Biomedical subjects

H Hagberg

Publications and source records attributed to H Hagberg.

At least 37 records · Page 2Linked to original sources

PubMed2001

Levels of dimethylarginines and cytokines in mild and severe preeclampsia.

BACKGROUND: The objectives were 1. to evaluate if the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine was altered in mild and severe forms of preeclampsia, and 2. to assess the relationship between dimethylarginines and the cytokine response in preeclampsia. METHODS: Asymmetric and symmetric dimethylarginine were measured with high performance liquid chromatography in women with mild (n=13) and severe (n=32) preeclampsia and in normotensive pregnant controls (n=20). Interleukin-4, -6, -8, -10 and tumor necrosis factor-alpha were analyzed by immunoassays in women with mild (n=8) and severe (n=17) preeclampsia and in normotensive pregnant controls (n=14). The Mann Whitney U-test and Spearman Rank test were used for statistical analysis. RESULTS: The plasma levels of dimethylarginine were increased in preeclamptic subjects. The elevation of symmetric dimethylarginine was more pronounced than that of asymmetric dimethylarginine. The control levels of interleukin-6, -8 and -10 were significantly higher at term than at gestational week 32-36. Interleukin-6 and -8 were significantly elevated in subjects with severe, but not mild, preeclampsia, whereas TNF-alpha and IL-10 were not significantly altered. Symmetric dimethylarginine levels correlated significantly with arterial blood pressure and serum levels of creatinine and uric acid. Dimethylarginine levels in plasma were, however, not related to the cytokine response. CONCLUSIONS: Plasma concentrations of both asymmetric and symmetric dimethylarginine were significantly elevated both in mild and severe preeclampsia. Symmetric, but not asymmetric, dimethylarginine correlated to the severity of the condition. Plasma levels of interleukin-6 and -8 were also elevated in severe preeclampsia but no direct correlations were found between these cytokines and dimethylarginines.

Arginine↗

PubMed2000

Subcellular distribution of calcium and ultrastructural changes after cerebral hypoxia-ischemia in immature rats.

Recent data imply that mitochondrial regulation of calcium is critical in the process leading to hypoxic-ischemic brain injury. The aim was to study the subcellular distribution of calcium in correlation with ultrastructural changes after hypoxia-ischemia in neonatal rats. Seven-day-old rats were subjected to permanent unilateral carotid artery ligation and exposure to hypoxia (7.7% oxygen in nitrogen) for 90 min. Animals were perfusion-fixed after 30 min, 3 h or 24 h of reperfusion. Sections were sampled for light microscopy and electron microscopy combined with the oxalate-pyroantimonate technique. At 30 min and 3 h of reflow, a progressive accumulation of calcium was detected in the endoplasmic reticulum, cytoplasm, nucleus and, most markedly, in the mitochondrial matrix of neurons in the gray matter in the core area of injury. Some mitochondria developed a considerable degree of swelling reaching a diameter of several microm at 3 h of reflow whereas the majority of mitochondria appeared moderately affected. Chromatin condensation was observed in nuclei of many cells with severely swollen mitochondria with calcium deposits. A whole spectrum of morphological features ranging from necrosis to apoptosis was seen in degenerating cells. After 24 h, there was extensive injury in the cerebral cortex as judged by breaks of mitochondrial and plasma membranes, and a general decrease of cellular electron density. In the white matter of the core area of injury, the axonal elements exhibited varicosity-like swellings filled with calcium-pyroantimonate deposits. Furthermore, the thin myelin sheaths were loaded with calcium. Numerous oligodendroglia-like cells displayed apoptotic morphology with shrunken cytoplasm and chromatin condensation, whereas astroglial necrosis was not seen. In conclusion, markedly swollen 'giant' mitochondria with large amounts of calcium were found at 3 h of reperfusion often in neuronal cells with condensation of the nuclear chromatin. The results are discussed in relation to mitochondrial permeability transition and activation of apoptotic processes.

Animals↗

PubMed2000

Impairment of mitochondrial respiration after cerebral hypoxia-ischemia in immature rats: relationship to activation of caspase-3 and neuronal injury.

Mitochondrial damage may play a key role in the development of necrotic and apoptotic hypoxic-ischemic (HI) brain damage. It has previously been shown that mitochondrial respiration is depressed in the cerebral cortex after HI in neonatal animals. The aim of the present study was to further characterize the time course of the mitochondrial impairment during reperfusion and the correlation between the respiratory control ratio and brain injury and activation of caspase-3. Rat pups were subjected to unilateral carotid artery ligation and exposed to hypoxia (7.7% oxygen). Mitochondrial respiration was measured 0-72 h after HI in a mitochondrial fraction isolated from cerebral cortex. Microtubule associated protein-2 (MAP2) and caspase-3 were analyzed with immunoblotting in cerebral cortex homogenates. In addition, the time course of caspase-3 activation was measured as DEVD cleavage. The mitochondrial respiratory control ratio in cerebral cortex decreased immediately after HI followed by a partial recovery at 3-8 h. Thereafter, a secondary drop occurred with a minimum reached at 24 h of reperfusion. The secondary loss of respiratory function was accompanied by depletion of MAP2, cleavage of caspase-3 and an increased caspase-3 -like activity at 3-24 h after the insult. In conclusion, the primary phase of mitochondrial dysfunction was paralleled by a moderate decrease of MAP2 and a limited activation of caspase-3. The secondary mitochondrial impairment was associated with neuronal injury and pronounced activation of caspase-3.

Animals↗

PubMed2000

Alterations in glutathione and amino acid concentrations after hypoxia-ischemia in the immature rat brain.

Hypoxic-ischemic brain injury involves an increased formation of reactive oxygen species. Key factors in the cellular protection against such agents are the GSH-associated reactions. In the present study we examined alterations in total glutathione and GSSG concentrations in mitochondria-enriched fractions and tissue homogenates from the cerebral cortex of 7-day-old rats at 0, 1, 3, 8, 14, 24 and 72 h after hypoxia-ischemia. The concentration of total glutathione was transiently decreased immediately after hypoxia-ischemia in the mitochondrial fraction, but not in the tissue, recovered, and then decreased both in mitochondrial fraction and homogenate after 14 h, reaching a minimum at 24 h after hypoxia-ischemia. The level of GSSG was approximately 4% of total glutathione and increased selectively in the mitochondrial fraction immediately after hypoxia-ischemia. The decrease in glutathione may be important in the development of cell death via impaired free radical inactivation and/or redox related changes. The effects of hypoxia-ischemia on the concentrations of selected amino acids varied. The levels of phosphoethanolamine, an amine previously reported to be released in ischemia, mirrored the changes in glutathione. GABA concentrations initially increased (0-3 h) followed by a decrease at 72 h. Glutamine levels increased, whereas glutamate and aspartate were unchanged up to 24 h after the insult. The results on total glutathione and GSSG are discussed in relation to changes in mitochondrial respiration and microtubule associated protein-2 (MAP2) which are reported on in accompanying paper [64].

Age Factors↗

PubMed2000

Synergistic activation of caspase-3 by m-calpain after neonatal hypoxia-ischemia: a mechanism of "pathological apoptosis"?

The relative contributions of apoptosis and necrosis in brain injury have been a matter of much debate. Caspase-3 has been identified as a key protease in the execution of apoptosis, whereas calpains have mainly been implicated in excitotoxic neuronal injury. In a model of unilateral hypoxia-ischemia in 7-day-old rats, caspase-3-like activity increased 16-fold 24 h postinsult, coinciding with cleavage of the caspase-3 proenzyme and endogenous caspase-3 substrates. This activation was significantly decreased by pharmacological calpain inhibition, using CX295, a calpain inhibitor that did not inhibit purified caspase-3 in vitro. Activation of caspase-3 by m-calpain, but not mu-calpain, was facilitated in a dose-dependent manner in vitro by incubating cytosolic fractions, containing caspase-3 proform, with calpains. This facilitation required the presence of some active caspase-3 and could be abolished by including the specific calpain inhibitor calpastatin. This indicates that initial cleavage of caspase-3 by m-calpain, producing a 29-kDa fragment, facilitates the subsequent cleavage into active forms. This is the first report to our knowledge suggesting a direct link between the early, excitotoxic, calcium-mediated activation of calpain after cerebral hypoxia-ischemia and the subsequent activation of caspase-3, thus representing a tentative pathway of "pathological apoptosis."

Animals↗

PubMed2000

NMDA blockade attenuates caspase-3 activation and DNA fragmentation after neonatal hypoxia-ischemia.

The aim was to study the effects of an NMDA receptor antagonist on caspase-3 activation and DNA fragmentation after hypoxia-ischemia (HI) in 7-day-old rats. Animals were treated with vehicle or MK-801 (0.5 mg/kg) directly after HI and sacrificed 8, 24 or 72h later. MK-801 reduced injury (by 53%), cells positive for active caspase-3 (by 39%) and DNA fragmentation (by 79%) in the cerebral cortex. Furthermore, MK-801 significantly decreased caspase-3 activity, and Western blots revealed a tendency towards decreased proteolytic cleavage of the caspase-3 proform. The data imply that NMDA receptors are involved in the activation of apoptotic processes in the immature brain after HI.

Animals↗

PubMed2000

[Spontaneous premature birth: physiopathology, predictors and management. The frequency is constant--early detection can improve therapeutic possibilities].

Premature birth is associated with increased perinatal morbidity and mortality. Spontaneous premature birth can be understood as a syndrome with a number of underlying causes including infection, maternal stress, uterine distention, placental hypoxia, bleeding and lack of prostaglandin dehydrogenase. Infection is probably the most important factor at low gestational age, with uterine distention and maternal stress increasing in significance further on. In the future we may become better able than we are at determining the specific reason in each individual case, which may lead to the development of more effective treatment. On the other hand, results have been very poor with respect to prevention, and in some countries we even note a slight increase in incidence. Although premature birth is often impossible to prevent, early detection and tocolytic therapy can delay labor long enough to permit effective corticosteroid therapy and transport when required to the appropriate obstetric clinic for optimal neonatal care.

Biomarkers↗

PubMed2000

Risk factors for side effects during first infusion of rituximab-definition of a low risk group.

Side effects from the first infusion of the monoclonal anti-CD20 antibody, rituximab, 375 mg/m2 was documented in 47 treatments (37 patients) and correlated to tumour mass and interval to previous cytostatic treatment. A significant correlation was found with less side effects in patients with a low tumour mass and/or if chemotherapy was recently administered. It is difficult to differ between these two parameters as they covariate, i.e. the majority of patients without or with a minimal tumour burden were recently treated with cytostatics. The reason why these patients have no or minimal side effects may be due to low numbers of CD20 positive cells in the circulation. The finding of a low-risk group for side effects from the first infusion of rituximab; has practical clinical implications, for example, hospitalization can be avoided. Concerning side effects, it may be an advantage to give rituximab after the introduction of successful chemotherapy.

Adult↗

PubMed2000

A more favourable clinical course of lymphoma relapsing after high-dose therapy: evidence of tumour heterogeneity?

Patients with Hodgkin's disease (HD) or large cell lymphomas who relapse after conventional chemotherapy have a poor prognosis without high-dose chemotherapy and stem cell transplantation (HDCT). Patients who relapse after HDCT have an extremely poor outcome. In the present study we describe four patients with relapsed HD (n=1) and large cell lymphomas (n=3) after HDCT. All had an aggressive clinical course before HDT. At relapse, however, they all have had prolonged remissions and/or spontaneous regressions on mild or no treatment. Possible explanations could be selection of less malignant clones or a lymphoma controlled by the immune system. The mechanisms are, however, unknown but warrant further studies of the molecular biology in these and similar cases.

Adult↗

PubMed2000

Long-term follow-up of autologous stem-cell transplantation for follicular and transformed follicular lymphoma.

Despite the fact that follicular lymphomas are both chemo- and radiosensitive, the disease is generally non-curable. These lymphomas often undergo transformation to a more malignant state. In order to improve the prognosis, high-dose treatment with stem cell support has been tested, but its role in the treatment of this disease is still unclear. Fourteen men and eight women with a median age of 45 yr (34-59) were treated with high-dose therapy with autologous stem cell transplantation between 1987 and 1996. The patients were selected to undergo intensive therapy because of an estimated short survival (median < 3 yr), even though they had chemosensitive disease and adequate performance status. Eleven patients' lymphomas had transformed, and the other eleven patients had one or more unfavourable prognostic signs such as advanced stage, bulky disease, multiple relapses, or short remission duration. The conditioning regimen has varied over the period, but BEAC (Becenum, etoposide, cytarabine, cyclophosphamide) or etoposide/cyclophosphamide with or without total body irradiation (TBI) was used in most patients. Nine patients had their stem cells purged. After a median follow-up time of 74 months overall survival was 81% and disease-free survival 72%. One toxic procedure-related death occured. There was no difference in outcome between patients with a transformed lymphoma compared to those without transformation. The patients treated with TBI had a significantly worse outcome. Toxicity was also much higher in TBI-treated patients, including four cases of secondary malignancy (three myelodysplastic syndrome (MDS) cases and one patient with breast carcinoma). This retrospective study, with the longest follow-up time so far reported, shows a promising 6-yr DFS of 72% in a group of follicular lymphoma patients with a bad prognosis. The outcome of patients with transformed lymphoma compared to historical controls is especially encouraging. The high incidence of MDS is worrying. The role of TBI should be questioned because this and other studies have not shown any advantage of using TBI. In the absence of randomised trials the role of high-dose treatment for patients with follicular lymphoma is still not defined.

Adult↗

PubMed2000

Correlation between caspase-3 activation and three different markers of DNA damage in neonatal cerebral hypoxia-ischemia.

Caspase-3 has been identified as a key protease that, by targeting a limited number of proteins, can disrupt essential homeostatic processes and initiate an orderly disassembly of cells, including degradation of genomic DNA. We demonstrate the usefulness of an antibody specific for activated caspase-3 in a model of neonatal rat hypoxia-ischemia (Hl) and correlate the spatial and temporal activation of caspase-3 with three different markers of DNA damage and with the loss of a neuronal marker [microtubule-associated protein 2 (MAP 2)]. An oligonucleotide hairpin probe (HPP) with one base overhang in the 3' end displayed a close colocalization with caspase-3 activation at 3 h post-Hl, whereas terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) appeared later (24 h post-Hl). A monoclonal antibody against single-stranded DNA appeared to stain an entirely different population of cells, not positive for active caspase-3, HPP, or TUNEL at this time point. After 24 h of reperfusion, however, when cellular injury is extensive, all markers stained a large number of cells with a high degree of colocalization, and all markers delineated regions with loss of MAP 2. We conclude that the HPP shows the best correlation with pathological caspase-3 activation in this model.

Animals↗

PubMed2000

Antenatal brain injury: aetiology and possibilities of prevention.

Although the aetiology of antenatal brain injury is often unclear, procedures can be employed to prevent or reduce the risk of injury. Defective neuropore closure can be prevented by periconceptional administration of folic acid, and the incidence of other severe malformations and genetic disorders can be reduced by early identification and termination of pregnancy. Antenatal identification of IUGR, administration of corticosteroids to cases with pending preterm birth, and treatment of maternal/fetal infections would also reduce the incidence of injury. Mothers can decrease the risk of injury by maintaining a good diet, avoiding smoking, alcohol intake and exposure to TORCH infections during pregnancy.

Anti-Inflammatory Agents↗

PubMed2000

Value of transsternal core biopsy in patients with a newly diagnosed mediastinal mass.

Histopathologic analysis of an anterior mediastinal mass of unknown origin is essential for treatment decision. Mediastinoscopy is the most common procedure performed to obtain biopsies, but general anaesthesia and hospitalization are necessary. The aim of this study was to evaluate whether transsternal core biopsies, an easy outpatient biopsy technique, could be an alternative to mediastinoscopy. A biopsy instrument that makes it possible to reach tumours hidden behind bone was used for transsternal CT-guided core biopsies in 21 patients with a newly diagnosed anterior mediastinal mass. No severe side effects were observed. In 19/21 (90%) patients the biopsies were diagnostic. In 2/21 patients additional biopsy techniques had to be used. In these two patients Hodgkin's disease was suspected in the first biopsy procedures. The diagnosis was confirmed by new core biopsies, from other parts of the tumour, not using a transsternal approach (transclavicular and parasternal, respectively). In addition, one mediastinoscopy was performed in a patient who was diagnosed with a non-Hodgkin's lymphoma but where more material was needed for lymphoma subclassification. It is concluded that CT-guided transsternal core biopsy is a clinically valuable method in patients with a newly diagnosed anterior mediastinal mass.

Adolescent↗

PubMed2000

Residual mass in aggressive lymphoma--does size, measured by computed tomography, influence clinical outcome?

Residual masses are frequently found in patients with aggressive lymphomas, following therapy. A study was undertaken to determine whether initial tumour size, changes during treatment, or size of the residual mass could provide prognostic information. Computed tomography (CT) examinations were carried out before, midway and after completion of chemotherapy in 37 patients with aggressive lymphoma with residual mass after treatment. The tumours were measured for both the greatest diameter sizes and area. The size of the residual mass correlated with the tumour size at diagnosis. Neither a large tumour size before treatment nor a large residual mass after treatment correlated with an increase in rate of relapse. The initial tumour reduction (measured after completion of half of the planned chemotherapy) was less pronounced in relapsing patients compared to relapse-free patients. Using a cut-off level of 70% tumour reduction (measured after completion of half of the planned chemotherapy), 66% of patients with a tumour reduction of < 70% relapsed, compared with 22% (p < 0.05) in those with more marked tumour regression.

Adolescent↗

PubMed2000

Anal sphincter tears: prospective study of obstetric risk factors.

OBJECTIVE: To evaluate intrapartum risk factors for anal sphincter tear. DESIGN: A prospective observational study. SETTING: Delivery unit at the University Hospital in Göteborg, Sweden. PARTICIPANTS: 2883 consecutive women delivered vaginally during the period between 1995 and 1997. Information was obtained, from patient records and from especially designed protocols which were completed during and after childbirth. MAIN OUTCOME MEASURES: Anal sphincter (third and fourth degree) tear. RESULTS: Anal sphincter tear occurred in 95 of 2883 women (3.3%). Univariate analysis demonstrated that the risk of anal sphincter tear was increased by nulliparity, high infant weight, lack of manual perineal protection, deficient visualisation of perineum, severe perineal oedema, long duration of delivery and especially protracted second phase and bear down, use of oxytocin, episiotomy, vacuum extraction and epidural anaesthesia. After analysis with stepwise logistic regression, reported as odds ratio, 95% confidence interval, the following factors remained independently associated with anal sphincter tear: slight perineal oedema (0.40, 0.26-0.64); manual perineal protection (0.49, 0.28-0.86); short duration of bear down (0.47, 0.24-0.91); no visualisation of perineum (2.77, 1.36-5.63); parity (0.59, 0.40-0.89); and high infant weight (2.02, 1.30-3.16). Analysis of variance showed that manual perineal protection had a stronger influence on lowering the frequency, and lack of visualisation of perineum and infant weight had a stronger influence on raising the frequency, of anal sphincter tears in nulliparous compared with parous women. CONCLUSIONS: Perineal oedema, poor ocular surveillance of perineum, deficient perineal protection during delivery, protracted final phase of the second stage, parity and high infant weight all constitute independent risk factors for anal sphincter tear. Such information is essential in order to reduce perineal trauma during childbirth.

Adult↗

PubMed2000

Cataracts after autologous bone marrow transplantation in children.

We recorded the incidence and degree of posterior subcapsular cataract (PSC) in 29 children who had undergone autologous (n = 28) or syngeneic (n = 1) bone marrow transplantation (BMT) due to haematologic or lymphoid malignancy. Conditioning prior to transplantation consisted either of a combination of chemotherapy and total body irradiation (TBI) (n = 21) or of chemotherapy only (n = 8). TBI was given in one fraction of 7.5 Gy. Nine patients had received previous cranial irradiation. The patients were followed for 4-10y (median 8 y) after transplantation. Of 29 patients, 22 developed PSC, all within 4 y after BMT. With the exception of one patient who developed unilateral PSC, all had received TBI. Conversely, 100% of those who received TBI developed PSC. In this group (+TBI), eight patients (38%) developed significant PSC, defined as best corrected visual acuity <0.8 in either eye. Six patients (10 eyes) have since needed surgical repair consisting of extracapsular cataract extraction and intraocular lens implantation. There was no clear relationship between previous cranial irradiation and cataract development, nor any other obvious baseline differences between those in the +TBI group who developed significant PSC and those who did not. Although effects of previous therapy cannot be ruled out, TBI appears to be the main cause of PSC in this group of patients. Twelve patients in the +TBI group had well-preserved visual acuity throughout the study, reflecting a slow progression of PSC. This compares favourably with previous reports of allogeneic BMT, possibly owing to less need for corticosteroids after autologous BMT. We conclude that the incidence of PSC was high after autologous BMT where the conditioning regimen included total body irradiation.

Adolescent↗

PubMed1999

Calpastatin is up-regulated in response to hypoxia and is a suicide substrate to calpain after neonatal cerebral hypoxia-ischemia.

In a model of cerebral hypoxia-ischemia in the immature rat, widespread brain injury is produced in the ipsilateral hemisphere, whereas the contralateral hemisphere is left undamaged. Previously, we found that calpains were equally translocated to cellular membranes (a prerequisite for protease activation) in the ipsilateral and contralateral hemispheres. However, activation, as judged by degradation of fodrin, occurred only in the ipsilateral hemisphere. In this study we demonstrate that calpastatin, the specific, endogenous inhibitor protein to calpain, is up-regulated in response to hypoxia and may be responsible for the halted calpain activation in the contralateral hemisphere. Concomitantly, extensive degradation of calpastatin occurred in the ipsilateral hemisphere, as demonstrated by the appearance of a membrane-bound 50-kDa calpastatin breakdown product. The calpastatin breakdown product accumulated in the synaptosomal fraction, displaying a peak 24 h post-insult, but was not detectable in the cytosolic fraction. The degradation of calpastatin was blocked by administration of CX295, a calpain inhibitor, indicating that calpastatin acts as a suicide substrate to calpain during hypoxia-ischemia. In summary, calpastatin was up-regulated in areas that remain undamaged and degraded in areas where excessive activation of calpains and infarction occurs.

Animals↗

PubMed1999

Chimeric monoclonal anti-CD20 antibody (rituximab)--an effective treatment for a patient with relapsing hairy cell leukaemia.

A case story is presented, describing a 46 y old man, with a relapsing hairy cell leukaemia. After treatment with monoclonal anti CD-20 antibodies (rituximab) 375mg/week, four times, a complete remission was obtained which has lasted >9 months. The rituximab treatment produced a better remission than earlier treatments with alpha-interferon and chlorodeoxyadenosine. In addition, in contrast to other treatments, no initial worsening of the pancytopenia was observed.

Antibodies, Monoclonal↗