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Biomedical subjects

H Hagberg

Publications and source records attributed to H Hagberg.

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

Glial fibrillary acidic protein in the cerebrospinal fluid: a possible indicator of prognosis in full-term asphyxiated newborn infants?

Glial fibrillary acidic protein (GFAP) is the structural protein of intermediate filaments in astroglia. GFAP has extensively been used as a marker of gliosis in neuropathology. It also appears in excessive amounts in the cerebrospinal fluid in various acute brain disorders. Hypoxic-ischemic encephalopathy after perinatal asphyxia is a condition in which levels of GFAP could be expected to be elevated if brain cell damage occurs. We examined levels of GFAP by a sensitive ELISA in the cerebrospinal fluid of full-term infants between 12 and 48 h after birth. Cerebrospinal fluid-GFAP increased 5-fold in infants after perinatal asphyxia compared with a reference group (675 versus 137 ng/L, p < 0.001). The levels of GFAP also increased gradually in accordance with the severity of the neurologic symptoms ranked as degree of hypoxic-ischemic encephalopathy. We conclude that the cerebrospinal fluid levels of GFAP might be an important adjunct in the neonatal assessment of infants subject to perinatal asphyxia, and together with other neuronal or glial proteins, it might also help in defining temporal relationships in asphyxia.

Asphyxia Neonatorum↗
PubMed1995

The effect of long term caffeine treatment on hypoxic-ischemic brain damage in the neonate.

There is considerable concern over the widespread use of caffeine during and after pregnancy. We have therefore examined the effect of perinatal caffeine use on the vulnerability of the immature brain to hypoxic ischemia (HI). Rat pups were exposed to caffeine during the first 7 d after birth by addition of a low or a high dose (0.3 or 0.8 g/L) of caffeine to the drinking water of their dams. At 7 d the pups were exposed to unilateral carotid occlusion+exposure to 7.70% oxygen for 100 min. The extent of HI brain damage was evaluated 2 wk after the insult. The effects of caffeine on A1 and A2a receptors, A1 mRNA and A2a mRNA, were examined by receptor autoradiography and in situ hybridization. Caffeine, theobromine, theophylline, and paraxanthine were analyzed in plasma of separate animals. Exposure to caffeine reduced HI brain damage from 40.3 +/- 3.2% in controls to 29.8 +/- 4.0% (p < 0.05) in low dose and 33.7 +/- 3.9% (NS) in the high dose group. The A1 receptor density measured as [3H]-1,3-dipropyl-8-cyclopentyl xanthine ([3H]-DPCPX) binding was not significantly affected after low dose caffeine but increased in the brain of rat pups in the high dose group. The A2a receptor density measured as [3H]-2[p-(2-carbonylethyl)-phenethylamino]-5'-N- ethylcarboxamidoadenosine ([3H]-CGS 21680) binding and the expression of A1 mRNA and A2a mRNA were not altered by caffeine treatment. In conclusion, low dose caffeine exposure (plasma levels corresponding to umbilical cord plasma in newborns of coffee-consuming mothers) reduced HI brain damage by 30% in 7-d-old rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

N-methyl-D-aspartate-induced 45Ca2+ release from pre-labelled adult rat hippocampus in vivo.

We report the results of microdialysis experiments investigating the NMDA-induced release of intracellular Ca2+ in different brain regions. Microdialysis probes were implanted stereotaxically into the striatum, thalamus and hippocampus dentate gyrus (DG) of adult rats. Dialysates were analysed for alterations in the concentration of ionized Ca2+ in an initially calcium-free medium and for changes in 45Ca efflux from the pre-labelled endogenous Ca2+ pools. The application of 5 mM of NMDA to the dialysis medium for 20 min in the striatum, resulted in increases in Ca2+ and 45Ca concentrations by 25% and 35% respectively. After NMDA perfusion in the hippocampus DG and in the thalamus, decreases in the Ca2+ concentration to 65.6% and 38.6% of the basal level respectively, were accompanied by increases in 45Ca efflux, exceeding 1,500% of the basal level in the hippocampus. Cell swelling, and the corresponding reduction of the extracellular space volume was insufficient to explain the huge increase in 45Ca efflux. Thus, our experiments demonstrated that in vivo in the rat hippocampus DG, NMDA induces the release of 45Ca to the extracellular space from unidentified intracellular calcium stores.

Animals↗
PubMed1994

Hypoxic-ischemic injury in the neonatal rat brain: effects of pre- and post-treatment with the glutamate release inhibitor BW1003C87.

In a model of perinatal hypoxia-ischemia (HI) we examined the neuroprotective efficacy of pre- and post-treatment with the glutamate release inhibitor BW1003C87 [5-(2,3,5-trichlorophenyl)-2,4-diamino-pyrimidine). Ipsilateral brain damage developed in 99% of rat pups subjected to HI (unilateral common carotid artery ligation and 100 min of 7.7% oxygen exposure) with a 26 +/- 16% (mean +/- S.D.) weight deficit of the damaged hemisphere 2 weeks after the insult. Pre-treatment with BW1003C87 (10 mg/kg intraperitoneally) reduced the brain damage by 46% (P < 0.05). A higher dose (20 mg/kg) of pre-treatment was not tolerated. Administration of BW1003C87 did not affect the rectal temperature of the rats. Post-treatment with BW1003C87 (10-30 mg/kg) offered no neuroprotection in this model. In conclusion, there was a neuroprotective effect from pre- but not post-treatment with BW1003C87 in this model, supporting the concept that intra-ischemic excitatory amino acid release is important for development of brain damage. The lack of post-treatment effect indicates that BW1003C87 did not attenuate deleterious EAA cycling during reflow in the neonatal brain.

Animals↗
PubMed1994

Changes in c-fos mRNA in the neonatal rat brain following hypoxic ischemia.

We used quantitative in situ hybridization to study changes in the expression of c-fos following hypoxic-ischemia (H-I) in the neonatal rat brain. 7-day-old rat pups were subjected to a unilateral ligation of the common carotid artery followed by a 2 h 15 min hypoxic period (7.7% O2 in N2). This resulted in the expected ipsilateral infarction of cortex, lateral hippocampus, lateral-superior aspects of the striatum and the white matter of the corpus callosum. Brain damage was not seen in the contralateral hemisphere subjected only to hypoxia. c-fos mRNA levels increased in the contralateral hemisphere immediately after the hypoxia and had returned towards normal levels 2 h thereafter. In the ipsilateral hemisphere, the expression of c-fos was delayed but very marked at 2 h. Animals subjected only to hypoxia showed little or no increase in c-fos mRNA. Thus the earliest recorded increase in c-fos after hypoxic ischemia, which occurred on the non-ischemic, contralateral side, may represent a generalized response to a more localized insult.

Animals↗
PubMed1994

Detection of tumor-specific cytotoxic drug activity in vitro using the fluorometric microculture cytotoxicity assay and primary cultures of tumor cells from patients.

The semi-automated fluorometric microculture cytotoxicity assay (FMCA), based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA) by viable cells, was employed for cytotoxic drug sensitivity testing of tumor cells from patients with hematological or solid tumors. In total, 390 samples from 20 diagnoses were tested with up to 12 standard cytotoxic drugs. The technical success rate for different tumor types ranged from 67 to 95%. Fluorescence was linearly related to cell number but variably steep depending on tumor type. Samples from most solid tumors thus showed higher signal-to-noise ratios than hematological samples. A wide spectrum of in vitro drug activity was obtained, with acute leukemias and non-Hodgkin's lymphomas being sensitive to almost all tested drugs, whereas renal and adrenocortical carcinomas were essentially totally resistant. Between these extremes were samples of breast and ovarian carcinomas and sarcomas. When in vitro response was compared with known clinical response patterns, a good correspondence was observed. The results indicate that the FMCA is a rapid and efficient method for in vitro measurement of tumor-specific drug activity both in hematological and in solid tumors. The assay may be suitable for new drug development and direction of phase-2 trials to suitable patients.

Antineoplastic Agents↗
PubMed1994

Changes in extracellular calcium concentration in the immature rat cerebral cortex during anoxia are not influenced by MK-801.

The extracellular calcium concentration ([Ca2+]ec) was recorded by calcium-sensitive microelectrodes in the parietal cortex of 9-11 day old rats during anoxia. During the first 10 min of anoxia, [Ca2+]ec increased from 1.1 mM to 1.5 +/- 0.23 mM, and thereafter it started to decrease reaching below basal level after around 13 min. The [Ca2+]ec decrease was either slow and continuous, or biphased with a rapid initial decrease followed by a continuous slow decrease. After 60 min of anoxia, the [Ca2+]ec had reached 0.2-0.3 mM. Changes in [Ca2+]ec in animals treated with the NMDA receptor antagonist MK-801 (0.3 mg/kg i.p.) did not display any significant differences compared to controls. Thus, the strong neuroprotective effect of MK-801 in ischemic situations in the immature brain can not be explained by a prevention of calcium entry during anoxic depolarization.

Animals↗
PubMed1994

Neuropathological endpoints in experimental stroke pharmacotherapy: the importance of both early and late evaluation.

This study addresses the issue of endpoint selection in the evaluation of neuroprotective drugs in experimental focal ischaemia. Previous work with the permanent middle cerebral artery (MCA) occlusion model in the rat has demonstrated that the ischaemic lesion does not acquire its final appearance until at least 28 days after the ictus. Therefore, the effect of the NMDA receptor blocker MK-801 (dizocilpine maleate) was evaluated both early (3 days) and late (28 days) after MCA occlusion to determine if the previously reported protective effect of a single post-ischaemic dose of MK-801 found in acute experiments remained after 28 days. Mk-801 (0.5 mg/kg, i.v.) or isotonic saline was randomly given to rats 30 min after MCA occlusion. Infarct volume and volume of ipsilateral and contralateral hemispheres were estimated from camera lucida drawings of 8 defined coronal histological sections of the brain. As expected, a 40% (p < 0.05) reduction of infarct size was found in MK-801 treated rats after 3 days. In animals evaluated 28 days after MCA occlusion, no significant difference in infarct size, total tissue loss (infarct volume+ipsilateral hemisphere atrophy) or remaining non-infarcted tissue (contralateral hemisphere--total tissue loss) was seen between the MK-801 and placebo treated rats. The results suggest that the single dose treatment with MK-801 postponed the evolution of the infarct, which at 3 days after MCA occlusion is still in progress, possibly by ameliorating oedema formation. It remains to be shown if a multiple dose treatment with NMDA receptor antagonists improves the final neuropathological outcome after experimental stroke.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Changes in adenosine receptors in the neonatal rat brain following hypoxic ischemia.

We used quantitative in situ hybridization and receptor autoradiography to study changes in adenosine receptors following hypoxia-ischemia (H-I) in the neonatal rat brain. Seven-day-old rat pups were subjected to a unilateral ligation of the common carotid artery followed by a 2 h 15 min hypoxic period (7.7% O2 in N2). Adenosine A1 receptor mRNA in cortex and several parts of hippocampus, and A2a mRNA was decreased in the ligated hemisphere 0 h, 1 h and 2 h following hypoxia. The binding of the A1 receptor selective antagonist [3H]8-cyclopentyl-1,3-dipropylxanthine (DPCPX) in the presence or in the absence of GTP decreased immediately after the hypoxic period in both hemispheres and returned thereafter gradually towards control. These results show that there are rapid changes in A1 receptor number on both sides of the brain, and of adenosine A1 and A2a receptor mRNA in the hemisphere that would later develop infarction. Decreases in adenosine receptors may worsen H-I brain damage and have consequences for the use of adenosine directed therapy.

Animals↗
PubMed1994

Increased intra- and extracellular concentrations of gamma-glutamylglutamate and related dipeptides in the ischemic rat striatum: involvement of glutamyl transpeptidase.

The present work relates to the possibility that the ATP-independent enzyme gamma-glutamyl transpeptidase (EC 2.3.2.2), which has been postulated to be part of an amino acid uptake system, is active during cerebral ischemia. This was evaluated in the ischemic rat striatum by determination of intra- and extracellular concentrations of gamma-glutamyl dipeptides (the products of the transpeptidation) and glutathione (the physiological gamma-glutamyl donor). An ischemic period (0-30 and 31-60 min) resulted in prominent increases in the respective concentration of extracellular gamma-glutamylglutamate (24- and 67-fold), gamma-glutamyltaurine + gamma-glutamylglycine (5.8- and 19-fold), and gamma-glutamylglutamine (2.6- and 6.8-fold) as revealed using in vivo microdialysis. The changes coincided with increased respective extracellular concentrations of glutamate (83- and 115-fold), taurine (17- and 25-fold), glycine (4.6- and 6.1-fold), and glutamine (1.7- and 2.1-fold). Furthermore, under anoxic conditions in vitro (0-30 and 0-60 min), respective striatal tissue concentrations were increased for gamma-glutamylglutamate (20- and 17-fold), gamma-glutamyltaurine (6.7- and 11-fold), gamma-glutamylglutamine (1.7- and 1.2-fold), and gamma-glutamylglycine (14- and 18-fold), whereas glutathione levels were, on an average, decreased by approximately 350 microM. In summary, gamma-glutamyl transpeptidase is involved in de novo dipeptide synthesis in the mammalian brain during anoxic conditions, indicating transport of amino acids such as glutamate.

Amino Acids↗
PubMed1994

In vitro drug sensitivity testing of tumor cells from patients with non-Hodgkin's lymphoma using the fluorometric microculture cytotoxicity assay.

BACKGROUND: Tumor cell drug sensitivity is an important determinant of chemotherapy response. Its measurement in vitro would aid in therapy individualization and new drug development. MATERIALS AND METHODS: The fluorometric microculture cytotoxicity assay (FMCA), based on production by viable cells of fluorescent fluorescein after 3 days of culture, was used for cytotoxic drug sensitivity testing of 73 samples of tumor cells from patients with non-Hodgkin's lymphoma (NHL). RESULTS: The technical success rate was 92%, and FMCA data showed good correlation to the Disc assay. NHL samples were considerably more drug sensitive than were samples from in vivo resistant tumors. There was no obvious difference in drug sensitivity for high- vs. low-grade or untreated vs. previously treated low-grade NHL. For 26 patients, clinical outcome was correlated to in vitro response giving a sensitivity and specificity of 93 and 48%, respectively. Cross-resistance between standard drugs was frequent in vitro. Resistance modulators potentiated the effect of vincristine and doxorubicin in 10-29% of the samples, most frequently from previously treated patients. CONCLUSIONS: The FMCA seems to report clinically relevant drug sensitivity data for NHL, and thus it could serve as a tool for optimization of chemotherapy in the future.

Cell Survival↗
PubMed1994

Multiclonality and altered RFLP patterns for immunoglobulin heavy-chain and T-cell receptor genes in relapsing lymphomas.

BACKGROUND: Alteration of morphological appearance as well as of clinical behaviour is common in relapsing non-Hodgkin's lymphomas. The aim of this study was to investigate the stability of the genes encoding the immunoglobulin heavy-chain and the T-cell receptor during the course of the disease in relapsing non-Hodgkin's lymphomas. MATERIAL AND METHODS: Nineteen patients with relapsed or progressive non-Hodgkin's lymphomas were analysed with respect to alterations of the restriction fragment length polymorphism (RFLP) pattern for Ig heavy chain (IgH) using probes for the C mu and J regions and for T-cell receptor (T-beta, T-gamma chain) genes. DNA was extracted from tumour material taken at different occasions during the course of the disease. RESULTS: All 19 cases showed clonal rearrangements of the IgH locus, and 2 cases showed simultaneous rearrangement of the genes coding for the T-cell receptors. Three or more rearranged bands, indicating more than one malignant clone, were detected in 1 case at the time of the diagnosis and in 5/19 (26%) cases in DNA from samples taken at relapse, all 6 cases showing discordant or transformed morphology. Altogether, in 11 out of 19 cases (58%), changes of the IgH rearrangement pattern could be visualized by RFLP. In all these cases except one, the new RFLP pattern included at least one rearranged band from the pattern of the first taken sample. In one case a clonal T-gamma receptor gene rearrangement was detected in a diagnostic sample but not in a sample taken at relapse. In 4 out of 6 cases with transformed lymphomas, clonal changes were observed at time of transformation. Evolution of clones with different RFLP patterns in different compartments were observed in 1 out of 6 studied cases. CONCLUSIONS: The present study illustrates that non-Hodgkin's lymphomas are unstable in their IgH genome. The observations of clonal evolution, multiclonality, and different clones in different compartments offer an explanation to the troublesome situation when treating relapsed lymphomas.

Cloning, Molecular↗
PubMed1994

Hypoxia-ischemia in the neonatal rat brain: histopathology after post-treatment with NMDA and non-NMDA receptor antagonists.

In a model of perinatal hypoxic-ischemic brain damage, we examined the neuroprotective efficacy of posttreatment with the NMDA receptor antagonist MK-801 and the AMPA receptor antagonist NBQX. Unilateral brain damage developed in 95% of rat pups subjected to hypoxia-ischemia with a 27.8 +/- 1.2% weight deficit of the damaged hemisphere. MK-801 in doses of 0.3 and 0.5 mg/kg i.p. reduced the brain damage by 61% (p < 0.001) and 43% (p < 0.001), respectively. A higher dose of MK-801 (0.75 mg/kg) did not offer neuroprotection. Treatment with NBQX (40 mg/kg) reduced the hemispheric lesion by 28% (p < 0.05). In conclusion, posttreatment with both NBQX and low doses of MK-801 reduced perinatal brain damage. The NMDA receptor antagonist offered stronger neuroprotection which is in agreement with a proposed NMDA receptor hyperactivity around postnatal day 7 in rats.

Animals↗
PubMed1994

Birth in standing position: a high frequency of third degree tears.

BACKGROUND: During the past years a major change in the use of delivery position has occurred in Sweden. Recumbent delivery positions have been replaced by a variety of positions: squatting, standing, lateral, kneeling and quadruped. The consequences of this shift in obstetrical practice for development of perineal lacerations are largely unknown. METHOD: Retrospective comparison of uncomplicated deliveries in standing (n = 650) and sitting (n = 264) position with respect to third degree lacerations. RESULTS: The standing and sitting delivery group were similar with respect to maternal, infant and delivery characteristics. The frequency of third degree tears was 2.50% in standing and 0.38% in sitting birth position (p < 0.05). In nulliparous women, third degree tears occurred in 4.2% in standing and 1.0% in sitting position. CONCLUSION: The present data implies that the risk of third degree lacerations is considerably higher (7 x) in standing than in sitting birth positions.

Delivery, Obstetric↗
PubMed1994

Diagnostics of malignant lymphomas with ultrasound guided 1.2 mm biopsy-gun.

In a retrospective analysis of 129 ultrasound-guided biopsy-gun biopsies (USGB) from patients with known or suspected malignant lymphoma, a histopathological diagnosis was obtained in 101 (78%) instances and no further procedures for histological verification were required. In the 28 cases with initially non-diagnostic results, 14 new USGBs were performed and a diagnosis was obtained in 11. Thus, a total success rate of 87% was achieved. The correct diagnosis was confirmed with either surgery, autopsy, or radiological or clinical follow-up (median 40 months). The diagnoses were categorised as Hodgkin's disease and high-grade or low-grade non-Hodgkin's lymphoma. Further subtyping of the lymphoma was possible in a few cases only. Immunohistochemistry was utilised only in a minor proportion of the cases (25/129), but refined the diagnosis in several instances. The biopsy-gun method was safe and minor adverse effects were seen in two patients only.

Adolescent↗
PubMed1994

Chlorambucil/prednisone vs. CHOP in symptomatic low-grade non-Hodgkin's lymphomas: a randomized trial from the Lymphoma Group of Central Sweden.

Two hundred fifty-nine previously untreated patients with low-grade non-Hodgkin's lymphomas (NHLs), Ann Arbor stages III and IV, entered a randomized multicenter trial comparing the therapeutic effect of chlorambucil/prednisone (ChP) vs. CHOP. All patients had symptomatic disease. The therapeutic aim was to achieve an asymptomatic state in the ChP group (n = 132), while in CHOP-treated patients (n = 127) the intention was to reach a complete remission (CR). The response rate (CR+PR at 8 months) was 36% in the ChP and 60% in the CHOP group (p < 0.01). Three and 5-year survival rates were 59% and 41% in the ChP group and 64% and 44% in the CHOP group. The corresponding median survival times were 46 and 52 months. After correction for intercurrent deaths, the overall 5-year survival was 49% for ChP and 54% for CHOP-treated patients. The differences were statistically not significant. The time from diagnosis to randomization (time with asymptomatic disease) was longer than one year in half of the patients. The median survival time from diagnosis was 68 months, with no differences between the treatment groups. In all histological subgroups (CLL, IC, CC, and CB-CC), a higher remission rate was seen with the CHOP regimen but with no statistically significant influence on survival. Comparing patients below and above 65 years of age, no significant difference in survival was noted between the two treatment groups. The results do not support the use of intensive chemotherapy as first-line therapy in symptomatic low-grade NHL.

Actuarial Analysis↗