hallmark of multiple sclerosis (MS). Using experimental autoimmune encephalomyelitis, a model of MS, we demonstrate that an immune-mediated attack of the optic nerve is accompanied by an early degeneration of retinal ganglion cells (RGCs). The decrease of neuronal cell density was correlated with functional disabilities as assessed by visual evoked cortical potentials and electroretinogram. Visual acuity was significantly reduced. DNA degradation and activation of caspase-3 in RGCs indicate that cell death of RGCs is apoptotic. These findings show for the first time that an inflammatory attack against myelin components can lead to acute neuronal cell loss by apoptosis.
Acute Disease↗
Reduction of potassium currents and phosphatidylinositol 3-kinase-dependent AKT phosphorylation by tumor necrosis factor-(alpha) rescues axotomized retinal ganglion cells from retrograde cell death in vivo.
Tumor-necrosis-factor-alpha (TNF-alpha) prevented secondary death of retinal ganglion cells (RGCs) after axotomy of the optic nerve in vivo. This RGC rescue was confirmed in vitro in a mixed retinal culture model. In accordance with our previous findings, TNF-alpha decreased outward potassium currents in RGCs. Antagonism of the TNF-alpha-induced decrease in outward potassium currents with the potassium channel opener minoxidilsulfate (as verified by electrophysiology) abolished neuroprotection. Western blot analysis revealed an upregulation of phospho-Akt as a consequence of TNF-alpha-induced potassium current reduction. Inhibition of the phosphatidylinositol 3-kinase-Akt pathway with wortmannin decreased TNF-alpha-promoted RGC survival. These data point to a functionally relevant cytokine-dependent neuroprotective signaling cascade in adult CNS neurons.
Animals↗
Matrix metalloproteinase (MMP)-2, MMP-7, and tissue inhibitor of metalloproteinase-1 are closely related to the fibroproliferative process in the liver during chronic hepatitis C.
BACKGROUND/AIMS: To study whether expression of matrix metalloproteinases and their inhibitors correlate with ongoing fibrogenesis, we measured hepatic mRNA levels of matrix metalloproteinase (MMP) -2, MMP-7, and MMP-9 as well as tissue inhibitor of metalloproteinase (TIMP) -1, TIMP-2, and TIMP-3 and compared it to histology, procollagen IV alpha-1 chain mRNA levels, and biochemical parameters in patients with chronic active hepatitis C (CAH). METHODS: Quantitative reverse transcription-polymerase chain reaction/enzyme-linked immunossorbent assay using in vitro transcribed competitor and standard RNA were performed from ten normal livers (N), 29 CAH liver biopsies and seven samples with hepatitis C virus (HCV)-induced end-stage cirrhosis (Ci). RESULTS: From N to Ci both TIMP and MMP RNA expression increased. However, none of the RNA levels differed significantly between CAH patients with and without fibrosis. Non-parametric correlation analysis and receiver operating characteristics curves show that MMP-2, MMP-7, and TIMP-1 provide the best discrimination between cirrhosis and pre-cirrhotic stages. They also correlate with histologic and biochemical inflammatory activity and with procollagen IV mRNA. CONCLUSION: Hepatic fibroproliferation is associated with alterations of hepatic TIMP and MMP expression. The relation of hepatic TIMP and MMP mRNA levels to disease stage and inflammatory activity underlines their potential as diagnostic markers in chronic liver disease.
Base Sequence↗
Protection by synergistic effects of adenovirus-mediated X-chromosome-linked inhibitor of apoptosis and glial cell line-derived neurotrophic factor gene transfer in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease.
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical, and neuropathological changes reminiscent of those occurring in idiopathic Parkinson's disease (PD). Here we show that a peptide caspase inhibitor, N-benzyloxy-carbonyl-val-ala-asp-fluoromethyl ketone, or adenoviral gene transfer (AdV) of a protein caspase inhibitor, X-chromosome-linked inhibitor of apoptosis (XIAP), prevent cell death of dopaminergic substantia nigra pars compacta (SNpc) neurons induced by MPTP or its active metabolite 1-methyl-4-phenylpyridinium in vitro and in vivo. Because the MPTP-induced decrease in striatal concentrations of dopamine and its metabolites does not differ between AdV-XIAP- and control vector-treated mice, this protection is not associated with a preservation of nigrostriatal terminals. In contrast, the combination of adenoviral gene transfer of XIAP and of the glial cell line-derived neurotrophic factor to the striatum provides synergistic effects, rescuing dopaminergic SNpc neurons from cell death and maintaining their nigrostriatal terminals. These data suggest that a combination of a caspase inhibitor, which blocks death, and a neurotrophic factor, which promotes the specific function of the rescued neurons, may be a promising strategy for the treatment of PD.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Expression of matrix metalloproteinase-2 and -9 and their inhibitors in peripheral blood cells of patients with chronic hepatitis C.
BACKGROUND: To clarify whether circulating matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) can be used as serum markers of fibroproliferation in chronic liver diseases, we studied the expression of MMP-2 and MMP-9 in relation to TIMP-1 and TIMP-2 in peripheral blood mononuclear leukocytes (MNLs) and polymorphonuclear leukocytes (PMLs), and compared this expression to circulating concentrations and hepatic histology in patients with chronic active hepatitis C (CAH). METHODS: Quantitative reverse transcription-PCR/ELISA assays were performed for MMP and TIMP RNA, and corresponding circulating protein concentrations were studied by ELISA in 20 healthy controls, 40 patients with CAH, and 20 patients with hepatitis C-induced cirrhosis (Ci). RESULTS: MMP-2 mRNA was found almost exclusively in the liver, MMP-9 mRNA in leukocytes. TIMP RNA-equivalents were decreased in MNLs of CAH patients, but neither MMP-9 nor TIMP RNA expression showed any correlation to the extent of inflammation and fibrosis. MMP-2 and TIMP-1 protein concentrations were increased in Ci patients and showed a wide overlap in CAH patients and healthy controls. MMP-9 values were lower in CAH and Ci patients than in healthy controls. TIMP-2 values showed a wide overlap in all three groups. The MMP-2/TIMP-1 and MMP-9/TIMP-1 ratios were lower in Ci patients than in healthy controls; the MMP-2/TIMP-2 and MMP-9/TIMP-2 ratios were not different. Circulating TIMP-1 and the MMP-2/TIMP-1 ratio correlated to the inflammatory activity in liver biopsies, but only the circulating MMP-2/TIMP-1 ratio also correlated with the degree of fibrosis. CONCLUSIONS: Peripheral blood cell expression of MMP-2, MMP-9, and TIMP revealed no correlation with the circulating concentrations of these proteins. Only the circulating MMP-2/TIMP-1 ratio correlated to the histological degree of fibrosis in hepatitis C and should be further evaluated as a progression marker in patients with chronic liver disease.
Hepatitis C, Chronic↗
Implicit and explicit memory in children with traumatic brain injury.
This study aimed to investigate whether implicit memory is preserved in children with traumatic brain injury (TBI). A fragmented picture-completion procedure (Snodgrass, Smith, Feenan, & Corwin, 1987) was used to compare implicit and explicit memory of 12 children with severe long-term TBI and 12 controls, matched for age and gender. On the implicit memory task, both the TBI and control groups were found to show significant priming. In addition, the extent of priming for the two groups was not found to be different. On the explicit memory task, however, the TBI group was found to perform significantly more poorly than the control group. These results are consistent with those reported in the adult TBI literature and have implications for understanding and rehabilitating memory impairments in children with TBI.
Adolescent↗
Participation in breast cancer screening: randomised controlled trials of doctors' letters and of telephone reminders.
The study used a randomised controlled trial to find out whether supporting letters from general practitioners accompanying the invitations from a screening centre affected participation in a population-based breast cancer screening program for women aged 50 to 64. A further randomised controlled trial compared the effect of postal reminders with telephone reminders for women who did not respond to an initial invitation to participate in the program. There were 482 women in the first trial and 641 in the second. Excluding women who were ineligible or could not be contacted, participation in screening was 71 per cent in the group which received letters from their general practitioners compared with 62 per cent in the group which did not receive letters (P = 0.059). In the group that received letters, 56 per cent were screened without a reminder compared with 43 per cent of the group that did not receive letters (P = 0.01). Fewer women who received letters from their general practitioners declined the invitation to be screened (P = 0.048). In the second trial, there was no difference in participation between the group receiving telephone reminders and the group receiving postal reminders. As in breast cancer screening programs in other countries, general practitioner endorsement of invitations increased participation in breast cancer screening. Postal reminders were as effective as telephone reminders in encouraging women who did not respond to an initial invitation to participate in screening.
Breast Neoplasms↗
Regulation of maternal messenger RNA translation during oogenesis and embryogenesis in Urechis caupo.
We have tested the hypothesis that the selective translation of mRNAs in oocytes and embryos is controlled by when during oogenesis individual maternal mRNAs are synthesized. In an earlier paper we described the isolation of cDNA probes to 21 maternal mRNAs which accumulate with different patterns during oogenesis in Urechis caupo (E. T. Rosenthal and F. H. Wilt, 1986, Dev. Biol. 117, 55-62). Many of these probes have now been used to analyze the translation of the maternal mRNAs in growing oocytes, full-grown oocytes, and embryos. The translation of all of the mRNAs studied changes dramatically when full-grown Urechis oocytes are fertilized. Our data do not support the idea that the translation of the different maternal mRNAs depends on when they were synthesized during oogenesis. This strongly suggests that, at some level, the ability of the cell's translational machinery to distinguish between different maternal mRNAs must reside directly, or indirectly, in the mRNA sequences. We have also found that in Urechis, as in Xenopus, the selective translation of maternal mRNAs is correlated with their selective adenylation. Consequently, we have sequenced the 3' ends of 16 translationally controlled maternal mRNAs in an effort to detect consensus sequences that might regulate adenylation. No such consensus sequences have been found, suggesting that the mRNA characteristics involved in the regulation of polyadenylation may reside in a wide variety of sequences or in more subtle features, such as secondary structure.
Animals↗
Efficacy of long-term antihypertensive therapy with enalapril.
We examined whether long-term antihypertensive monotherapy with enalapril decreased clinical casual blood pressure (BP) as well as BP at work and during stress, and whether this angiotensin-converting enzyme (ACE) inhibitor had an adverse effect on the physiologic hemodynamic pattern during experimental mental stress. Seventeen male patients with hitherto untreated mild-to-moderate essential hypertension (mean age: 47 +/- 8 years) had 24-hour BP monitored noninvasively with the Physioport system before and during treatment with enalapril (5-10 mg/day) for 6 months. They also had a mental stress test, physical exercise test, and the cold pressor test before and after therapy. After the diagnostic observation period, average clinical casual BP was 150 +/- 12/102 +/- 7 mg Hg. Average BP at work, stress BP during all types of stimulation in the laboratory, and clinical casual BP significantly decreased during monotherapy with enalapril. Neither the circadian rhythm nor the hemodynamic pattern during mental stress was significantly altered by enalapril. BP increases during emotional stress were not significantly attenuated by the ACE inhibitor. These results demonstrated that enalapril effectively lowers BP without altering the physiologic hemodynamic pattern during emotional stress.
Adult↗
Comparison of non-invasive respiratory and arterial blood gas analysis. A recovery room study on acute respiratory depression.
The effect on invasive and non-invasive oxygen, carbon dioxide and haemoglobin saturation measures of two repeated doses of alfentanil 0.5 microgram/kg were tested in 16 patients scheduled for elective cataract surgery under periocular anaesthesia. Alfentanil caused an acute respiratory depression, which was demonstrated as increased levels of arterial and end-tidal carbon dioxide and concomitant decrease in arterial and end-tidal oxygen levels as well as decreased arterial blood saturation and pulse oximeter readings. There was a good correlation between the non-invasive respiratory parameters and blood gas levels, as well as between pulse oximetry numbers and oxygen saturation of arterial blood. Therefore, hypoventilation and concurrent hypoxaemia can be predicted by monitoring end-tidal CO2.
Aged↗
[With one another - for one another].
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Adult↗
Urea as a selective inhibitor of human tissue alkaline phosphatases.
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Alkaline Phosphatase↗
Tissue inhibitors of metalloproteinases in liver and serum/plasma in chronic active hepatitis C and HCV-induced cirrhosis.
BACKGROUND/AIMS: The development of liver cirrhosis can be described as a process of tissue remodeling, which involves increased matrix turnover. In order to determine whether the expression of tissue inhibitors of metalloproteinases (TIMPs) reflects these changes and can be used as a marker for the activity of ongoing fibrosis, we studied TIMP-1, 2 and -3 in liver and serum/plasma of patients with chronic hepatitis C, hepatitis C virus-induced cirrhosis and healthy controls. METHODOLOGY: Northern and Western blot analysis, reverse transcriptase polymerase chain reaction and ELISA measurements were performed. RESULTS: Reverse transcriptase polymerase chain reaction showed transcripts of all 3 TIMPs in liver tissue. TIMP-1 and -2 were also detectable in lymphocytes and granulocytes, which did not contain any TIMP-3. mRNA for TIMP-1 and -3, but not for TIMP-2, was detectable by Northern blot in normal human liver and increased in fibrosis and cirrhosis. Western blotting demonstrated the presence of all 3 TIMP proteins in healthy liver. TIMP-1 and TIMP-2 levels increased, but TIMP-3 was unchanged in cirrhosis compared to normal tissue. ELISA studies showed that the increase of TIMP-1 occurred only in advanced cirrhosis, while levels did not elevate in chronic hepatitis with or without fibrosis. In plasma, some of the cirrhotic patients had very high TIMP-1 values, while mean circulating TIMP-1 levels were not significantly different between controls, hepatitis C and cirrhotic patients. Serum TIMP-2 levels were higher in chronic hepatitis and cirrhosis than in controls, but did not differ between patients with or without histologic fibrosis. CONCLUSIONS: In normal human liver there is expression of all 3 TIMPs studied. The amount of hepatic TIMP-1 protein increases late in the fibrotic process, and there is a weak correlation between the activity of fibroproliferation and hepatic or circulating amounts of TIMP-1. Currently there is no evidence that measurement of TIMP-2 and TIMP-3 in liver or blood improves diagnosis of fibroproliferation in chronic hepatitis C.
Biomarkers↗